* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference:
[1] Chemische Berichte, 1900, vol. 33, p. 987[2] Chemische Berichte, 1901, vol. 34, p. 1654
6
[ 119-65-3 ]
[ 136918-14-4 ]
[ 491-30-5 ]
[ 2439-04-5 ]
[ 643-79-8 ]
Reference:
[1] Journal of Physical Chemistry A, 1998, vol. 102, # 34, p. 6760 - 6765
7
[ 491-30-5 ]
[ 119-65-3 ]
[ 394-67-2 ]
Reference:
[1] Patent: JP2018/70562, 2018, A,
[2] Patent: JP2018/70562, 2018, A,
[3] Patent: JP2018/70562, 2018, A,
[4] Patent: JP2018/70562, 2018, A,
8
[ 491-30-5 ]
[ 394-67-2 ]
Reference:
[1] Patent: CN108558758, 2018, A,
9
[ 491-30-5 ]
[ 1532-71-4 ]
Reference:
[1] Yakugaku Zasshi, 1931, vol. 51, p. 542,571; dtsch. Ref. S. 73, 76[2] Chem.Abstr., 1931, p. 5427
[3] Recueil des Travaux Chimiques des Pays-Bas, 1943, vol. 62, p. 466
[4] Patent: EP446604, 1991, A2,
10
[ 491-30-5 ]
[ 15298-58-5 ]
Reference:
[1] Journal of Organic Chemistry, 1958, vol. 23, p. 1071
11
[ 491-30-5 ]
[ 66728-98-1 ]
Reference:
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 217 - 222
12
[ 491-30-5 ]
[ 51206-40-7 ]
Yield
Reaction Conditions
Operation in experiment
96%
at 140℃; for 0.166667 h;
A mixture of 2.90 g, 19.07mMol of isocarbostyril and 14.40 g, 33.68mMol of phosphorus pentabromide were allowed to melt together at 140 °C. The melt turned into a red liquid and after about 10 minutes the reaction mixture solidified and was cooled. The reaction mixture was crushed up and dumped into ice water. The resulting solid was filtered and air-dried. wt. 5.50 g, 96percent yield, mp.=94-96°. Rf=0.66 in 40percent ethyl acetate in hexanes.
96%
at 140℃; for 0.166667 h;
Preparation of Intermediate A: A mixture of 2.90 g, 19.07mMol of isocarbostyril and 14.40 g, 33.68mMol of phosphorus pentabromide were allowed to melt together at 140 0C. The melt turned into a red liquid and after about 10 minutes the reaction mixture solidified and was cooled. The reaction mixture was crushed up and dumped into ice water. The resulting solid was filtered and air-dried, wt. 5.50 g, 96percent yield, mp.=94-96°. Rf=0.66 in 40percent ethyl acetate in hexanes.
71.3%
at 125 - 140℃;
In a 250ml three neck flask fitted with overhead stirrer and condenser which is also connected to a scrubber solution, 1-hydroxyisoquinoline (lO.g, 68.89mmol) and PBrs (53.38g, 124 mmol) were taken. The reaction mixture was gradually heated to 140°C. At about 125°C - 130°C the solid melts and a deep read solution obtained which on further heating converts to yellowish solid at ~135°C. The reaction mixture was heated at this temperature for lOmin then allowed to cool to room temperature. The pale yellow solid was crushed and added in portions into ice with stirring to obtain a pale yellow powder which was filtered and washed with water (150ml) and dried in an oven at 50°C under vacuum. The crude solid was purified by recrystallisation from EtOAc/heptane (14. lg, 99.93percent HPLC, 71.3percent yield). 1H-NMR (600MHz, CDCI3, TMS): S= 8.47 (s, 1H), 8.32(d, 1H), 8.19 (m, 1H), 7.72(m, 1H).
A mixture of 2.90 g, 19.07 mMol of isocarbostyril and 14.40 g, 33.68 mMol of phosphorus pentabromide were allowed to melt together at 140° C. The melt turned into a red liquid and after about 10 minutes the reaction mixture solidified and was cooled. The reaction mixture was crushed up and dumped into ice water. The resulting solid was filtered and air-dried. wt. 5.50 g, 96percent yield, mp.=94-96°. Rf=0.66 in 40percent ethyl acetate in hexanes.
With caesium carbonate; In acetonitrile; at 15 - 40℃; for 10h;
According to Process B, Compound 3 can be formed starting from 8 via non-isolated compound 9 as follows. Compound 8 (80 g, 55 mmol), cesium carbonate (CS2CO3, 215 g, 66 mmol), and acetonitrile (800 mL) were charged to the reactor. The temperature was adjusted from 15 to 25 C and iodomethane charged to the reactor (Mel, 86 g, 0.61 mol) while maintaining a batch temperature below 25 C. The batch was heated to 40 C and agitated for 10 hours to form Compound 9. The batch was cooled to 25 C, filtered into a fresh reactor to remove solids, and the solids washed twice with acetonitrile. The combined organic layers were concentrated via atmospheric distillation to about 320 mL.
