* 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 phosphorus; hydrogen iodide In water; acetic acid for 24 h; Reflux
A mixture of 1,3-dichloroisoquinoline (5.00 g, 25.2 mmol), red phosphorus, (1.72 g, 55.5 mmol), and hydriodic acid (10.5 mL, 58.1 mmol) in acetic acid (25 mL) was heated to reflux for 24 hours. The reaction mixture was cooled and poured onto ice, and the resulting solution brought to pΗ 7 by the addition of ION aqueous sodium hydroxide. The solution was extracted with dichloromethane (2 x 50 mL), and the organic layers concentrated. The residue was purified by silica gel chromatography (elution with 10percentEtOAc/hexanes) to provide 1.01 g (24percent) of the title compound. MS (DCIZNH3) mZz 164 (M+H)+.
24%
With phosphorus; hydrogen iodide In water; acetic acid for 24 h; Reflux
A mixture of 1,3-dichloroisoquinoline (5.00 g, 25.2 mmol), red phosphorus, (1.72 g, 55.5 mmol), and hydriodic acid (10.5 mL, 58.1 mmol) in acetic acid (25 mL) was heated to reflux for 24 hours. The reaction mixture was cooled and poured onto ice, and the resulting solution brought to pΗ 7 by the addition of ION aqueous sodium hydroxide. The solution was extracted with dichloromethane (2 x 50 mL), and the organic layers concentrated. The residue was purified by silica gel chromatography (elution with 10percentEtOAc/hexanes) to provide 1.01 g (24percent) of the title compound. MS (DCIZNH3) mZz 164 (M+H)+.
23%
Stage #1: With hydrogenchloride; tin; acetic acid In water at 55 - 60℃; for 3 h; Stage #2: With ammonia In water
EXAMPLE 60C 3-chloroisoquinoline The product from Example 60B (6.73 g, 33.8 mmol) was suspended in glacial acetic acid (37 mL) and concentrated HCl (13 mL), treated with tin powder (12.1 g, 101.9 mmol), and heated at 55-60° C. for 3 hours with stirring. The mixture was allowed to cool to room temperature and the precipitated tin salts were removed by filtration through Celite. The filtrate was basified to pH 9 with concentrated NH4OH and then extracted with ethyl acetate. The organic extracts were combined, washed with saturated NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound as a gummy yellow residue (1.28 g, 23percent).
Reference：
[1] Patent: WO2010/45401, 2010, A1, . Location in patent: Page/Page column 88
[2] Patent: WO2010/45402, 2010, A1, . Location in patent: Page/Page column 87
[3] Patent: US2005/113576, 2005, A1, . Location in patent: Page/Page column 30
[4] Chemische Berichte, 1886, vol. 19, p. 1655,2356
[5] Chemische Berichte, 1886, vol. 19, p. 1655,2356
[6] Journal of the Chemical Society, 1948, p. 777,781
[7] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3651 - 3660
[8] Patent: US4409017, 1983, A,
[9] Patent: WO2010/127855, 2010, A1, . Location in patent: Page/Page column 136; 137
2
[ 7742-73-6 ]
[ 119-65-3 ]
[ 19493-45-9 ]
Yield
Reaction Conditions
Operation in experiment
71%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at 25℃; for 2.5 h; Inert atmosphere
General procedure: PdCl2(dppf), PdCl2(tbpf) and (A.caPhos)PdCl2. A mixture of the halogenated heterocycle (0.66 mmol) in anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes. Then, PdCl2(dppf) (27.0 mg, 0.033 mmol, 5.0 molpercent), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature under argon for the proper time and then worked up as described above.
Reference：
[1] Journal of Molecular Catalysis A: Chemical, 2014, vol. 393, p. 191 - 209
With P,P-dichlorophenylphosphine oxide In tetrahydrofuran; water at 20 - 160℃;
EXAMPLE 60B 1,3-dichloroisoquinoline The product from Example 60A (6.5 g, 40.4 mmol) was treated with phenylphosphonic dichloride (11.5 mL, 81.1 mmol) and heated at 160° C. for 3 hours. The reaction was allowed to cool to room temperature and stand overnight. The resulting waxy orange material was dissolved in tetrahydrofuran (200 mL), treated with water (60 mL), and then concentrated under reduced to remove the tetrahydrofuran. The remaining aqueous material was neutralized with concentrated NH4OH and extracted with ethyl acetate. The ethyl acetate phases were combined, washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as yellow flakes (6.92 g, 74percent).
Reference：
[1] Patent: US2005/113576, 2005, A1, . Location in patent: Page/Page column 30
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3651 - 3660
[3] Patent: US6340759, 2002, B1, . Location in patent: Example 17
[4] Patent: WO2010/127855, 2010, A1, . Location in patent: Page/Page column 136; 137
6
[ 6627-91-4 ]
[ 7742-73-6 ]
Yield
Reaction Conditions
Operation in experiment
84.5%
With phosphorus pentachloride; trichlorophosphate In 2-cyanomethylbenzoic acid at 20 - 70℃; for 17.5 h;
16.2 Preparation of 1,3-dichloroisoquinoline 1.3 g (6.24 mmol) of phosphorus pentachloride were dissolved in 6 ml of phosphoryl chloride and admixed with 1.0 g (6.21 mmol) of o-cyanomethylbenzoic acid from example 16.1 in portions.After stirring at room temperature for 90 min, all had dissolved, and the solution was heated to 70° C. for 16 h.After the mixture had been cooled, it was poured cautiously onto 50 g of ice and admixed with 50 ml of ethyl acetate.The phases were separated and the aqueous phase was extracted twice with 50 ml each time of acetic acid.The combined organic phases were washed with 50 ml of H2O and 50 ml of saturated NaHCO3 solution, and dried over MgSO4, and the solvent was removed under reduced pressure.The brown, crystalline crude product was purified by filtering together with dichloromethane/cyclohexane (1:1) through a short silica gel column (2*15 cm).1.04 g (5.25 mmol, 84.5percent) of 1,3-dichloroisoquinoline were obtained.
