* 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.
Stage #1: With n-butyllithium In tetrahydrofuran at -65℃; for 0.5 h; Inert atmosphere Stage #2: at -65℃; for 1 h; Inert atmosphere
To a solution of 4-bromoisoquinoline 24a (2.0 g, 9.6 mmol) in 30 mL re-distilled THF was added n-butyl lithium (4.0 mL, 10 mmol, 2.5 M in THF) dropwisely at -65° C. under N2 atmosphere. The resulting mixture was stirred for 30 mm at this temperature before N,N-dimethylformamide (730 mg, 10 mmol) was added dropwise, and stirred for additional 1 h at this temperature. After the reaction was over, 100 mL saturated aq. NH4Cl was added to the reaction mixture, and the mixture was extracted with EtOAc (50 mL*3). The combined organic layers were washed with 100 mL brine, dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0-100percent EtOAc/PE) to give isoquinoline-4-carbaldehyde 31a (550 mg, yellow solid, yield: 36percent). 1H NMR (400 MHz, CDCl3): δ 10.41 (s, 1H), 9.45 (s, 1H), 9.22 (d, J=8.4 Hz, 1H), 8.96 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.96-7.92 (m, 1H), 7.76 (t, J=8.4 Hz, 1H).
Reference：
[1] Tetrahedron, 1998, vol. 54, # 35, p. 10317 - 10328
[2] European Journal of Organic Chemistry, 2009, # 26, p. 4458 - 4467
[3] Patent: US2017/37050, 2017, A1, . Location in patent: Paragraph 0346-0349
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8611 - 8615[2] Angew. Chem., 2013, vol. 125, # 33, p. 8773 - 8777,5
4
[ 1532-97-4 ]
[ 109-72-8 ]
[ 22960-16-3 ]
Reference：
[1] Patent: US4584379, 1986, A,
5
[ 1532-97-4 ]
[ 82102-37-2 ]
[ 5470-80-4 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 12, p. 6112 - 6120
6
[ 1532-97-4 ]
[ 23687-25-4 ]
Reference：
[1] Synthetic Communications, 2004, vol. 34, # 1, p. 137 - 149
[2] Journal of the American Chemical Society, 2006, vol. 128, # 31, p. 10028 - 10029
[3] Angewandte Chemie - International Edition, 2015, vol. 54, # 12, p. 3773 - 3777[4] Angew. Chem., 2015, vol. 127, # 12, p. 3844 - 3848,5
[5] Organic Letters, 2014, vol. 16, # 2, p. 556 - 559
[6] Journal of the American Chemical Society, 1942, vol. 64, p. 783
[7] Patent: US2005/20623, 2005, A1, . Location in patent: Page 104
[8] Patent: WO2013/13816, 2013, A1,
[9] Patent: US2013/29995, 2013, A1,
[10] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 4, p. 803 - 806
7
[ 1532-97-4 ]
[ 23687-25-4 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: With lithium amide In 1,2-dimethoxyethane at 80℃; for 20 h; Sealed vial Stage #2: With hydrogenchloride In 1,2-dimethoxyethane; water at 20℃; for 0.0833333 h; Stage #3: With sodium hydrogencarbonate In 1,2-dimethoxyethane; water
4-Bromo-/5O-quinoline (0.208 g, 1.00 mmol), (CyPF-J-Bu)PdCl2 (7.30 mg, 1.00 x 10"2 mmol), and LiNH2 (0.230 g, 10.0 mmol) in 20.0 mL DME gave 0.118 g (82percent) of 4-Amino-/.yoe-quinoline as a solid.
80%
Stage #1: With ammonia; sodium t-butanolate In 1,2-dimethoxyethane at 90℃; for 20 h; Stage #2: With hydrogenchloride In 1,2-dimethoxyethane; water at 20℃; for 0.0833333 h; Stage #3: With sodium hydrogencarbonate In 1,2-dimethoxyethane; water
Stage #1: With n-butyllithium In tetrahydrofuran at -65℃; for 0.5 h; Stage #2: With N-fluorobis(benzenesulfon)imide In tetrahydrofuran at -65℃; for 2 h;
To a solution of n-butyl lithium (133 mL, 332.5 mmol, 2.5 M in THF) in 760 mL THF was added a solution of 4-bromoisoquinoline 24a (20 g, 96.6 mmol) in 144 mL THF dropwise at -65° C. and the resulting mixture was stirred at this temperature for another 30 mm after the completion of addition. A solution of N-fluorobenzenesulfonimide (66.68 g, 211.7 mmol) in 216 mL THF was added at -65° C. in 1 h dropwisely. After being stirred for another 1 h at this temperature, the reaction mixture was warmed to room temperature slowly with stirring, after the reaction is over, 300 mL saturated aq. NH4Cl was added slowly, extracted with EtOAc (300 mL*3). The combined organic layers were washed with 300 mL brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (0-100percent EtOAc/PE) to give 4-fluoroisoquinoline 24b (8.5 g, red oil, yield: 60percent).