Example 13 1-Bromoisoquinoline A mixture of 9.0 g of 1-hydroxyisoquinoline and 40 ml of phosphorus tribromide is inserted for 15 minutes into a preheated oil bath at 135oC. The resulting 2 layers are cooled and concentrated in vacuo. The residue is treated with ice, water, and sodium carbonate. The reaction mixture is extracted with chloroform, dried over sodium sulfate and concentrated. The product is purified by column chromatography, yielding 6.8 g of pale yellow crystals, mp 41-43oC.
With ammonium acetate; acetic acid; at 100℃; for 3h;
A solution of 1 -chloroisoquinoline (8.1 g) in glacial acetic acid (170 mL) was treated with ammonium acetate (25 g). The reaction mixture was then heated at 100 C for 3h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was quenched with ice and the solid formed was filtered and dried on the filter (5.8 g, 80%). 1H NMR (400 MHz, DMSO-d6): delta 1 1.24 (s, 1 H), 8.18 (d, J= 8.4 Hz, 1 H), 7.63-7.71 (m, 2H), 7.45-7.49 (m, 1 H), 7.15-7.18 (m, 1 H), 6.55 (d, J= 7.2 Hz, 1 H). MS (ESI+): 146.0, HPLC (Method A) Rt 2.23min; HPLC purity 98.2 %
With trichlorophosphate; In acetonitrile; at 110℃; for 0.0833333h;Microwave irradiation;
General procedure: A solution of 6,7-dimethoxyisoquinolin-1(2H)-one(200 mg, 0.97 mmol), phosphoryl trichloride (0.268 mL, 2.92 mmol) inacetonitrile (5 mL) was stirred at 110 C for 5 minutes under microwaveirradiation. The reaction was quenched with a saturated aqueous sodium bicarbonatesolution and stirred at ambient temperature for 1 h. It was filtered throughcelite and washed with ethyl acetate. The filtrate was concentrated to dryness.The crude material was purified by flash chromatography, eluting with heptanesand ethyl acetate (1:0 to 0:1) to give the desired product as a gum (99 mg,45.4 %).
With trichlorophosphate; at 100℃; for 2h;
Isoquinolin-1(2H)-one (500mg) was added to phosphorus oxychloride (10mL),The reaction system was then stirred at 100C for 2 hours.After the reaction was completed, the solvent was concentrated, the reaction residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered,The solvent was concentrated to obtain 1-chloroisoquinoline (450 mg, 80% yield) as an off-white solid compound. The product was directly used in the next step without purification.
Preparation 6 1,4-Dichloro-7-isoquinolinesulphonyl chloride STR107 A solution of N-chlorosuccinimide (9.66 g, 72 mmol) in MeCN (80 mL) was added dropwise to a stirred solution of 1-(2H)-isoquinolone (10 g, 69 mmol) in MeCN (250 mL) which was being heated under reflux. The mixture was heated under reflux for an additional 1.5 h and then cooled to room temperature. The resulting precipitate was collected by filtration, with MeCN rinsing, and then dried in vacuo to give 4-chloro-1(2H)-isoquinolone (11.3 g, 62.9 mmol) as a pale pink solid. 1 H (DMSO-d6, 300 MHz) delta 7.5 (1H, s), 7.6 (1H, dd), 7.8-7.9 (2H, m), 8.25 (1H, d), 11.5 (1H, br s), ppm. LRMS 180, 182 (MH+), 359, 361, 363 (M2 H+).
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 2h;
Intermediate 6 4-bromoisoquinolin-1(2H)-one [0497] [0498] To a solution of isoquinolin-1(2H)-one (105 mg, 0.723 mmol) in DMF (2 mL), was added NBS (142 mg, 0.796 mmol). The mixture was stirred at rt for 2 h, then was concentrated. The crude product was purified via preparative HPLC to afford 110 mg (68%) of Intermediate 6. [0499] MS (ESI) m/z: 223.9 (M+H)+; 1H NMR (500 MHz, DMSO-d6) delta 11.57 (br. s., 1H), 8.24 (dd, J=8.0, 0.8 Hz, 1H), 7.88-7.83 (m, 1H), 7.79-7.75 (m, 1H), 7.61 (ddd, J=8.0, 7.1, 1.1 Hz, 1H), 7.55 (s, 1H).
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 2h;
A. solution of isoquinoiin~ (2H)-one (150 rag, 1.03 mmol) in DMF (5 ml.) was treated with NBS (184 rag, 1 .03 mmol). The mixture was stirred at rt for 2 h and then poured into H20 (15 ml.). The formed precipitate was collected by filtration, washed with water and dried by lyophilization to give the title compound as a white solid.
With phosphorus pentabromide; at 140℃; for 0.166667h;Neat (no solvent);
A mixture of 2.90 g, 19.07 mMol of <strong>[491-30-5]isocarbostyril</strong> and 14.40 g, 33.68 mMol of phosphorus pentabromide were allowed to melt together at 140 C. The melt turned into a red liquid and after about 10 minutes the reaction mixture solidified and was cooled. The reaction mixture was crushed up and dumped into ice water. The resulting solid was filtered and air-dried. wt. 5.50 g, 96% yield, mp.=94-96. Rf=0.66 in 40% ethyl acetate in hexanes.