With phosphorus; hydrogen iodide; In water; acetic acid; for 24.0h;Reflux;
A mixture of 1,3-dichloroisoquinoline (5.00 g, 25.2 mmol), red phosphorus, (1.72 g, 55.5 mmol), and hydriodic acid (10.5 mL, 58.1 mmol) in acetic acid (25 mL) was heated to reflux for 24 hours. The reaction mixture was cooled and poured onto ice, and the resulting solution brought to pEta 7 by the addition of ION aqueous sodium hydroxide. The solution was extracted with dichloromethane (2 x 50 mL), and the organic layers concentrated. The residue was purified by silica gel chromatography (elution with 10%EtOAc/hexanes) to provide 1.01 g (24%) of the title compound. MS (DCIZNH3) mZz 164 (M+H)+.
24%
With phosphorus; hydrogen iodide; In water; acetic acid; for 24.0h;Reflux;
A mixture of 1,3-dichloroisoquinoline (5.00 g, 25.2 mmol), red phosphorus, (1.72 g, 55.5 mmol), and hydriodic acid (10.5 mL, 58.1 mmol) in acetic acid (25 mL) was heated to reflux for 24 hours. The reaction mixture was cooled and poured onto ice, and the resulting solution brought to pEta 7 by the addition of ION aqueous sodium hydroxide. The solution was extracted with dichloromethane (2 x 50 mL), and the organic layers concentrated. The residue was purified by silica gel chromatography (elution with 10%EtOAc/hexanes) to provide 1.01 g (24%) of the title compound. MS (DCIZNH3) mZz 164 (M+H)+.
23%
EXAMPLE 60C 3-chloroisoquinoline The product from Example 60B (6.73 g, 33.8 mmol) was suspended in glacial acetic acid (37 mL) and concentrated HCl (13 mL), treated with tin powder (12.1 g, 101.9 mmol), and heated at 55-60 C. for 3 hours with stirring. The mixture was allowed to cool to room temperature and the precipitated tin salts were removed by filtration through Celite. The filtrate was basified to pH 9 with concentrated NH4OH and then extracted with ethyl acetate. The organic extracts were combined, washed with saturated NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound as a gummy yellow residue (1.28 g, 23%).
With phosphorus; hydrogen iodide; acetic acid;
(a) A mixture of 1,3-dichloroisoquinoline (26.0 g; prepared according to the method of G Simchen, Angew. Chem. Internat. Ed. 5 (7), 663, 1966), acetic acid (125 ml), hydrogen iodide (55 ml) and red phosphorus (9.0 g) was heated with stirring at a temperature of 170 C. for a period of 3 hours. After cooling the mixture was poured into ice-water and the aqueous mixture was neutralized with aqueous sodium hydroxide. The aqueous mixture was extracted with dichloromethane and the organic extract was dried over anhydrous magnesium sulfate. The solvent was evaporated to give an oil which was purified by column chromatography over silica gel (eluant dichloromethane) to give 3-chloroisoquinoline (18.23 g) mp<50 C.
Step-b product (5 g, 0.025 mol) was suspended in a mixture of glacial acetic acid (27.5 mL) and concentrated hydrochloric acid (9.7 mL). Tin powder was added to it and the mixture was heated at 55 0C for 3 hours. TLC showed complete consumption of starting material. The reaction mixture was filtered through sintered funnel and the filtrate was diluted with water. The overall filtrate was basified with ammonium hydroxide solution up to pH = 9 and extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with sodium bi carbonate solution and brine. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the crude compound 4, which was directly taken to next step (yield: 2 g).
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride In 1,2-dimethoxyethane at 90℃; regioselective reaction;
86%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; ethanol at 90℃; for 120h; regioselective reaction;
3 3.3. 3-Chloro-1-(2-methoxynaphthalen-1-yl)isoquinoline (11)
1,3-Dichloroisoquinoline 9 (6.85 g, 34.6 mmol) was added to a dry Schlenk tube under nitrogen followed by Pd(PPh3)4 (2.00 g,0.73 mmol) and stirred under vacuum. Anhydrous, degassed DME (150 mL) was added and the mixture was stirred for 15 min. Arylboronic acid (10) (7.00 g, 34.6 mmol), dissolved in the minimum amount of degassed ethanol (50 mL), was then added. Sodium carbonate solution (35 mL, 2M) was added and a white precipitate was formed instantly. The yellow mixture was refluxed at 90 °C for 5 d. The reaction mixture was cooled to room temperature and water (100 mL) and dichloromethane (100 mL) were added. The organic layer was separated and concentrated in vacuo to give a brown oil which was re-dissolved in dichloromethane (100 mL), washed with water (50 mL), brine (30 mL), and then dried over MgSO4. The solution was filtered and evaporated in vacuo to give a dark brown solid which was stirred in diethyl ether (50 mL) for 1 h and filtered to give the title compound 11 as an off-white solid (9.5 g, 86%). This material was used without any further purification. Rf=0.30, 2:1 (CH2Cl2:pentane); m.p. 172-173°C (lit [15]. m.p. 159-160°C); 1H NMR (300MHz; CDCl3) δ=8.00 (d, 1H, J=8.9Hz), 7.86-7.81 (m, 3H), 7.66 (dd, 1H, J1=6.9Hz, J2=1.3Hz), 7.48 (d, 1H, J=8.5Hz), 7.42-7.24 (m, 4H), 7.04 (d, 1H, 8.1Hz), 3.76 (s, 3H, OCH3); 13C NMR (75MHz; CDCl3) 159.10 (4°), 154.9 (4°), 145.1 (4°), 138.3 (4°), 133.6 (4°), 131.1, 130.9, 129.0 (4°), 128.0, 127.7, 127.3, 127.01 (4°), 127.02, 126.1, 124.6, 123.8, 120.6 (4°), 119.3, 113.3, 56.5 (OMe); IR (KBr) νmax 1621, 1576, 1547, 1510, 1264, and 1069cm-1; HRMS (ES+): calculated mass 320.0842, found 320.0840; C20H14ClNO: calculated C, 75.12; H, 4.41; N, 4.38, found, C, 75.12; H, 4.44; N, 4.28.