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 10, p. 3792 - 3795
[2] Patent: US2017/37050, 2017, A1, . Location in patent: Paragraph 0301; 0302
[3] Patent: US2007/179127, 2007, A1, . Location in patent: Page/Page column 47-48
[4] Patent: US2009/48223, 2009, A1, . Location in patent: Page/Page column 101
[5] Patent: US2010/93789, 2010, A1, . Location in patent: Page/Page column 46
10
[ 119-65-3 ]
[ 1532-97-4 ]
Yield
Reaction Conditions
Operation in experiment
23.8%
at 100℃;
lntermediate-12: 3-Bromoisoquinoline: To a stirred solution of isoquinoline (24 g, 186 mmol) in AcOH (50 mL) was added NBS (36.2 g, 204.6 mmol) at RT and the reaction mixture was heated to 100 2C overnight. Then it was cooled to RT and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (5percent EtOAc:Hexanes) to furnish the title compound (9.2 g, 23.8percent) as an oil.
Reference：
[1] Patent: WO2013/5168, 2013, A2, . Location in patent: Page/Page column 40
[2] Journal fuer Praktische Chemie (Leipzig), 1891, vol. <2> 43, p. 199
[3] Journal of the American Chemical Society, 1940, vol. 62, p. 3030
[4] Journal of the American Chemical Society, 1940, vol. 62, p. 3030
[5] Journal of the American Chemical Society, 1945, vol. 67, p. 1268
[6] Journal of the American Chemical Society, 1945, vol. 67, p. 1268
[7] Synthesis, 2002, # 1, p. 83 - 86
[8] Archiv der Pharmazie, 2003, vol. 336, # 4-5, p. 258 - 263
Reference：
[1] Yakugaku Zasshi, 1931, vol. 51, p. 73[2] Chem. Zentralbl., 1931, vol. 102, # II, p. 2330
[3] Yakugaku Zasshi, 1928, vol. 48, # 9, p. 109[4] Chem. Zentralbl., 1931, vol. 102, # II, p. 2330
28
[ 557-21-1 ]
[ 1532-97-4 ]
[ 34846-65-6 ]
Yield
Reaction Conditions
Operation in experiment
27.4%
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 120℃; Inert atmosphere
lntermediate-13: lsoquinolin-4-carbonitrile: To a stirred solution of 3-bromoisoquinoline (lntermediate-12) (9.2 g, 44.2 mmol) in DMF (15 mL) were added, Pd(PPh3)4 (10.2 g, 8.84 mmol) and Zn(CN)2 (10.34 g, 88.44 mmol, 2.0 eq) and the solution was degassed with N2 for 20 min. It was then heated to 120 2C overnight. After the completion (TLC), reaction mixture was cooled to RT, filtered and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (10percent EtOAc:Hexanes) to afford the desired compound (3.4 g, 27.4percent) as pale yellow solid.
Example 64: Synthesis of 4-(3-(2-fluoro-4-methoxybenzylidene)-3 ,4,5,6- 5 tetrahydropyridin-2-yl)isoquinoline dihydrochloride.; The preparation of 4-(3-(2-fluoro-4-methoxybenzylidene)-3,4,5,6- tetrahydropyridin-2-yl)isoquinoline dihydrochloride is described below.; A. Step 1: Preparation of Intermediate 9; Intermediate 9 was prepared as described in Tyson, F.T. J. Am. Chem. Soc, 1939, 61 (I )5 183 -185. Briefly, 4-Bromoisoquinoline (3.36 g, 16.2 mmol) and Cu(I)CN (2.17 g, 24.2 mmol) were combined as the dry solids in a round bottom flask fitted with a magnetic stirrer and vigeraux column under N2. Heat was applied.15 At approximately 1500C, the mixture began to stir freely. At approximately 23O0C, the reaction mixture formed a black solid that began to splatter onto the sides of the flask. The reaction was cooled to room temperature and treated with concentrated NH4OH overnight. This mixture was then extracted 3 times with EtOAc. The EtOAc extracts were washed with dilute NH4OH(Hq) and brine, then combined, dried 0 over Na2SO4, treated with decolorizing charcoal, filtered through celite, then concentrated under reduced pressure. The recovered material was dissolved into a mixture of hot isopropanol and methanol to re-crystallize. The crystals were recovered by vacuum filtration, washed with fresh isopropanol and dried under vacuum giving 1.47 g (58percent) of yellow crystals. LC-MS: RT = 7.86 min, [M+H]+ = 5 155.1.