89%
With phosphorus pentabromide; at 140 - 145℃; for 0.166667h;
In a 50 ml. round-bottom flask, <strong>[491-30-5]isocarbostyril</strong> (0.50 g, 3.4 mmol) and phosphorus pentabromide (2.7 g, 9.8 mmol) were heated at 140-145 C for 10 min. The solid melted and lightened in color. The liquid solidified, and the reaction was stirred for an additional 10 min. On completion, the reaction mixture was cooled to room temperature, and ice/H20 (10 ml.) was poured into the flask. The solid precipitate was collected by filtration, washed with H20 (2 x 50 ml_), and dried under vacuum to obtain 860 mg (89% yield) of (1) as a buff-colored solid.
With platinum(IV) oxide; hydrogen; In trifluoroacetic acid; at 110℃; under 15001.5 Torr; for 24h;Autoclave;
[0593] An autoclave was charged with compound VIII-1 (4.0 g, 27.6 mmol), PtO2 (400 mg) and 50 mL of TFA. The mixture was stirred at 110 C. under hydrogen (pressure 2.0 MPa) for 1 day, then the solution was filtered, and the solid was washed with MeOH. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel with petroleum ether/EtOAc (10:1?5:1?1:1?1:5?EtOAc) to give compound VIII-2 (2.1 g, 51% yield) as white solid. 1H NMR (CDCl3, 400 MHz) delta 12.85 (brs, 1H), 7.16 (d, J=6.4 Hz, 1H), 6.02 (d, J=6.4 Hz, 1H), 2.60-2.50 (m, 4H), 1.81-1.71 (m, 4H). MS (ESI) m/z [M+H]+ 149.8
51%
With platinum(IV) oxide; hydrogen; trifluoroacetic acid; at 110℃; under 15001.5 Torr; for 24h;Autoclave;
An autoclave was charged with VIII-1 (4.0 g, 27.6 mmol), Pt02 (400 mg) and 50 mL of TFA. The mixture was stirred at 110C under hydrogen (pressure 2.0 MPa) for 1 day, then the solution was filtered, and the solid was washed with MeOH. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel with petroleum ether/EtOAc (10:1-*5:1-*1:1-*1:5-*EtOAc) to give VIII-2 (2.1 g, 51% yield) as white solid. ?H NMR (CDC13, 400 MHz) 5 12.85 (brs, 1H), 7.16 (d, J = 6.4 Hz, 1H), 6.02 (d, J = 6.4 Hz, 1H), 2.60-2.50 (m, 4 H), 1.81-1.71 (m, 4H). MS (ESI) m/z [M+H] 149.8.
With N-chloro-succinimide; In acetonitrile (MeCN); acetonitrile;
Preparation 67 7-Chlorosulphonyl-1,4-dichloroisoquinoline A solution of N-chlorosuccinimide (9.66 g, 72 mmol) in acetonitrile (MeCN) (80 mL) was added dropwise to a stirred solution of 1-(2H)-isoquinolone (10 g, 69 mmol) in MeCN (250 mL) which was being heated under reflux. The mixture was heated under reflux for an additional 1.5 h and then cooled to room temperature. The resulting precipitate was collected by filtration, with MeCN rinsing, and then dried in vacuo to give 4-chloro-1(2H)-isoquinolone (11.3 g, 62.9 mmol) as a pale pink solid. 1H (DMSO-d6, 300 MHz) delta7.5 (1H, s), 7.6 (1H, dd), 7.8-7.9 (2H, m), 8.25 (1H, d), 11.5 (1H, br s), ppm. LRMS 180, 182 (MH+), 359, 361, 363 (M2H+).
With N-chloro-succinimide; In acetonitrile;
Preparation 6 1,4-Dichloro-7-isoquinolinesulphonyl chloride A solution of N-chlorosuccinimide (9.66 g, 72 mmol) in MeCN (80 mL) was added dropwise to a stirred solution of 1-(2H)-isoquinolone (10 g, 69 mmol) in MeCN (250 mL) which was being heated under reflux. The mixture was heated under reflux for an additional 1.5 h and then cooled to room temperature. The resulting precipitate was collected by filtration, with MeCN rinsing, and then dried in vacuo to give 4-chloro-1(2H)-isoquinolone (11.3 g, 62.9 mmol) as a pale pink solid. 1H (DMSO-d6, 300 MHz) delta7.5 (1H, s), 7.6 (1H, dd), 7.8-7.9 (2H, m), 8.25 (1H, d), 11.5 (1H, br s), ppm. LRMS 180, 182 (MH+), 359, 361, 363 (M2H+).