85%
With cesium fluoride In 1,2-dimethoxyethane for 6h; Heating;
79%
With cesium fluoride In 1,2-dimethoxyethane at 90℃; for 18h;
With cesium fluoride In 1,2-dimethoxyethane for 6h; Heating;
60%
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride In Dimethyl ether at 85℃; for 36h; Inert atmosphere;
1 Step 1-Synthesis of 3-chloro-1-phenylisoquinoline
Step 1-Synthesis of 3-chloro-1-phenylisoquinoline A 2 L 3 neck RBF was charged with caesium fluoride (CsF) (48.3 g, 318 mmol) in dimethylether (DME) (750 mL) at room temperature (-22° C.). The mixture was sparged with argon for 15 minutes, then 1,3-dichloroisoquinoline (30 g, 151 mmol) and phenyl boronic acid (18.5 g, 151 mmol) were added. Then tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) (21 g, 18.18 mmol) was added to form the reaction mixture, which was further sparged with argon for 5 minute. The reaction was heated to 85° C. under an atmosphere of argon for 36 hours. The reaction mixture was then cooled and directly concentrated. Water was added to the residual and the mixture was extracted with EtOAc. The combined organic fractions were dried with MgSO4 and concentrated. The residual was dry loaded onto a 330 g HPLC silica column and eluted with 0-10% EtOAc/Hexane. The combined pure fractions were concentrated to yield 3-chloro-1-phenylisoquinoline as an off-white solid (21.8 g, 60%).
56%
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride In 1,2-dimethoxyethane for 48h; Inert atmosphere; Reflux;
Stage #1: 1,3-dichloroisoquinoline; tributyl(1-ethoxyvinyl)stannane With triphenylphosphine; bis(dibenzylideneacetone)-palladium(0) In toluene at 110℃;
Stage #2: With hydrogenchloride In toluene at 20℃; for 12h;
Stage #1: acetic acid tert-butyl ester With n-butyllithium; 1,1,1,3,3,3-hexamethyl-disilazane In toluene at -78 - 20℃; for 1.25h;
Stage #2: 1,3-dichloroisoquinoline In toluene at 20℃; for 0.5h;
69.d
d) (3-Chloro-isoquinolin-1-yl)-acetic acid ethyl ester 1,1, 1,3, 3, 3-Hexamethyl-disilazane (27.4 ml, 20.37 g, 126.2 mmol) are dissolved in dry toluene (150 ml). After cooling to-78 °C, n-BuLi (79 ml of a 1.6 M solution in hexanes, 126.2 mmol) is slowly added during 20 minutes. The white suspension is stirred at-78 °C for 15 minutes and at RT for 15 minutes, after which time a clear bright yellow solution is obtained. This solution is canulated into a second two-necked flask, containing Pd2 (dba) 3 (1.39 g, 1.51 mmol) and (2'-Dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (1.25 g, 3.18 mmol). After stirring at RT for 10 minutes, the clear dark red solution is cooled to-10 °C. Acetic acid tert-butyl ester (15.7 ml, 13.5 g, 116.1 mmol) is added during 5 min. After 10 minutes at-10 °C, 1, 3-Dichloro-isoquinoline (10.0 g, 50.49 mmol) is added in one portion. The dark red solution is allowed to warm to RT. After 30 minutes at RT, TLC analysis indicates complete conversion of the starting material. The reaction mixture is filtered through a 2-cm pad of silica, which is rinsed with EtOAc/MeOH 98: 2. After concentration, the residue is purified by FCC (toluene/CH2CI2 2: 1 to toluene/EtOAc 100: 0 to 99: 1 to 98: 2 to 97: 3 to 96: 4 to 94: 6 to 90: 10) to afford (3-Chloro-isoquinolin-1-yl)-acetic acid tert.-butyl ester.
N1-(3-chloro-1-isoquinolinyl)-N3,N3-dimethyl-1,3-propanediamine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: 1,3-dichloroisoquinoline; 1-amino-3-(dimethylamino)propane for 0.5h; Heating / reflux;
Stage #2: With hydrogenchloride In methanol
6.1
Example 6.1; /^-[S-tl-benzofuran-Z-ylJ-l-isoquinolinyll-A^.W^dimethyl-l^-propanediamine dihydrochloride (81) (Scheme 6); ^-(S-chloro-l-isoquinolinyO-A^.A/'-dimethyl-ljS-propanediamine dihydrochloride (K); 1,3-Dichloroisoquinoline (1.00 g, 5.05 mmol) and /V,/V-dimethyl-1,3-propanediamine (2.0 mL) were heared to reflux in a sealed tube for 0.5 h. The mixture was quenched with water and extracted with EtOAc. The solvent was removed in vacuo and the residue was dissolved in MeOH and treated with HCI in MeOH (1.25 M, 20 mL). The solvent was removed in vacuo and the compound was recrystallised from MeOH/acetone to give K (1.682 g, 99%) as a microcrystalline solid. 1H NMR (DMSO-d6) 8 ppm 10.30 (bs, 1H), 8.29 (d, 1H, J=8.4 Hz), 8.06 (bs, 1H), 7.62-7.70 (m, 2H), 7.49 (ddd, 1H, J=8.3, 6.5, 1.6 Hz), 6.99 9s, 1H), 3.54 (t, 2H, J=6.6 Hz), 3.10-3.18 (m, 2H), 2.76 (d, 6H, J=5.0 Hz), 2.00-2.09 (m, 2H). ACPI-MS Found: [M+H]+= 266, 264.