Reference：
[1] Synthetic Communications, 2004, vol. 34, # 1, p. 137 - 149
[2] Patent: WO2007/89626, 2007, A2, . Location in patent: Page/Page column 71
[3] Archiv der Pharmazie, 1993, vol. 326, # 10, p. 785 - 790
[4] Archiv der Pharmazie, 2003, vol. 336, # 4-5, p. 258 - 263
30
[ 1532-97-4 ]
[ 34846-65-6 ]
Yield
Reaction Conditions
Operation in experiment
44.6%
at 250℃; for 0.75 h;
To 4-bromo isoquinoline (2 g, 9.613 mmol) is added copper (I) cyanide (1.29 g, 14.42 mmol), and the mixture is heated to 250° C. for 45 minutes, where the pressure is taken down to 5-10 torr. The mixture which turns black at this point begins to distil over, giving crystals in the condenser. The condenser is cleaned with dichloromethane and the volatiles in the solution are removed in vacuo to give the desired product (0.66 g, 44.6percent) as colorless crystals.
Reference：
[1] Pharmaceutical Bulletin, 1954, vol. 2, p. 72,76
[2] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 2, p. 939 - 950
[3] European Journal of Organic Chemistry, 2016, vol. 2016, # 8, p. 1606 - 1611
37
[ 1532-97-4 ]
[ 7159-36-6 ]
Reference：
[1] Journal of Organic Chemistry, 1957, vol. 22, p. 565
38
[ 1532-97-4 ]
[ 3749-21-1 ]
Yield
Reaction Conditions
Operation in experiment
94%
With 3-chloro-benzenecarboperoxoic acid In chloroform
13A. 4-Bromoisoquinoline 2-oxide A solution of 4-bromoisoquinoline (4.16 g, 18.6 mmol) in chloroform (100 mL) was added dropwise over 1 h to a solution of 70percent mCPBA (12.4 g, 50.3 mmol) in chloroform (100 mL) at rt. After stirring 18 h, the reaction mixture was washed with 1 N NaOH (2*150 mL), dried (MgSO4) and concentrated under reduced pressure to afford compound 13A (4.23 g, 94percent) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.43 (s, 1H), 8.09 (d, 1H, J=8 Hz), 7.70 (m, 3H).
94%
With 3-chloro-benzenecarboperoxoic acid In chloroform
13A. 4-Bromoisoquinoline 2-oxide A solution of 4-bromoisoquinoline (4.16 g, 18.6 mmol) in chloroform (100 mL) was added dropwise over 1 h to a solution of 70percent mCPBA (12.4 g, 50.3 mmol) in chloroform (100 mL) at rt. After stirring 18 h, the reaction mixture was washed with 1 N NaOH (2*150 mL), dried (MgSO4) and concentrated under reduced pressure to afford compound 13A (4.23 g, 94percent) as an off-white solid. 1H NMR(400 MHz, CDCl3) .box. 8.71 (s, 1H), 8.43 (s, 1H), 8.09 (d, 1H, J=8 Hz), 7.70 (m, 3H).
57.6%
With 3-chloro-benzenecarboperoxoic acid In dichloromethane for 3 h;
2d) 4-BROMO-1-CHLORO-ISOQUINOLINE To a solution of 4-bromoisoquinoline (52. 08 g, 0. 250 MOL) in methylene chloride (600 mL) is added m-chloroperbenzoic acid (64.47 g, 0.250 MOL). The mixture is stirred for 2.5 hours. To the mixture is added 1.5 g of m-chloroperbenzoic acid and the mixture is stirred for 30 minutes. The solution is washed with 1 N NAOH, brine, and then dried over sodium sulfate. The solvent is removed to give a white solid. The solid is crystallized from hot acetone to yield 32.22 g (57.6percent) of a white SOLID. 1H, 13C NMR consistent with structure. The N-oxide (15.75 g, 0.0703 mol) is dissolved in chloroform (50 mL) and cooled in an ice bath. Phosphorus OXYCHLORIDE (20 mL) is added dropwise and then the mixure is warmed to room temperature and then heated to reflux for 1.5 hours. The mixture is allowed to cool to room temperature and is then poured over ice. The aqueous mixture is neutralized to pH 7-8 with NAHCO3 AND then extracted with chloroform. The organic phase is washed with brine, dried over sodium sulfate and the solvent is removed. The residue is purified by flash chromatography (SIO2/5percent ETHYL acetate/hexanes). Collected 12.22 g (72percent). M+H = 389. 'H NMR ; 5 8. 50 (s, 1H), 8.40 (d, 1H), 8.20 (d, 1H), 7.92 (t, 1H), 7.79 (t, 1H).
94%
With 3-chloro-benzenecarboperoxoic acid In chloroform
A. 4-Bromo-isoquinoline 2-oxide (470A) A solution of 4-bromoisoquinoline (4.16 g, 18.6 mmol) in 100 mL of chloroform was added dropwise over 1 h to a solution of 70percent mCPBA (12.4 g, 50.3 mmol) in 100 mL of chloroform at room temperature. After stirring 18 h, the reaction mixture was washed with 1N NaOH (2*150 mL), dried over magnesium sulfate and concentrated in vacuo to afford 4.23 g (94percent) of compound 470A as an off-white solid. 1H NMR-400 MHz (CDCl3): δ 8.71 (s, 1H), 8.43 (s, 1H), 8.09 (d, 1H, J=8 Hz), 7.70 (m, 3H).