With N-chloro-succinimide; In acetonitrile;
Preparation 6 1,4-Dichloro-7-isoquinolinesulphonyl chloride A solution of N-chlorosuccinimide (9.66 g, 72 mmol) in MeCN (80 mL) was added dropwise to a stirred solution of 1-(2H)-isoquinolone (10 g, 69 mmol) in MeCN (250 mL) which was being heated under reflux. The mixture was heated under reflux for an additional 1.5 h and then cooled to room temperature. The resulting precipitate was collected by filtration, with MeCN rinsing, and then dried in vacuo to give 4-chloro-1(2H)-isoquinolone (11.3 g, 62.9 mmol) as a pale pink solid. 1H (DMSO-d6, 300 MHz) delta 7.5 (1H, s), 7.6 (1H, dd), 7.8-7.9 (2H, m), 8.25 (1H, d), 11.5 (1H, br s), ppm. LRMS 180, 182 (MH+), 359, 361, 363 (M2H+).
Preparation 90 4-Bromo-1-chloro-7-isoquinolinesulphonyl chloride STR198 A suspension of isoquinolinol (10 g, 68.9 mmol) in MeCN (250 ml) at 50 C., was treated with N-bromosuccinimide (12.6 g, 70.8 mmol) whereupon almost complete solution occurred before a thick white precipitate was formed. After heating under reflux for 3 h, the reaction mixture was cooled in ice and the solid filtered, washed with MeCN, and dried to afford 4-bromo-1-(2H)-isoquinolone (7.6 g, 34.0 mmol). 1 H (DMSO-d6, 300 MHz) delta 7.55 (1H, s), 7.6 (1H, m), 7.75 (1H, d), 7.85 (1H, m), 8.2 (1H, d), 11.55 (1H, br s) ppm. LRMS 223, 225 (MH+).
With trichlorophosphate In methanol; ethanol; water; acetonitrile
7.a EXAMPLE 7 (Compound No. 25)
(a) 1-(1-Piperazinyl)isoquinoline. 65 ml of phosphorus oxychloride are added dropwise to a suspension of 52.8 g (363 mmol) of 1(2H)-isoquinolinone in 250 ml of acetonitrile, the mixture is heated under reflux for 3 h and the solvent is evaporated off. The residue (305 mmol) is dissolved in methanol, a solution of 75 g (870 mmol) of piperazine in methanol is added and the solvent is evaporated off. The residue is heated to 120° C. for 4 h and allowed to cool, 500 ml of water are added, the mixture is stirred and filtered and the filtrate is extracted with ethyl acetate. After separation, washing with water, drying and evaporation of the organic phase, 57 g of base are obtained in the form of an oil. The latter is dissolved in 400 ml of ethanol, 30.7 g of fumaric acid are added, the mixture is heated under reflux for 30 min and left to stand and the precipitate is separated off by filtration and recrystallized in a 1:1 ethanol/water mixture. 64 g of fumarate are finally isolated. Melting point: 201°-203° C.
Preparation 90 4-Bromo-1-chloro-7-isoquinolinesulphonyl chloride A suspension of isoquinolinol (10 g, 68.9 mmol) in MeCN (250 ml) at 50C, was treated withN-bromosuccinimide (12.6 g, 70.8 mmol) whereupon almost complete solution occurred before a thick white precipitate was formed. After heating under reflux for 3 h, the reaction mixture was cooled in ice and the solid filtered, washed with MeCN, and dried to afford 4-bromo-1-(2H)-isoquinolone (7.6 g, 34.0 mmol). 1H (DMSO-d6, 300MHz) delta 7.55 (1H, s), 7.6 (1H, m), 7.75 (1H, d), 7.85 (1H, m), 8.2 (1H, d), 11.55 (1H, br s) ppm. LRMS 223, 225 (MH+).
EXAMPLE 17 : 2-(4-Fluorobenzyl)isoquinolin-1 (2H)-one (Final Compound 13-01)According to Scheme 11: To a solution of NaHMDS (2eq, 3.00mmol, 0.50g) in THF (3mL) at 0C was added isoquinolin-l(2H)-one (leq, 1.00mmol, 0.20g) dissolved in TEtaF (3mL) and DMF (5mL). The reaction mixture was stirred for 10 min at 0C then cooled at -70C. The l-(bromomethyl)-4-fluorobenzene (4eq, 4.00mmol, 0.80g) was added in one portion to the reaction mixture. The reaction mixture was allowed to warm to room temperature, for one hour. Upon completion the reaction mixture was concentrated under vacuum and the crude residue partitioned between water and AcOEt, the aqueous layer was extracted with AcOEt. The combined organic layers were successively washed with water (2*30mL), HCl (IM, 2*30mL), brine (2*20mL), dried over Na2SO4, filtered and evaporated to afford a yellow oil. The crude compound was purified on silica gel using cyclohexane/AcOEt 80/20 as eluent to afford 2-(4-fluorobenzyl)isoquinolin-l(2H)-one as a white solid (0.70mmol, 0.26g, 74%). M.p.: 107C; LC (XTerra RP18, 3.5mum, 3.0x50mm Column): RT = 3.76 min; MS m/z (CI) [MH]+= 254; 1H NMR (DMSO-d6) delta 5.16 (s, 2H), 6.67 (d, J=7.2Hz, 1H), 7.14- 7.18 (m, 2H), 7.37-7.39 (m, 2H), 7.51 (m, 1H), 7.60 (d, J=7.2 Hz51H), 7.66 (m, 1H), 7.71 (m, 1H), 8.23 (m, 1H).