With P,P-dichlorophenylphosphine oxide; at 130℃; for 2h;
phenylphosphonic dichloride (7.0 mL, 48 mmol) was added drop-wise with stirring to homophthalimide (0.94 g, 5.8 mmol). The mixture was then heated to 130C for 2h during which time the initial aggregate turned to a dark brown solution. The solution was allowed to cool and water (35 mL) was added drop-wise [Caution] with stirring. Diethyl ether (50 mL) was added and the organic layer was separated. The aqueous layer was extracted with diethyl ether (3×30 mL). The ether layers were combined, washed with 1M NaOH (2×20 mL), water (20 mL), brine (20 mL), dried over MgSO4, filtered and evaporated in vacuo to yield the title compound 9 as an off-white solid (0.91g, 79%). Rf=0.70, (CH2Cl2); m.p. 121-123C (lit [44]. 120-121C); 1H NMR (300MHz; CDCl3) delta=8.27 (dd, 1H, J1=8.4Hz, J2=0.9Hz), 7.77-7.75 (m, 2H), 7.69-7.64 (m, 2H); 13C NMR (75MHz; CDCl3) 151.1 (4), 143.3 (4), 139.4 (4), 132.4, 129.0, 126.8, 126.5, 125.9 (4), 120.0; IR (KBr) numax 2918, 1553, and 746cm-1.
74%
With P,P-dichlorophenylphosphine oxide; In tetrahydrofuran; water; at 20 - 160℃;
EXAMPLE 60B 1,3-dichloroisoquinoline The product from Example 60A (6.5 g, 40.4 mmol) was treated with phenylphosphonic dichloride (11.5 mL, 81.1 mmol) and heated at 160 C. for 3 hours. The reaction was allowed to cool to room temperature and stand overnight. The resulting waxy orange material was dissolved in tetrahydrofuran (200 mL), treated with water (60 mL), and then concentrated under reduced to remove the tetrahydrofuran. The remaining aqueous material was neutralized with concentrated NH4OH and extracted with ethyl acetate. The ethyl acetate phases were combined, washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as yellow flakes (6.92 g, 74%).
With P,P-dichlorophenylphosphine oxide; at 160℃; for 4h;
A mixture of step-a product (5g, 0.031 mol) and phenylphosphoryl dichloride (8.7 mL, 0.06 mol) were heated at 160 C for 4 hours. TLC showed complete consumption of starting material. It was cooled to ambient temperature and diluted with water (200 mL). The resulting mixture was extracted with 10% ethyl acetate in hexane (3 x 200 mL). The whole organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the crude compound. It was purified by column chromatography (silica gel: 100-200; eluent: 2% ethyl acetate in hexane) to get the pure compound (1.5 g).
Stage #1: Homophthalic acid With ammonium hydroxide Heating;
Stage #2: With P,P-dichlorophenylphosphine oxide at 160℃; for 3h;
3.1.2 Method 2
To homophthalic acid (12.50 g, 69.4 mmol) was added ammonium hydroxide (15.8 mL, 0.16mol). This mixture was vacuum distilled until a brown solid remained and then heated gently at normal pressure with a Bunsen burner until an orange oil resulted. The flask was allowed to cool and phenylphosphonic dichloride (30 mL, 0.21 mol) was added and the mixture heated to 160°C for 3h after which time the resultant solution was cooled and poured onto ice water [Caution]. The solution was extracted with dichloromethane (3×100 mL) and the organic layer was washed sequentially with 20% NaOH (2×50 mL), water (50 mL), brine (50 mL), and then dried over MgSO4. The organic layer was filtered and evaporated in vacuo to yield the crude product which was purified by column chromatography over silica gel (CH2Cl2) to give the title compound 9 (10.3g, 75%), which was identical to a sample prepared according to method 1.
Multi-step reaction with 2 steps
1.1: aq. NH3 / Heating
1.2: 1,2-dichloro-benzene / 3 h / 200 °C
2.1: 6.75 g / dichlorophenylphosphine oxide / 3 h / 160 °C / neat
16.3 16.3; Preparation of 1-t-butoxy-3-chloroisoquinoline
16.3 Preparation of 1-t-butoxy-3-chloroisoquinoline 1.0 g (5.05 mmol) of 1,3-dichloroisoquinoline from example 16.2 was dissolved in 20 ml of dry toluene, admixed with 0.68 g (6.06 mmol) of potassium tert-butoxide and stirred at 80° C. for 3 h.After the mixture had been cooled, it was filtered together with 50 ml of dichloromethane through a short silica gel column (1*5 cm) and the solvent was removed under reduced pressure. 1.06 g (4.50 mmol, 89.1%) of 1-t-butoxy-3-chloroisoquinoline were obtained.