Reference：
[1] Patent: US2004/19063, 2004, A1,
[2] Patent: US2004/181064, 2004, A1,
[3] Journal of Medicinal Chemistry, 1995, vol. 38, # 21, p. 4234 - 4243
[4] Chemical Communications, 2018, vol. 54, # 32, p. 3977 - 3980
[5] Organic and Biomolecular Chemistry, 2016, vol. 14, # 24, p. 5820 - 5825
[6] Organic Process Research and Development, 2006, vol. 10, # 1, p. 70 - 77
[7] Patent: WO2005/28444, 2005, A1, . Location in patent: Page/Page column 51
[8] Pharmaceutical Bulletin, 1954, vol. 2, p. 72,76
[9] Patent: US2004/77605, 2004, A1,
[10] Patent: US2005/119228, 2005, A1,
[11] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 2, p. 939 - 950
[12] European Journal of Organic Chemistry, 2016, vol. 2016, # 8, p. 1606 - 1611
[13] New Journal of Chemistry, 2016, vol. 40, # 12, p. 10227 - 10232
[14] Organic and Biomolecular Chemistry, 2017, vol. 15, # 15, p. 3165 - 3169
39
[ 1532-97-4 ]
[ 5796-98-5 ]
[ 3749-21-1 ]
Reference：
[1] Patent: US2002/103203, 2002, A1,
40
[ 1532-97-4 ]
[ 33930-63-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 28, p. 5081 - 5085
[2] Green Chemistry, 2018, vol. 20, # 14, p. 3302 - 3307
41
[ 1532-97-4 ]
[ 58142-46-4 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 0 - 20℃; for 1 h;
4-Bromo-5-nitroisoquinoline (11). Potassium nitrate (5.34 g; 0.052 mol) was added to 20 mL of concentrated sulfuric acid and slowly dissolved by careful heating. The resulting solution was added dropwise to a solution of 4-bromoisoquinoline (10 g, 0.048 mol) dissolved in 40 mL of the same acid at O0C. After removal of the cooling bath, the solution was stirred for one hour at room temperature. The reaction mixture was then poured onto crushed ice (400 g) and made basic with ammonium hydroxide. The resulting yellow precipitate was collected by filtration and the filtrate was extracted with diethyl ether (3 x 500 mL), dried (Na2SO4), and concentrated to give a yellow solid that was combined with the initial precipitate. Recrystallization from methanol gave 12.1 g (89percent) of 11 as slightly yellow crystals
89%
With potassium nitrate In sulfuric acid at 0 - 20℃; for 1 h;
Potassium nitrate (5.34 g; 0.052 mol) was added to 20 mL of concentrated sulfuric acid and slowly dissolved by careful heating. The resulting solution was added dropwise to a solution of 4-bromoisoquinoline (10 g, 0.048 mol) dissolved in 40 mL of the same acid at 0° C. After removal of the cooling bath, the solution was stirred for one hour at room temperature. The reaction mixture was then poured onto crushed ice (400 g) and made basic with ammonium hydroxide. The resulting yellow precipitate was collected by filtration and the filtrate was extracted with diethyl ether (3*500 μL), dried (Na2SO4), and concentrated to give a yellow solid that was combined with the initial precipitate. Recrystallization from methanol gave 12.1 g (89percent) of 11 as slightly yellow crystals: mp 172-174° C.; 1H NMR (300 MHz, CDCl3) δ 9.27 (s, 1H); 8.87 (s, 1H); 8.21 (dd, 1H, J=6.6, 1.2 Hz); 7.96 (dd, 1H, J=6.6, 1.2 Hz); 7.73 (t, 1H, J=7.5 Hz); CIMS m/z 253 (M+H+, 100percent); 255 (M+H++2, 100percent); Anal. Calc'd for C9H5BrN2O2: C, 42.72; H, 1.99; N, 11.07. Found: C, 42.59; H, 1.76; N, 10.87.
With ammonia; copper(II) sulfate; In 1,4-dioxane; water; at 165℃; for 21h;Sealed tube;
A suspension of 4-bromoisoquinoline (25.0 g), copper(II) sulfate pentahydrate (30.4 g, Nacalai Tesque), 28% aqueous ammonia (100 ml) and 1,4-dioxane (100 ml) was stirred in a sealed tube at 165 C. for 21 hours. The reaction mixture was cooled to room temperature, the insoluble matters were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate (150 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the title compound (13.2 g).