c) 5-((1-oxoisoquinolin-2(1H-yl)methyl)furan-2-carboxylic acid A solution of 1-hydroxychinolin (100 mg, 0.689 mmol) in dry THF (12 ml) was treated with LHMDS (1N in hexane, 1.45 ml, 1.45 mmol) and kept at 11 for 90 min. The reaction mixture was cooled to -10 C., before methyl 5-(chloromethyl)furan-2-carboxylate (120 mg, 0.689 mmol) and NaI (103 mg, 0.689 mmol) were added, and stirring was continued for 18 h while warming to rt. All volatiles were removed in vacuo. The crude product was partitioned between EA (10 ml) and water (20 ml), washed with brine (20 ml), dried over Na2SO4, filtered and concentrated. Purification by column chromatography (CombiFlash Companion, 12 g SiO2, heptane to EA) afforded the substituted ester which was dissolved in EtOH (2 ml) and LiOH (2N, 0.420 ml, 0.840 mmol). After stirring at it for 18 h, the reaction mixture was acidified with 1N HCl, and all volatiles were removed in vacuo. The remaining residue was suspended in MeOH (2 ml) and filtered. Concentration of the filtrate afforded the title compound. LCMS RtM=1.71 min, [M+H]+=284.1.
3-(1-oxo-1H-isoquinolin-2-yl)propionic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
General procedure: A suspension of commercially available 1,6-naphthyridin-5(6H)-one 4a (188mg, 1.29mmol) and NaH (37mg, 1.55mmol) in dry DMF (10mL) was left under stirring at 0C for 1h. Then, a solution of <strong>[3395-91-3]methyl 3-bromopropionate</strong> (197muL, 1.81mmol) in dry DMF (3mL) was added dropwise and the reaction mixture was stirred at 50C for 18h. After quenching NaH with saturated NH4Cl solution (5mL), the reaction mixture was extracted with CHCl3 (3× 15mL) and the organic phase was washed first with saturated NaHCO3 solution (2× 20mL) and then with distilled water (2×20mL). The organic layer was dried over Na2SO4 and filtered, and the solvent was removed in vacuo. The crude was purified by column chromatography (CHCl3/MeOH=95:5) to give the title compound 5a as a white solid (183mg, 61%); Rf=0.48 (CHCl3/MeOH 95:5). 1H NMR (300MHz, CDCl3): delta 2.90 (t, 2H, J=6.6Hz), 3.68 (s, 3H), 4.28 (t, 2H, J=6.6Hz), 6.8 (d, 1H, J=7.0Hz), 7.4 (dd, 1H, J=7.6Hz), 7.5 (d, 1H, J=7.0Hz), 8.7 (d, 1H, J=7.6Hz), 8.90 (s, 1H)
A suspension of commercially available isoquinolin-1(2H)-one 4c (200mg, 1.38mmol) and NaH (40mg, 1.66mmol) in dry DMF (10mL) was left under stirring at 0C for 1h. Then, a solution of ethyl 2-bromoacetate (214muL, 1.93mmol) in dry DMF (3mL) was added dropwise and the reaction mixture was stirred at room temperature for 2h. Work-up was carried out in the same way as for compound 5a. Purification by column chromatography (EtOAc/n-hexane 4:6) yielded the title ester 5c as white crystals (220mg, 69%); Rf=0.43 (EtOAc/n-hexane 4:6). 1H NMR (300MHz, CDCl3): delta 1.29 (t, 3H, J=7.0Hz), 4.25 (q, 2H, J=7.0Hz), 4.71 (s, 2H), 6.53 (d, 1H, J=7.3Hz), 7.01 (d, 1H, J=7.3Hz), 7.48-7.53 (m, 2H), 7.65 (t, 1H, J=7.0Hz), 8.42 (d, 1H, J=8.1Hz).
2-bromo-6-(1-oxoisoquinolin-2(1H)-yl)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 130℃;Inert atmosphere;
General procedure: 4.1.5 2-Bromo-6-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)benzaldehyde (6a) A solution of 6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one (9.96 g, 49.1 mmol) and 2,6-dibromobenzaldehyde (15.5 g, 58.9 mmol) in anhydrous DMF (120 mL) was degassed with nitrogen for 10 min, followed by addition of CuI (4.69 g, 24.6 mmol), K2CO3 (13.55 g, 98.2 mmol) under continuous flow of nitrogen. The reaction mixture was stirred at 130 C for 20 h. After addition of water (50 mL) and extraction with EtOAc (300 mL), the organic phases were washed with saturated brine, and the combined organic layer was dried over Na2SO4. The solvent was removed in vacuo and the crude product was purified on a silica gel column using DCM/CH3OH (40:1, v/v) as eluent to afford 6a (11.5 g, 60.7%) as a white solid. 4.1.31 2-Bromo-6-(1-oxoisoquinolin-2(1H)-yl)benzaldehyde (6f) Using a method similar to that of 6a, compound 6f was synthesized as a white solid (100 mg, 64.1%). MS (ESI) m/z 328.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): delta 10.09 (s, 1H), 8.19 (d, J = 7.48 Hz, 1H), 7.93 (d, J = 7.80 Hz, 1H), 7.87-7.70 (m, 3H), 7.60-7.53 (m, 2H), 7.47 (d, J = 7.40 Hz, 1H), 6.78 (d, J = 7.40 Hz, 1H).