89%
In toluene Reflux;
2
Potassium tert-butoxide (2.2 g, 19.3 mmol) is added to a solution of 1,3-dichloroisoquinoline (3.2 g, 16.12 mmol) in toluene (40 mL). The solution is then heated at reflux, cooled to ambient temperature, and filtered through a silica pad. The filtrate is concentrated under reduced pressure and the residual yellow liquid is purified by distillation (210° C., 0.1 mm Hg), yielding 1-tert-butoxy-3-chloroisoquinoline (3.4 g, 89%).At -78° C., sodium (0.28 g, 12.3 mmol) is added slowly to liquid ammonia (40 mL) followed by tris(3,5-dimethylphenyl)phosphine (2.1 g, 6.0 mmol), and the resulting mixture is stirred for 2 hours. A solution of 1-tert-butoxy-3-chloroisoquinoline (1.4 g, 6.0 mmol) in tetrahydrofuran (6 mL) is then added drop-wise and the resulting mixture slowly warmed to ambient temperature over 16 hours. The residue is quenched with water (30 mL), extracted with diethyl ether (3×25 mL), and the combined extracts are percolated through a column of magnesium sulfate-ZSM-5. The filtrate is concentrated under reduced pressure and the opaque residue is purified by a re-crystallization from methanol, yielding 1-tert-butoxy-3-(bis(3,5-dimethylphenyl)phosphino)isoquinoline (0.94 g, 73%) as a white solid.1-tert-butoxy-3-(bis(3,5-dimethylphenyl)phosphino)isoquinoline (0.96, 2.2 mmol) is dissolved in neat concentrated formic acid (9 mL), and the solution is stirred at ambient temperature for 1 hour. Precipitation of the isoquinolone was induced by dilution with H2O (25 mL), and the suspension is filtered through a glass frit. The white flakes are washed with 70% formic acid solution (3×5 mL). The combined aqueous formic acid filtrates are concentrated under reduced pressure, and the opaque residue is crystallized from acetone yielding 3-bis(3,5-dimethylphenyl)phosphino-2H-isoquinolin-1-one (0.55 g, 66%).
With phosphorus pentachloride; trichlorophosphate In 2-cyanomethylbenzoic acid at 20 - 70℃; for 17.5h;
16.2 16.2 Preparation of 1,3-dichloroisoquinoline
16.2 Preparation of 1,3-dichloroisoquinoline 1.3 g (6.24 mmol) of phosphorus pentachloride were dissolved in 6 ml of phosphoryl chloride and admixed with 1.0 g (6.21 mmol) of o-cyanomethylbenzoic acid from example 16.1 in portions.After stirring at room temperature for 90 min, all had dissolved, and the solution was heated to 70° C. for 16 h.After the mixture had been cooled, it was poured cautiously onto 50 g of ice and admixed with 50 ml of ethyl acetate.The phases were separated and the aqueous phase was extracted twice with 50 ml each time of acetic acid.The combined organic phases were washed with 50 ml of H2O and 50 ml of saturated NaHCO3 solution, and dried over MgSO4, and the solvent was removed under reduced pressure.The brown, crystalline crude product was purified by filtering together with dichloromethane/cyclohexane (1:1) through a short silica gel column (2*15 cm).1.04 g (5.25 mmol, 84.5%) of 1,3-dichloroisoquinoline were obtained.
60.B 1,3-dichloroisoquinoline
EXAMPLE 60B 1,3-dichloroisoquinoline The product from Example 60A (6.5 g, 40.4 mmol) was treated with phenylphosphonic dichloride (11.5 mL, 81.1 mmol) and heated at 160° C. for 3 hours. The reaction was allowed to cool to room temperature and stand overnight. The resulting waxy orange material was dissolved in tetrahydrofuran (200 mL), treated with water (60 mL), and then concentrated under reduced to remove the tetrahydrofuran. The remaining aqueous material was neutralized with concentrated NH4OH and extracted with ethyl acetate. The ethyl acetate phases were combined, washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as yellow flakes (6.92 g, 74%).
EXAMPLE 60C 3-chloroisoquinoline The product from Example 60B (6.73 g, 33.8 mmol) was suspended in glacial acetic acid (37 mL) and concentrated HCl (13 mL), treated with tin powder (12.1 g, 101.9 mmol), and heated at 55-60 C. for 3 hours with stirring. The mixture was allowed to cool to room temperature and the precipitated tin salts were removed by filtration through Celite. The filtrate was basified to pH 9 with concentrated NH4OH and then extracted with ethyl acetate. The organic extracts were combined, washed with saturated NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound as a gummy yellow residue (1.28 g, 23%).
With hydrogenchloride; In acetic acid;
Example 60C 3-chloroisoquinoline The product from Example 60B (6.73 g, 33.8 mmol) was suspended in glacial acetic acid (37 mL) and concentrated HCl (13 mL), treated with tin powder (12.1 g, 101.9 mmol), and heated at 55-60 C. for 3 hours with stirring. The mixture was allowed to cool to room temperature and the precipitated tin salts were removed by filtration through Celite. The filtrate was basified to pH 9 with concentrated NH4OH and then extracted with ethyl acetate. The organic extracts were combined, washed with saturated NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound as a gummy yellow residue (1.28 g, 23%).
In water; 2,4-dichlorophenoxyacetic acid dimethylamine
2 3-Chloro-1-(N-ethylsulfonyl-N-methyl)aminoisoquinoline STR14
Example 2 3-Chloro-1-(N-ethylsulfonyl-N-methyl)aminoisoquinoline STR14 A solution of 0.62 g (5 mmol) of ethylsulfonic acid N-methylamide in 10 ml of anhydrous DMA was added dropwise under an argon protective gas atmosphere to a suspension of 0.22 g (7.6 mmol) of sodium hydride (as an 80% strength dispersion in oil) in 5 ml of anhydrous DMA. The mixture was stirred at room temperature for 1 hour, then 1.09 g (5.5 mmol) of 1,3-dichloroisoquinoline were added, and the mixture was stirred overnight at RT and then for a further 8 h at 80° C. The solvent was distilled off under reduced pressure, the residue was stirred with water and the precipitated solid was filtered off with suction. After purification of the crude product by chromatography on silica gel, 0.34 g of 3-chloro-1-(N-ethylsulfonyl-N-methyl)aminoisoquinoline was obtained; m.p. 116°-118° C.
ethyl 4-(3-chloro-1-isoquinolyloxy)phenoxyacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate In <i>N</i>-methyl-acetamide; chloroform; water; acetone
1 Ethyl 4-(3-chloro-1-isoquinolyloxy)phenoxyacetate (17)
EXAMPLE 1 Ethyl 4-(3-chloro-1-isoquinolyloxy)phenoxyacetate (17) A mixture of ethyl 4-hydroxyphenoxyacetate (1.0 g), 1,3-dichloroisoquinoline (1.0 g), anhydrous potassium carbonate (0.7 g) and dry dimethylformamide (10 ml) was heated, with stirring, at a temperature of 120°-130° C. for a period of 3 hours. The solvent was removed by distillation under reduced pressure and the residue was treated with water. The aqueous mixture was extracted with a mixture of acetone and chloroform and the solvents were removed from the organic extract by distillation under reduced pressure. The residue was chromatographed over silica gel with chloroform elution to give ethyl 4-(3-chloro-1-isoquinolyloxy)phenoxyacetate (1.2 g), mp 97° C. The assigned structure was confirmed by proton magnetic resonance spectroscopy, mass spectrometry and elemental analysis.