Example 64: Synthesis of 4-(3-(2-fluoro-4-methoxybenzylidene)-3 ,4,5,6- 5 tetrahydropyridin-2-yl)isoquinoline dihydrochloride.; The preparation of 4-(3-(2-fluoro-4-methoxybenzylidene)-3,4,5,6- tetrahydropyridin-2-yl)isoquinoline dihydrochloride is described below.; A. Step 1: Preparation of Intermediate 9; Intermediate 9 was prepared as described in Tyson, F.T. J. Am. Chem. Soc, 1939, 61 (I )5 183 -185. Briefly, 4-Bromoisoquinoline (3.36 g, 16.2 mmol) and Cu(I)CN (2.17 g, 24.2 mmol) were combined as the dry solids in a round bottom flask fitted with a magnetic stirrer and vigeraux column under N2. Heat was applied.15 At approximately 1500C, the mixture began to stir freely. At approximately 23O0C, the reaction mixture formed a black solid that began to splatter onto the sides of the flask. The reaction was cooled to room temperature and treated with concentrated NH4OH overnight. This mixture was then extracted 3 times with EtOAc. The EtOAc extracts were washed with dilute NH4OH(Hq) and brine, then combined, dried 0 over Na2SO4, treated with decolorizing charcoal, filtered through celite, then concentrated under reduced pressure. The recovered material was dissolved into a mixture of hot isopropanol and methanol to re-crystallize. The crystals were recovered by vacuum filtration, washed with fresh isopropanol and dried under vacuum giving 1.47 g (58%) of yellow crystals. LC-MS: RT = 7.86 min, [M+H]+ = 5 155.1.
To a solution of 4-bromoisoquinoline (1 g, 4.80 mmol) in a solution of THF-diethyl ether (60 mL, 2:1) at -78 C was added n-BuLi (2.5 M in THF, 3.8 mL, 9.62 mmol) dropwise and the mixture was allowed to stir at the same temperature for 1 h. To this solution was added a solution of DMF (0.9 mL, 12 mmol. 2.5 eq) in THF (5 mL) dropwise and the resulting mixture was allowed to stir at -78 C for 2 h. Progress was monitored by TLC and LCMS. After completion,the reaction mixture was diluted with saturated, aqueous NH4C1 (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. Removal of solvent gave the crude product which was purified by CombiFlash to afford isoquinoline-4-carbaldehyde (553 mg, 73%).LCMS: 158 [M+1]
36%
To a solution of 4-bromoisoquinoline 24a (2.0 g, 9.6 mmol) in 30 mL re-distilled THF was added n-butyl lithium (4.0 mL, 10 mmol, 2.5 M in THF) dropwisely at -65 C. under N2 atmosphere. The resulting mixture was stirred for 30 mm at this temperature before N,N-dimethylformamide (730 mg, 10 mmol) was added dropwise, and stirred for additional 1 h at this temperature. After the reaction was over, 100 mL saturated aq. NH4Cl was added to the reaction mixture, and the mixture was extracted with EtOAc (50 mL*3). The combined organic layers were washed with 100 mL brine, dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0-100% EtOAc/PE) to give isoquinoline-4-carbaldehyde 31a (550 mg, yellow solid, yield: 36%). 1H NMR (400 MHz, CDCl3): delta 10.41 (s, 1H), 9.45 (s, 1H), 9.22 (d, J=8.4 Hz, 1H), 8.96 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.96-7.92 (m, 1H), 7.76 (t, J=8.4 Hz, 1H).
4-Bromo-/5O-quinoline (0.208 g, 1.00 mmol), (CyPF-J-Bu)PdCl2 (7.30 mg, 1.00 x 10"2 mmol), and LiNH2 (0.230 g, 10.0 mmol) in 20.0 mL DME gave 0.118 g (82%) of 4-Amino-/.y°-quinoline as a solid.
A solutionof 4-bromo isoquinoline (15g, 73 mmol, commercial material) in 200 mL dimethyl-3,4, 5,6-tetrahydro-2(1H)-pyrimidinone(DMPU, Aldrich) was added solid potassium methoxide (5.6gm, 80 mmol). The reaction vessel was immersed in an oil bath at105 C for 20 min. The color of mixture changed rapidly from its initial very pale to dark greenish brown immediately after warming. The reaction vessel was removed from the oil bath and was diluted with water, the organic residues were partitioned into ether by multiple extraction with portions of ether. TLC analysis showed two new, spots (1: 1 v/v mixture of hexanes and ethyl acetate as eluent) of roughly equal size. These were separated on silica-gel (Merck, type-H) column eluted with straight hexanes, followed by gradual addition of ether into the mobil phase. The desired product, 4-methoxy isoquinoline (4. 1gm, 35.3%) was isolated after evaporation of solvents. The other product was also isolated as the reduction by-product isoquinoline. The identity of the by-product was confirmed by NMR comparison with authentic material. Example 222a: LC/MS Rt-min(MH+) [method C]: 1.16(160).'H NMR (400 MHz, CHLOROFORM-D)8 4.07 (s, 3 H) 7.61(m, 1 H) 7.69 (m, 1 H) 7.93 (d, J=8. 07 Hz,1 H) 8.08 (s,1 H) 8.19 (d, J=8. 56 Hz,1 H) 8.89 (s, 1 H). [Note: this compound was previously prepared in Zoltewicz, John A.; Oestreich, Terence M.; Sale, Alan A, Journal of the American Chemical Society (1975), 97 (20), 5889-96 in a"Monel Bomb", and later by a"focused microwave"initiated procedure inChemg, Yie-Jia, Tetrahedron (2002), 58 (6), 1125- 1129. The present procedure required neither special high pressure apparatus nor preparative scale microwave equipment].