With magnesium bis(monoperoxyphthalate)hexahydrate; In methanol; at 20℃; for 2h;Inert atmosphere;
General procedure: To a solution of substituted 2-(dimethylamino)isoquinolin-1(2H)-ones 7a,b in MeOH was added magnesium monoperoxyphthalate (MMPP). After stirring at r.t. for 2 h, the mixture was diluted with Et2O (100 mL) and treated with sat. aq NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure. Recrystallization (cyclohexane) of the crude mixture provided 8a or 8b. Isoquinolin-1(2H)-one (8a). Following the general procedure using 7a (1.54 g, 8.2 mmol, 1 equiv) magnesium monoperoxyphthalate (10.1 g, 20.4 mmol) in MeOH (20 mL) at r.t. for 2 h gave 7a as a yellow solid; yield: 809 mg (68%); mp>160 C (Lit.18a 211-214 C); Rf = 0.15 (cyclohexane-EtOAc, 1:1). All physical and spectroscopic data of 8a are identical to those published in the literature. 1H NMR (300 MHz, CDCl3, 25 C): delta = 6.56 (d, J = 7.1 Hz, 1 H, CH), 7.15 (dd, J = 0.3, 7.2 Hz, 1 H, CH), 7.52 (ddd, J = 1.1, 7.1, 8.1 Hz, 1 H, CHarom), 7.57 (d, J = 7.9 Hz, 1 H, CHarom), 7.68 (ddd, J = 8.0, 7.0, 1.3 Hz, 1 H, CHarom), 8.43 (dt, J = 0.7, 8.1 Hz, 1 H, CHarom), 10.69 (br s, 1 H, NH). HRMS (ESI+): m/z [MH+] calcd for C9H7NO: 146.0607; found: 146.0599.
General procedure: To a solution of bromomethyl derivative 9 or 12 and 18-crown-6 (1-2 mol%) in dry toluene (10 mL) was added K2CO3 (1.1 equiv) and KI (0.1 equiv) with stirring at r.t. for 10 min. The solution of isoquinolin-1(2H)-one 8a or 8b (1.2 equiv) in dry toluene (10 mL) was added slowly to the mixture. The mixture was then heated at reflux under argon for 24 h. After cooling, the mixture was filtered through a columnof Celite 545. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (silica gel, cyclohexane-EtOAc) to provide the expected products in good yields. 2-(2-Bromobenzyl)isoquinolin-1(2H)-one (10). Following the general procedure using 8a (750 mg, 5.2 mmol), 18-crown-6 (1 mol%), K2CO3 (785 mg, 5.7 mmol), KI (84 mg, 0.5 mmol), and 1-bromo-2-(bromomethyl)benzene (9, 1.55 g, 6.2 mmol). The resulted crude mixture was purified by flash chromatography (cyclohexane-EtOAc, 9:1 to 7:3) to give 10 as a pale yellow solid; yield: 1.21 g (74%); mp 115 C; Rf = 0.7 (cyclohexane-EtOAc, 3:2). 1H NMR (300 MHz, CDCl3, 25 C): delta = 5.34 (s, 2 H, CH2N), 6.53 (d, J = 9 Hz, 1 H, CH), 7.16-7.19 (m, 3 H, CHarom), 7.25 (d, J = 7 Hz, 1 H, CH), 7.52-7.70 (m, 4 H, CHarom), 8.49 (d, J = 9 Hz, 1 H, CHarom). 13C NMR (75 MHz, CDCl3, 25 C): delta = 51.7 (CH2N), 106.7 (CH), 123.3 (Cq), 126 (CH), 126.2 (Cq), 127 (CHarom), 127.9 (CHarom), 128.1 (CHarom), 129.3 (CHarom), 129.4 (CHarom), 131.5 (CHarom), 132.4 (CHarom), 132.9 (CHarom), 135.9 (Cq), 137 (Cq), 162.3 (C=O). HRMS (ESI+): m/z found for C16H12BrNO (calcd): 314.0174 ([MH+], 314.0181), 315.0208 ([MH + 1]+, 315.0181), 316.0156 ([MH + 2]+, 316.0181), 317.0188 ([MH + 3]+, 317.0181).
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 120℃; for 2h;Inert atmosphere;
General procedure: Following a reported procedure,1 copper iodide (5 mol %), potassium phosphate tribasic (2.00 equiv), the corresponding 2-hydroxypyridine (1.00 equiv) and the corresponding 2-bromopyridine (2.00 equiv) were suspended in toluene [0.4 M] under N2. N,N?-Dimethylethylenediamine (0.10 equiv) was added and the resulting mixture was stirred 20 h at 120 C. The resulting mixture was allowed to cool to rt and then quenched with water. A small amount of N,N?-dimethylethylenediamine was added to dissolve the residual copper salts into the aqueous phase. The layers were separated and the aqueous layer was extracted three times with EtOAc (20 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. A purification by flash chromatography (eluent DCM/EtOAc 1:1 with 4%vv of NEt3) affordeded the desired product.