Reference Example 19 4-(1-Isoquinolyl)-1-piperazinecarboxylic acid tert-butyl ester The procedure similar to that described in Reference Example 15 was repeated using commercially available 1,3-dichloroisoquinoline to give the desired compound (77%, 2 steps).
isobutyl 1-(3-chloroisoquinolin-1-yl)piperidin-4-ylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine In N,N-dimethyl-formamide at 160℃; for 0.05h; Microwave;
A mixture of 1,3-dichloroisoquinoline (0.16 g, 0.78 mmol), isobutyl piperidin- 4-ylcarbamate (0.16 g, 0.78 mmol), Et3N (0.11 mL, 0.78 mmol), and DMF (0.5 mL) was sealed in a microwave vessel and heated by microwave irradiation at 1600C for three minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield isobutyl l-(3-chloroisoquinolin-l-yl)piperidm- 4-ylcarbamate. LC/MS: mJz 362.2 (M+H)+ at 3.98 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
EXAMPLE 60B 1,3-dichloroisoquinoline The product from Example 60A (6.5 g, 40.4 mmol) was treated with phenylphosphonic dichloride (11.5 mL, 81.1 mmol) and heated at 160 C. for 3 hours. The reaction was allowed to cool to room temperature and stand overnight. The resulting waxy orange material was dissolved in tetrahydrofuran (200 mL), treated with water (60 mL), and then concentrated under reduced to remove the tetrahydrofuran. The remaining aqueous material was neutralized with concentrated NH4OH and extracted with ethyl acetate. The ethyl acetate phases were combined, washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as yellow flakes (6.92 g, 74%).
In tetrahydrofuran; water;
Example 60B 1,3-dichloroisoquinoline The product from Example 60A (6.5 g, 40.4 mmol) was treated with phenylphosphonic dichloride (11.5 mL, 81.1 mmol) and heated at 160 C. for 3 hours. The reaction was allowed to cool to room temperature and stand overnight. The resulting waxy orange material was dissolved in tetrahydrofuran (200 mL), treated with water (60 mL), and then concentrated under reduced to remove the tetrahydrofuran. The remaining aqueous material was neutralized with concentrated NH4OH and extracted with ethyl acetate. The ethyl acetate phases were combined, washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as yellow flakes (6.92 g, 74%).
9.1
Starting material dissolved in ethanol and hydrazine hydrate (10.0 eq) was added to form a mixture, the mixture was stirred at 50-60° C. (oil temperature) for several hours (completion was checked by TLC), the solvent was evaporated, water was added and the resulting mixture was extracted with ethyl acetate, dried and concentrated to form a crude preparation that was used without further purification for the next step. The crude preparation was dissolved in chloroform (or toluene, acetic acid, or another suitable solvent), anhydride was added (1.0 eq), the mixture was heated at 50-60° C. (oil temperature) for several hours (completion checked by TLC), the solvent was evaporated, and the preparation was purified by Prep-TLC to provide the desired compound.
Stage #1: (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 0.5h;
Stage #2: 1,3-dichloroisoquinoline In DMF (N,N-dimethyl-formamide) at 20℃; for 12h;
B.III.24.1 Example 24: Preparation of Compound 24.; Step 1:
To a solutionof N-BOC-3- (R)-hydroxy-L-proline (6.22 g, 26.9 mmol) in DMF (250 mL) at0 C was added NaH (60%, 3.23 g, 80.8 mmol) by several portions. The formed suspension was stirred at this temperature for 30 min. 1,3-dichloro- isoquinoline (5.33 g, 26.9 mmol) was added as solid in one portion and the final mixture was stirred at the ambient temperature for 12 h. Quenched with iced 5% citric acid (aq), extracted with EtOAC (300 mL). The aqueous phase was extracted with EtOAC again. The combined organic layers were washed with 5% citric acid (aq) and brine respectively, dried over MgS04, filtered. The filtrate was evaporated in vacuo to dryness to yield 10.53 g (99.8%)of 4- (6-methoxy-isoquinolin-1-yloxy)- pyrrolidine-1, 2-dicarboxylic acid1-tert-butyl ester as an off-white foam. This material was used in the next step reaction as crude without further purification. 'H NMR (CD30D) 8 1.43, 1.44 (rotamers, 9H), 2.39-2. 44 (m, 1H), 2.68-2. 72 (m, 1H), 3.80-3. 90 (m, 2H), 4.44-4. 52 (m, 1H), 5.77 (b, 1H), 7.39 (s, 1H), 7.58 (t, J=7. 3 Hz, 1H), 7.71-7. 78 (m, 2H), 8.16 (d, J=7. 5 Hz, 1H) ; LC-MS (retention time: 1.80 min, method B), MS m/z 392 (M++H).