With sodium carbonate;palladium diacetate; triphenylphosphine; In 1,2-dimethoxyethane; water;Heating / reflux;
Step B: A solution of the product from Step A (1.0 g, 5.1 mmol) in 1,2-dimethoxyethane (10 ml) was treated with aqueous sodium carbonate (6.0 ml, 2 M solution), 4-bromoisoquinoline (1.0 g, 4.8 mmol) and catalytic palladium acetate and triphenylphosphine. The mixture was heated at reflux for 2 hours. Additional palladium acetate and triphenylphosphine were added and the reaction was refluxed overnight. The reaction was cooled to room temperature and diluted with water. The product was extracted with methylene chloride twice, washed with water and dried over anhydrous magnesium sulfate to give a brown oil (1.5 g, 83.1% AUC HPLC).
With n-butyllithium; In tetrahydrofuran; hexane; ethyl acetate;
EXAMPLE 11 3-(isoquinolin-4-yl)-8-methyl-8-azabicyclo[3.2.1]octane A solution of 4-bromoisoquinoline in tetrahydrofuran is cooled to -78 C. To this solution is added dropwise n-butyllithium (1.6 M in hexane), and the resultant solu-tion is stirred for 30 minutes. To this solution is then added dropwise triisopropylborate and the reaction mixture is then stirred for 18 hours at room temperature. The reaction mixture is then partitioned between ethyl acetate and saturated aqueous sodium chloride. The phases are separated and the aqueous phase extracted well with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is sonicated in a mixture of hexane:ethyl acetate. The resulting suspension is filtered to provide isoquinolin-4-ylboronic acid.
In tetrahydrofuran; N-methyl-acetamide; ethanol; hexane; carbon dioxide;
EXAMPLE 1 n-Butyllithium in n-hexane (90 ml, 2.4 M) was added at room temperature to a mixture of 500 ml of anhydrous ether and 500 ml of tetrahydrofuran under nitrogen. The solution was cooled to -68 C. and there was added 20.8 g of 4-bromoisoquinoline portionwise over a period of 30 minutes while maintaining the temperature at about -67 C. When addition was complete, the dark brown solution was stirred at -68 C. for 30 minutes. Then, a solution of 73 g of dimethylformamide in 150 ml of tetrahydrofuran at -68 C. was added all at once. The temperature rose to -57 C. and the reaction turned lighter brown. The mixture was stirred in dry ice for 15 minutes and then 100 ml of chilled ethanol was added over a period of 5 minutes. This was followed by the addition of 100 ml of saturated ammonium chloride solution and then 100 ml of saturated aqueous sodium chloride solution. The solution was then warmed to room temperature, the layers separated and the aqueous layer was washed once with ether. The organic layers were combined and dried over sodium sulfate and the solvent was evaporated. The resulting orange-brown oil was then dried. The residue was recrystallized from ethanol to give 4-isoquinolinecarboxaldehyde melting at about 104-105 C.
EXAMPLE 11 3-(isoquinolin-4-yl)-8-methyl-8-azabicyclo[3.2.1]octane A solution of 4-bromoisoquinoline in tetrahydrofuran is cooled to -78C. To this solution is added dropwise n -butyllithium (1.6 M in hexane), and the resultant solu-tion is stirred for 30 minutes. To this solution is then added dropwise triisopropylborate and the reaction mixture is then stirred for 18 hours at room temperature. The reaction mixture is then partitioned between ethyl acetate and saturated aqueous sodium chloride. The phases are separated and the aqueous phase extracted well with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is sonicated in a mixture of hexane:ethyl acetate. The resulting suspension is filtered to provide isoquinolin-4-ylboronic acid.
Referential Example 4 4-Fluoro-5-isoquinolinesulfonyl chloride From 4-bromoisoquinoline (75.0 g), 4-aminoisoquinoline (39.8 g) was synthetically obtained following J. Am. Chem. Soc., 64, 783 (1942).
To 4-bromo isoquinoline (2 g, 9.613 mmol) is added copper (I) cyanide (1.29 g, 14.42 mmol), and the mixture is heated to 250 C. for 45 minutes, where the pressure is taken down to 5-10 torr. The mixture which turns black at this point begins to distil over, giving crystals in the condenser. The condenser is cleaned with dichloromethane and the volatiles in the solution are removed in vacuo to give the desired product (0.66 g, 44.6%) as colorless crystals.