With pyridine; copper diacetate; In toluene; at 70℃;
2-Cyclopropyl-2H-isoquinolin-1-one R-11 To a solution of 2H-isoquinolin-1-one O-11 (1.000 g; 6.889 mmol)) in toluene (10 mL), cyclopropylboronic acid (1.775 g; 20.667 mmol), copper (II) acetate (1.251 g; 6.889 mmol) and pyridine (2.500 mL; 31.606 mmol) are added. The mixture is heated overnight at 70 C. A 2N aqueous HCl solution (20 mL) is added, followed by ethyl acetate (50 mL) and the suspension is filtered off. The phases are separated and the aqueous layer is extracted 3 times with ethyl acetate (50 mL). The combined organic layers are dried with Na2SO4, filtered off and concentrated under reduced pressure. The crude product is purified by Combiflash (Column Redisep Rf, 40 g; gradient: cyclohexane/EtOAc=100%/0% to 50%/50% over 20 column volumes; flow rate=40 mL/min; detection wavelength: 254 nm) HPLC-MS: (M+H)+=186; tRet=0.89 min; method M1
With Selectfluor; In acetonitrile; at 20℃; for 2.5h;Inert atmosphere;
According to the prior art document (Non-Patent Document 3), under a nitrogen atmosphere,To a solution of 1-hydroxyisoquinoline (6a) (290 mg) in acetonitrile(15 mL) and methanol (2 mL) was added selectfluor(Trade name) (1062 mg), and the mixture was stirred at room temperature for 2.5 hours.The reaction mixture was cooled with ice and diluted with ethyl acetate, to which water was added and stirred.The aqueous layer was removed and the organic layer was washed with water, sodium bicarbonate water and 20%And dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure to give 4-fluoro-1-hydroxy-3-methoxy-3,4-dihydroisoquinoline (7a) in the form of brown caramel(About 2: 1) (313 mg).This was used for the next reaction without purification.
4-(4-methylphenylthio)isoquinoline-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With silver hexafluoroantimonate; In 1,2-dichloro-ethane; at 80℃; for 12h;High pressure;
Isoquinoline-1 (2Eta)-one (10 mmol), bis(4-methylphenyl) sulfide (15 mmol), silver hexafluoroantimonate (7 mmol) were sequentially added to the pressure-resistant reaction tube at room temperature. And dichloroethane (6 mL). The reaction mixture is then reacted at 80 C for 12 hours. Time. The reaction was quenched and concentrated under reduced pressure to give a crude material which was washed with a mixture of petroleum ether and ethyl acetate. Flash column chromatography gave the corresponding product 4-(4-methylphenylthio)isoquinolin-1(2H)-one. Yield 96%
4-((4-chlorophenyl)thio)isoquinolin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With silver hexafluoroantimonate; In 1,2-dichloro-ethane; at 80℃; for 11h;High pressure;
At room temperature, isoquinoline-1 (2Eta)-one (10 mmol), bis(4-chlorophenyl)disulfide (llmmol), silver hexafluoroantimonate (8 mmol) were sequentially added to the pressure-resistant reaction tube. And dichloroethane (6 mL). The reaction mixture was then reacted at 80 C for 11 hours. The reaction was quenched and concentrated under reduced pressure to give a crude material which was washed with a mixture of petroleum ether and ethyl acetate. Fast column chromatography to obtain the corresponding product 4-(4-Chlorophenylthio)isoquinolin-1 (2H)-one. Yield 90%;
4-(2-monofluorophenylthio)isoquinoline-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With silver hexafluoroantimonate; In 1,2-dichloro-ethane; at 100℃; for 9h;High pressure;
At room temperature, isoquinoline-1 (2Eta)-one (10 mmol), bis(2-fluorophenyl)disulfide was sequentially added to a pressure-resistant reaction tube. Ether (10 mmol), silver hexafluoroantimonate (ll mmol) and dichloroethane (6 mL). The reaction mixture is then reacted at 100 C for 9 hours. Time. The reaction was stopped, concentrated under reduced pressure to give a crude product, and finally rinsed with a mixture of petroleum ether and ethyl acetate. Chromatography gave the corresponding product 4-(2-fluorophenylthio)isoquinolin-1(2H)-one. Yield 90%;
4-((4-methoxyphenyl)thio)isoquinolin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With silver hexafluoroantimonate; In 1,2-dichloro-ethane; at 80℃; for 10h;High pressure;
At room temperature, isoquinoline-1 (2Eta)-one (10 mmol), bis(4-methoxyphenyl)disulfide (13 mmol), silver hexafluoroantimonate were sequentially added to a pressure-resistant reaction tube. (8 mmol) and dichloroethane (8 mL). The reaction mixture was then reacted at 80 C for 10 hours. The reaction was stopped, concentrated under reduced pressure to give a crude material, which was washed with a mixture of petroleum ether and ethyl acetate. 4-(4-Methoxyphenylthio)isoquinolin-1(2Eta)-one. Yield 95%;
