* 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 tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 120℃; Inert atmosphere
To a stirred solution of 3-bromoisoquinoline (Intermediate-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° C. 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
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
4
[ 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] Chemistry - A European Journal, 2015, vol. 21, # 38, p. 13246 - 13252
14
[ 100-52-7 ]
[ 117908-22-2 ]
[ 34846-65-6 ]
[ 1459-20-7 ]
[ 117908-29-9 ]
Reference:
[1] Chemical & Pharmaceutical Bulletin, 1988, vol. 36, # 3, p. 930 - 939
15
[ 34846-65-6 ]
[ 7159-36-6 ]
Yield
Reaction Conditions
Operation in experiment
59.3%
With water; potassium hydroxide In ethanolReflux
To a stirred solution of isoquinolin-4-carbonitrile (Intermediate-13) (3.0 g, 19.45 mmol) in EtOH (30 mL) was added KOH (20 g in 20 mL water) and the mixture was refluxed overnight. It was then cooled to RT and concentrated under reduced pressure. The aqueous layer was washed with Et2O and neutralized using 1N HCl. It was extracted with EtOAc and the organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (2 g, 59.3percent) as an off white solid.
59.3%
Reflux
lntermediate-14: lsoquinolin-4-carboxylic acid: To a stirred solution of isoquinolin-4-carbonitrile (lntermediate-13) (3.0 g, 19.45 mmol) in EtOH (30 mL) was added KOH (20 g in 20 mL water) and the mixture was refluxed overnight. It was then cooled to RT and concentrated under reduced pressure. The aqueous layer was washed with Et20 and neutralized using 1 N HCI. It was extracted with EtOAc and the organic layer was dried over Na2S04, filtered, and concentrated to give the title compound (2 g, 59.3percent) as an off white solid.
Reference:
[1] Patent: US2013/178457, 2013, A1, . Location in patent: Paragraph 0221
[2] Patent: WO2013/5168, 2013, A2, . Location in patent: Page/Page column 40
[3] Journal of the American Chemical Society, 1940, vol. 62, p. 3030
[4] Journal of the American Chemical Society, 1939, vol. 61, p. 183
[5] Archiv der Pharmazie, 2003, vol. 336, # 4-5, p. 258 - 263
With water; potassium hydroxide; In ethanol;Reflux;
To a stirred solution of <strong>[34846-65-6]isoquinolin-4-carbonitrile</strong> (Intermediate-13) (3.0 g, 19.45 mmol) in EtOH (30 mL) was added KOH (20 g in 20 mL water) and the mixture was refluxed overnight. It was then cooled to RT and concentrated under reduced pressure. The aqueous layer was washed with Et2O and neutralized using 1N HCl. It was extracted with EtOAc and the organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (2 g, 59.3percent) as an off white solid.
59.3%
With ethanol; potassium hydroxide;Reflux;
lntermediate-14: lsoquinolin-4-carboxylic acid: To a stirred solution of <strong>[34846-65-6]isoquinolin-4-carbonitrile</strong> (lntermediate-13) (3.0 g, 19.45 mmol) in EtOH (30 mL) was added KOH (20 g in 20 mL water) and the mixture was refluxed overnight. It was then cooled to RT and concentrated under reduced pressure. The aqueous layer was washed with Et20 and neutralized using 1 N HCI. It was extracted with EtOAc and the organic layer was dried over Na2S04, filtered, and concentrated to give the title compound (2 g, 59.3percent) as an off white 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 (58%) of yellow crystals. LC-MS: RT = 7.86 min, [M+H]+ = 5 155.1.
With [2,2]bipyridinyl; aluminum (III) chloride; bis(acetylacetonate)nickel(II); zinc(II) oxide; In 1,2-dimethoxyethane; at 140℃; for 12h;Sealed tube;
General procedure: No special protection is required. In the air, a magnetic stirrer is added to the clean single-mouth reaction tube.p-Bromoanisole (IIa, 0.2 mmol, 1.0 equiv),Nickel diacetylacetonate (Ni(acac) 2, 0.01 mmol, 5 mol%),Aluminum chloride (AlCl3, 0.02 mmol, 10 mol%),Bipyridine(dipy, 0.04 mmol, 20 mol%),Zinc oxide (ZnO, 0.2 mmol, 1.0 equiv), formamide (1.0 mL)Sealing the reaction tube with ethylene dimethoxide (1,2-dimethoxyethane, 0.5 mL);After reacting at 140 C for 12 hours,Thin layer chromatography analysis showed complete consumption of the crude bromoanisole.Stop heating, cooling; extract, direct wet loading,200-300 mesh silica gel column chromatography,A mixed solvent of ethyl acetate and petroleum ether (1:10) was rinsed.Separating the compound of formula Ia22.6mg,The yield was 85%.
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.
Isoquinoline-4-carboxylic acid hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With hydrogenchloride; water; at 150℃; for 8h;
B. Step 2; Preparation of Intermediate 10; Intermediate 10 was prepared as described in Tyson et aL Briefly, Intermediate 9 (1.47g, 9.5 mmol) was transferred to a reaction vessel and treated with concentrated hydrochloric acid (12 mL). The reaction vessel was sealed and the reaction mixture was heated to 1500C with stirring for 8 hours, then cooled to room temperature. This gave a white solid that was recovered by vacuum filtration, washed with isopropanol, and dried under vacuum giving 1.74 g (87%) of a white crystalline solid. LC-MS: RT = 3.64 min, [M+H]+ = 174.1.
With hydrogenchloride; In water; for 7h;
The product from step A (0.66 g, 4.2 mmol) is dissolved in concentrated HCl (6 ml) and heated in a sealed tube for 7 hours. It is then cooled and water is removed in vacuo to the desired product as a white powder.
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃;Inert atmosphere;
To a stirred solution of 3-bromoisoquinoline (Intermediate-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 C. 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); 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.