To a solution of n-butyl lithium (133 mL, 332.5 mmol, 2.5 M in THF) in 760 mL THF was added a solution of 4-bromoisoquinoline 24a (20 g, 96.6 mmol) in 144 mL THF dropwise at -65° C. and the resulting mixture was stirred at this temperature for another 30 mm after the completion of addition. A solution of N-fluorobenzenesulfonimide (66.68 g, 211.7 mmol) in 216 mL THF was added at -65° C. in 1 h dropwisely. After being stirred for another 1 h at this temperature, the reaction mixture was warmed to room temperature slowly with stirring, after the reaction is over, 300 mL saturated aq. NH4Cl was added slowly, extracted with EtOAc (300 mL*3). The combined organic layers were washed with 300 mL brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (0-100percent EtOAc/PE) to give 4-fluoroisoquinoline 24b (8.5 g, red oil, yield: 60percent).
Reference Example 1 4-Fluoroisoquinoline A solution of n-butyllithium in n-hexane (1.58 M, 60.1 ml, Kanto Chemicals) was added with tetrahydrofuran (345 ml), and the mixture was sufficiently cooled on a dry ice-acetone bath. The mixture was added dropwise with a solution of 4-bromoisoquinoline (9.0 g, Tokyo Kasei Kogyo) in tetrahydrofuran (65 ml) over 1 hour so that the temperature of the reaction mixture should not exceed -65° C. The mixture was stirred at the same temperature for 30 minutes, and then added dropwise with a solution of N-fluorobenzenesulfonimide (30 g, Tokyo Kasei Kogyo) in tetrahydrofuran (100 ml) over 1 hour so that the temperature of the reaction mixture should not exceed -65° C. Subsequently, the mixture was stirred at the same temperature for 1 hour, then the cooling bath was removed, and the mixture was gradually warmed to room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (300 ml) and ethyl acetate (300 ml), and stirred at room temperature for 12 hours. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate 3 times (200 ml for each time). The combined organic layer was washed with saturated brine (500 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was added with chloroform (250 ml), and the insoluble matters were removed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (3.6 g). MS (m/z): 148 (MH+) 1H-NMR (CDCl3) delta (ppm): 7.26-7.71 (1H, m), 7.75-7.82 (1H, m), 8.03 (1H, dd, J=1.2 Hz, J=8.4 Hz), 8.10 (1H, d, J=8.4 Hz), 8.38 (1H, s), 9.08 (1H, s)
A solution of n-butyllithium in n-hexane (1.58 M, 60.1 ml, Kanto Chemicals) was added with tetrahydrofuran (345 ml), and the mixture was sufficiently cooled on a dry ice-acetone bath. The mixture was added dropwise with a solution of 4-bromoisoquinoline (9.0 g, Tokyo Kasei Kogyo) in tetrahydrofuran (65 ml) over 1 hour so that the temperature of the reaction mixture should not exceed -65° C. The mixture was stirred at the same temperature for 30 minutes, and then added dropwise with a solution of N-fluorobenzenesulfonimide (30 g, Tokyo Kasei Kogyo) in tetrahydrofuran (100 ml) over 1 hour so that the temperature of the reaction mixture should not exceed -65° C. Subsequently, the mixture was stirred at the same temperature for 1 hour, then the cooling bath was removed, and the mixture was gradually warmed to room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (300 ml) and ethyl acetate (300 ml), and stirred at room temperature for 12 hours. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate 3 times (200 ml for each time). The combined organic layer was washed with saturated brine (500 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was added with chloroform (250 ml), and the insoluble solids were removed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (3.6 g).MS (m/z): 148 (MH+)1H-NMR (CDCl3) delta (ppm): 7.26-7.71 (1H, m), 7.75-7.82 (1H, m), 8.03 (1H, dd, J=1.2 Hz, J=8.4 Hz), 8.10 (1H, d, J=8.4 Hz), 8.38 (1H, s), 9.08 (1H, s)
Reference Example 1; 4-Fluoroisoquinoline; A solution of n-butyllithium in n-hexane (1.58 M, 60.1 ml, Kanto Chemicals) was added with tetrahydrofuran (345 ml), and the mixture was sufficiently cooled on a dry ice-acetone bath. The mixture was added dropwise with a solution of 4-bromoisoquinoline (9.0 g, Tokyo Kasei Kogyo) in tetrahydrofuran (65 ml) over 1 hour so that the temperature of the reaction mixture should not exceed -65° C. The mixture was stirred at the same temperature for 30 minutes, and then added dropwise with a solution of N-fluorobenzenesulfonimide (30 g, Tokyo Kasei Kogyo) in tetrahydrofuran (100 ml) over 1 hour so that the temperature of the reaction mixture should not exceed -65° C. Subsequently, the mixture was stirred at the same temperature for 1 hour, then the cooling bath was removed, and the mixture was gradually warmed to room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (300 ml) and ethyl acetate (300 ml), and stirred at room temperature for 12 hours. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate 3 times (200 ml for each time). The combined organic layer was washed with saturated brine (500 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was added with chloroform (250 ml), and the insoluble solids were removed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (3.6 g).MS (m/z): 148 (MH+)1H-NMR (CDCl3) delta (ppm): 7.26-7.71 (1H, m), 7.75-7.82 (1H, m), 8.03 (1H, dd, J=1.2 Hz, J=8.4 Hz), 8.10 (1H, d, J=8.4 Hz), 8.38 (1H, s), 9.08 (1H, s)
With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere; Schlenk technique;
General procedure: As a typical experiment, the reaction of the aryl bromide (1 mmol), benzothiophene (1.5 mmol) and KOAc (0.196 g, 2 mmol) at 150C during 16 h in DMF or DMAc (4 mL) in the presence of Pd(OAc)2 (0.224 mg,0.001 mmol) or (1.12 mg, 0.005 mmol) prepared as a solution in DMAc (1 mg of Pd(OAc)2 in 1 mL of DMAc) under argon affords the coupling product after evaporation of the solvent and purificationon silica gel.