With 2,2,2-tris(hydroxymethyl)ethylamine In dimethyl sulfoxide at 20 - 100℃;
21
Example 212'-O-{3-[(3-chloro-1-isoquinolinyl)amino]propyl}-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A; To a solution of 1,3-dichloroisoquinoline (100 mg, 0.505 mmol) in DMSO (10 ml) tris(hydroxymethyl)aminoethane (306 mg, 2.52 mmol) and Intermediate 1 were added. The reaction mixture was stirred at 100° C. for 7 hours followed by stirring at r.t. over night. The reaction mixture was then diluted with EtOAc (20 mL) and washed with water (40 mL). Water was added (20 mL) to the organic layer and pH adjusted to 5 by addition of 1MHCl. The water layer was extracted with DCM (2×30 mL). To organic extracts at pH 5 water was added and pH adjusted to 9.5 by addition of NH4OH. Organic extracts at pH 9.5 were evaporated yielding crude product (0.3 g) which was recrystallised from acetone/petrol ether yielding the title product (0.273 g).MS (ES+): 967.78 [MH]+ 13C-NMR (DMSO-d6) δ/ppm: 177.49, 156.09, 144.29, 138.70, 130.82, 126.25, 125.87, 123.55, 116.85, 106.57, 102.4, 94.63, 82.60, 80.22, 77.75, 77.38, 76.69, 75.21, 73.95, 73.18, 72.86, 70.34, 68.99, 67.12, 65.03, 64.16, 61.80, 49.22, 45.18, 42.05, 41.95, 41.35, 39.12, 36.04, 35.01, 32.75, 29.50, 27.83, 26.23, 22.34, 21.78, 21.39, 21.34, 18.90, 18.07, 15.10, 11.34, 8.67, 7.08.
Stage #1: 2-methoxymethyl-4-triphenylmethylpiperazine With n-butyllithium In diethyl ether; hexane at 0℃; for 0.333333h;
Stage #2: 1,3-dichloroisoquinoline In diethyl ether; hexane at 20℃; for 14h;
IV
A solution of compound 13 (1.00 g, 2.685 mmol) in dry ether (15 mL) was cooled to 0° C and then w-butyllithium (2.685 mmol) was added. The mixture was stirred for 20 min at 0° C and then 1,3-dichloroisoquinoline (0.354 g, 1.79 mmol) in dry ether ( ~ 2 mL) was added to the mixture. The reaction was allowed to warm to room temperture, stirred for 14 h, and then quenched with saturated NaHCO3 (5 mL). The mixture was diluted with ether, transferred to a separation funnel and washed with brine. The organic portion wash dried (K2CO3), filtered and solvent removed in vacuo to provide a crude yellow foam. Purification of the foam by chromatography (silica gel, EtOAc rhexanes, 1:4) afforded 0.909 g of the intermediate coupled material, which was used directly in the next transformation.
144.a
1, 3-Dichloroisoquinoline (2.75 g, 13.89 mmol) was added in small portions to a cold (0 0C) solution of fuming nitric acid (10 mL) and concentrated sulfuric acid(10 mL) . The mixture was allowed to stir at 0 °C for 0.5h before it was gradually warmed to 25 0C where it stirred for 16 h. The mixture was then poured into a beaker containing chopped ice and water and the resulting suspension was stirred for Ih at 0 0C before it was filtered to afford Cap-144, step a (2.73 g, 81%) as a yellow solid which was used as is. Rt = 2.01 min.(Cond.-Dl) ; 95% homogenity index; LCMS: Anal. CaIc. for[M+H] + C9H5Cl2N2O2 : 242 . 97 ; found : 242 . 92 .
91%
With sulfuric acid; nitric acid In water at 0 - 5℃; for 2h;
1,3-Dichloro-5-nitroisoquinoline (27)
Aq. HNO3 (67%, 430 mg) in conc. H2SO4(3.0 mL) was added dropwise to 1,3-dichloroisoquinoline 26 (1.00g, 5.1 mmol) in conc. H2SO4 (5.0 mL) at 5°C. The mixture was stirred at 0-5°C for 2 h, then poured onto ice. Theprecipitate was collected, washed (H2O), dried and recrystallised(EtOAc / petroleum ether) to give 27 (1.12 g, 91%) as a yellow powder: mp 168-170°C (lit.2 mp168-170°C); 1H NMR (CDCl3) d7.80 (1 H, t, J = 7.8 Hz, 7-H), 8.55(1 H, s, 4-H), 8.62 (1 H, dd, J =7.8, 1.8 Hz, 6-H), 8.72 (1 H, dt, J =8.5, 1.1 Hz, 8-H); 13C NMR (CDCl3) (HSQC / HMBC) d 115.16 (4-C), 126.00 (4a-C), 126.64 (7-C), 129.63 (6-C), 131.60 (8a-C),133.12 (8-C), 144.01 (5-C), 147.08 (3-C), 151.75 (1-C).
81%
With sulfuric acid; nitric acid at 0 - 25℃; for 16.5h;
a
1,3-Dichloroisoquinoline (2.75 g, 13.89 mmol) was added in small portions to a cold (0 0C) solution of fuming nitric acid (10 mL) and concentrated sulfuric acid (10 mL). The mixture was allowed to stir at 0 0C for 0.5h before it was gradually warmed to 25 0C where it stirred for 16 h. The mixture was then poured into a beaker containing chopped ice and water and the resulting suspension was stirred for Ih at 0 0C before it was filtered to afford Cap- 144, step a (2.73 g, 81%) as a yellow solid which was used as is. Rt - 2.01 min. {Cond. DJ); 95% homogenity index; LCMS:Anal. CaIc. for [M+H]+ C9H5Cl2N2O2: 242.97; found: 242.92.
81%
With sulfuric acid; nitric acid at 0 - 25℃; for 16.5h;
a
1,3-Dichloroisoquinoline (2,75 g, 13.89 mmol) was added in small portions to a cold (0 0C) solution of fuming nitric acid (10 mL) and concentrated sulfuric acid (10 mL). The mixture was stirred at 0 0C for 0.5 h before it was gradually warmed to 250C where it stirred for 16 h. The mixture was then poured into a beaker containing chopped ice and water and the resulting suspension was stirred for 1 h at 0 0C before it was filtered to afford Cap- 144, step a (2.73 g, 81%) as a yellow solid which was used directly. Rt = 2.01 min. (Cond. Dl); 95% homogenity index; LCMS: Anal. CaIc. for [M+H]+ C9H5Cl2N2O2: 242.97; found: 242.92.