4-((4-cyanophenyl)thio)isoquinolin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With silver hexafluoroantimonate; In 1,2-dichloro-ethane; at 140℃; for 11h;High pressure;
At room temperature, isoquinoline-1 (2Eta)-one (10 mmol), <strong>[6339-51-1]bis(4-cyanophenyl)disulfide</strong> (ll mmol), and hexafluoro-silverate (silver) were sequentially added to a pressure-resistant reaction tube. 8 mmol) and dichloroethene (6 mL). The reaction mixture was then reacted at 140 C for 11 hours. The reaction was stopped, concentrated under reduced pressure to give a crude material, which was washed with a mixture of petroleum ether and ethyl acetate. 4-(4-Cyanophenylthio)isoquinolin-1 (2H)-one. Yield 70%;
With silver hexafluoroantimonate; In 1,2-dichloro-ethane; at 100℃; for 12h;High pressure;
At room temperature, isoquinoline-1 (2Eta)-one (10 mmol), diphenyl disulfide (12 mmol), silver hexafluoroantimonate (10 mmol) and dichloroethane were sequentially added to the pressure-resistant reaction tube. Alkane (6 mL). The reaction mixture was then reacted at 100 C for 12 hours. The reaction was stopped, concentrated under reduced pressure to give a crude product, and finally washed with a mixture of petroleum ether and ethyl acetate. 4-phenylthioisoquinolin-1(2Eta)-one. Yield 98%;
4-((3-fluorophenyl)thio)isoquinolin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With silver hexafluoroantimonate; In 1,2-dichloro-ethane; at 90℃; for 11h;High pressure;
Isoquinoline-1 (2Eta)-one (10 mmol), bis(3-fluorophenyl)disulfide (12 mmol), and silver hexafluoroantimonate (llmmol) were sequentially added to a pressure-resistant reaction tube at room temperature. And dichloroethane (6 mL). The reaction mixture was then reacted at 90 C for 11 hours. The reaction was stopped, concentrated under reduced pressure to give a crude material, which was washed with a mixture of petroleum ether and ethyl acetate. 4-(3-Fluorophenylthio)isoquinolin-1 (2H)-one. Yield 90%;
2-bromomethyl-5-p-tolyl-1,3,4-thiadiazole[ No CAS ]
[ 491-30-5 ]
2-((5-p-tolyl-1,3,4-thiadiazol-2-yl)methyl)isoquinolin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.2%
Dissolve isoquinoline-1(2H)-one (5.0 mmol) in dry DMF (40 mL) and add sodium hydride in portions(10.0 mmol), after stirring at room temperature for 0.5 h,2-Bromomethyl-5-p-tolyl-1,3,4-thiadiazole (5.5 mmol) was added.The resulting mixture was stirred at room temperature for 5 h.The reaction was monitored by TLC. After the reaction is over, the reaction product is poured into 100 mL of water.A white precipitate precipitated and allowed to stand overnight. Filter by suction, wash the solid three times with 1M aqueous HCl, and dry.The crude product was purified by silica gel column chromatography (EtOAc:EtOAcThe white solid was obtained in 1.38 g, yield: 83.2%.
3) under the conditions of 105 ,2 mmol of the compound 2 prepared in the step 2) was reacted with 2 mmol of isoquinolone in 10 mL of toluene for 12 hours to obtain a crude product of the compound 3, isoquinolinium ether, the crude product was washed with water, ethyl acetate was Washing with petroleum ether gave a white powder, i.e., isoquinolinium ether derivative, yielding about 85.8%.
3) 2 mmol of the compound 2 prepared in the step 2) was reacted with 2 mmol of isoquinolone in 10 mL of toluene at 108 C for 12 hours to obtain a crude product of the compound 3, i.e., isoquinolinium ether. The crude product was washed with water, extracted with ethyl acetate and evaporatedThe product was washed with petroleum ether to give a white powder, i.e., isoquinolinium ether, yielding about 87.3%.
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver(I) acetate; potassium hydrogencarbonate; In benzonitrile; at 80℃; for 24h;
The preparation steps are as follows: In the air, add a magnetic tube, benzoic acid (0.25mmol, 30.5mg), N-vinylformamide (1.5mmol, 106uL), [Cp * RhCl2] 2 (5mol %, 10.2 mg), AgOAc (0.25 mmol, 42 mg), KHCO3 (0.05 mmol, 5 mg) and benzonitrile (1.25 mL).Then plug in the rubber plug.Heat and stir in an 80 C oil bath for 24h.After the reaction is completed, the reaction system is cooled to room temperature,Filter with a glass sand funnel with diatomaceous earth,And washed with dichloromethane and ethyl acetate,The filtrates were combined, the solvent was distilled off under reduced pressure, petroleum ether / ethyl acetate (3: 1) was used as the mobile phase, and the product was purified by flash silica gel column chromatography.The yield of this example is 79%.