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃;Inert atmosphere;
lntermediate-13: lsoquinolin-4-carbonitrile: To a stirred solution of 3-bromoisoquinoline (lntermediate-12) (9.2 g, 44.2 mmol) in DMF (15 mL) were added, Pd(PPh3)4 (10.2 g, 8.84 mmol) and Zn(CN)2 (10.34 g, 88.44 mmol, 2.0 eq) and the solution was degassed with N2 for 20 min. It was then heated to 120 2C overnight. After the completion (TLC), reaction mixture was cooled to RT, filtered and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (10% EtOAc:Hexanes) to afford the desired compound (3.4 g, 27.4%) as pale yellow solid.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; toluene;Reflux;
General procedure: 3-Methoxynaphthalen-2-ylboronic acidADDINRW.CITE{{31 Chowdhury,S. 2002}}2 (4.44g, 22.0mmol), 4-bromoisoquinoline (4.58g,22.0mmol), and tetrakis(triphenylphosphine)palladium(0) (380mg, 0.33mmol,1.5mol%) were suspended in 180ml toluene and 50mlethanol under an atmosphere of nitrogen. To this solution, a 0.5M aqueous solution of Na2CO3 (264ml, 132mmol) was added.The mixture was refluxed overnight, cooled to room temperature, diluted with saturated aqueous NH4Cl, and extracted exhaustively with ethylacetate. Drying of the combined extracts over MgSO4 and evaporationof the solvents under reduced pressure afforded (methoxynaphthalen-2-yl)isoquinolineas off-white solid which was used in the next step without further purification.(Methoxynaphthalen-2-yl)isoquinoline (5.82g, 20.0mmol)was refluxed in 250ml 48% aqueous HBr overnight. The mixture wascooled to 0C, neutralized with NaHCO3, extracted exhaustively with ethyl acetate and dried over anhydrous MgSO4, before the volatiles were removed under reduced pressure. Pyridine (1.3ml, 15.5mmol) and subsequently trifluormethanesulfonic anhydride (2.2ml, 13.2mmol) were added dropwise in 10min to a solution of the crude 3-(isoquinolin-4-yl)naphthalen-2-ol(3.00g, 11.0mmol) in 500ml CH2Cl2at 0C under an atmosphere of nitrogen. The mixture was stirred for 1.5hat 0C, before it was washed with water and brine. The combined organic layers were dried over anhydrous MgSO4. Evaporation of the solventand purification by flash chromatography on silica gel (petroleum ether/CH2Cl21/1) afforded 3b (506mg, 1.25mmol,7% over four steps) as a yellow oil.
With cetyltrimethylammonim bromide; In water; at 20℃; for 1.5h;Green chemistry;
General procedure: One mmol each of the isoquinolines (1a-c), phenacyl bromide (2a-f)/ 2-bromoacetonitrile (2g), and benzoyl isothiocyanate (3) were taken in a 100 ml RB flask.Then water (50 ml), CTAB (4 mmol) and Amberlite resin 420 (1 mmol) were added andthe mixture was stirred continuously for 1.5 h at room temperature. After completion of the reaction (monitored by TLC), the solid was filtered off, washed thoroughly withwater (until free from CTAB), Then the solid was dried, and dissolved in chloroform andagain filtered to separate base (Amberlite resin 420) from solution. The compound furtherpurified by recrystallization from chloroform to yield the thiazolo[2,3-a]isoquinolin-4-ium derivatives (4a-r).
With ammonium peroxydisulfate; caesium carbonate; In dimethyl sulfoxide; at 20.0℃; for 24.0h;Inert atmosphere; Irradiation; Green chemistry;
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.
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