81%
Stage #1: 1,3-dichloroisoquinoline With sulfuric acid; nitric acid at 0 - 25℃;
Stage #2: With water at 0℃; for 1h;
Cap-144.a
1,3-Dichloroisoquinoline (2.75 g, 13.89 mmol) was added in small portions to a cold (0 °C) solution of fuming nitric acid (10 mL) and concentrated sulfuric acid (10 mL). The mixture was stirred at 0 °C for 0.5 h before it was gradually warmed to 25 °C where it stirred for 16 h. The mixture was then poured into a beaker containing chopped ice and water and the resulting suspension was stirred for 1 h at 0 °C before it was filtered to afford Cap-144, step a (2.73 g, 81%) as a yellow solid which was used directly. Rt = 2.01 min. (Cond.-Dl); 95%homogenity index; LCMS: Anal. Calc. for [M+H]+ C9H5CI2 2O2: 242.97; found: 242.92.
81%
With sulfuric acid; nitric acid at 0 - 25℃; for 16.5h;
144.a
1,3-Dichloroisoquinoline (2.75 g, 13.89 mmol) was added in small portions to a cold (0 °C) solution of fuming nitric acid (10 mL) and concentrated sulfuric acid (10 mL). The mixture was stirred at 0 °C for 0.5 h before it was gradually warmed to 25 °C where it stirred for 16 h. The mixture was then poured into a beaker containing chopped ice and water and the resulting suspension was stirred for 1 h at 0 °C before it was filtered to afford Cap-144, step a (2.73 g, 81%) as a yellow solid which was used directly. Rt = 2.01 min. (Cond.-Dl); 95% homogenity index; LCMS: Anal. Calc. for [M+H]+ C9H5C12N202: 242.97; found: 242.92.
81%
With sulfuric acid; nitric acid at 0 - 25℃;
a
Cap- 144, Step a[00256] 1,3-Dichloroisoquinoline (2.75 g, 13.89 mmol) was added in small portions to a cold (0 °C) solution of fuming nitric acid (10 mL) and concentrated sulfuric acid (10 mL). The mixture was stirred at 0 °C for 0.5 h before it was gradually warmed to 25 °C where it stirred for 16 h. The mixture was then poured into a beaker containing chopped ice and water and the resulting suspension was stirred for 1 h at 0 °C before it was filtered to afford Cap- 144, Step a (2.73 g, 81%) as a yellow solid which was used directly. Rt = 2.01 min. (Cond.-Dl); 95% homogenity index; LC-MS: Anal. Calc. for [M+H]+ C9H5C12N202: 242.97; found: 242.92.
81%
With sulfuric acid; nitric acid at 0 - 25℃; for 16.5h;
1,3-Dichloroisoquinoline (2.75 g, 13.89 mmol) was added in small portions to a cold (0 °C) solution of fuming nitric acid (10 mL) and concentrated sulfuric acid (10 mL). The mixture was stirred at 0 °C for 0.5 h before it was gradually warmed to 25 °C where it stirred for 16 h. The mixture was then poured into a beaker containing chopped ice and water and the resulting suspension was stirred for 1 h at 0 °C before it was filtered to afford Cap-144, step a (2.73 g, 81%) as a yellow solid which was used directly. Rt = 2.01 min (Cond.-Dl); 95% homogenity index; LCMS: Anal. Calc. for [M+H]+ C9H5CI2N2O2: 242.97; found: 242.92.
81%
With sulfuric acid; nitric acid at 0 - 25℃; for 16.5h;
1,3-Dichloroisoquinoline (2.75 g, 13.89 mmol) was added in small portions to a cold (0 °C) solution of fumingnitric acid (10 mL) and concentrated sulfuric acid (10 mL). The mixture was stirred at 0 °C for 0.5 h before it was graduallywarmed to 25 °C where it stirred for 16 h. The mixture was then poured into a beaker containing chopped ice and waterand the resulting suspension was stirred for 1 h at 0 °C before it was filtered to afford Cap-144, step a (2.73 g, 81%) asa yellow solid which was used directly. Rt = 2.01 min (Cond.-D1); 95% homogenity index; LCMS: Anal. Calc. for [M+H]+C9H5Cl2N2O2: 242.97; found: 242.92.
81%
With sulfuric acid; nitric acid at 0 - 25℃; for 16.5h;
144.a
1,3-Dichloroisoquinoline (2.75 g, 13.89 mmol) was added in small portions to a cold (0° C.) solution of fuming nitric acid (10 mL) and concentrated sulfuric acid (10 mL). The mixture was stirred at 0° C. for 0.5 h before it was gradually warmed to 25° C. where it stirred for 16 h. The mixture was then poured into a beaker containing chopped ice and water and the resulting suspension was stirred for 1 h at 0° C. before it was filtered to afford Cap-144, step a (2.73 g, 81%) as a yellow solid which was used directly. Rt=2.01 min (Cond.-D1); 95% homogenity index; LCMS: Anal. Calc. for [M+H]+ C9H5Cl2N2O2: 242.97; found: 242.92.
With sulfuric acid; nitric acid at 0 - 25℃;
a
1,3-Dichloroisoquinoline (2.75 g, 13.89 mmol) was added in small portions to a cold (0° C.) solution of fuming nitric acid (10 mL) and concentrated sulfuric acid (10 mL). The mixture was stirred at 0° C. for 0.5 h before it was gradually warmed to 25° C. where it stirred for 16 h. The mixture was then poured into a beaker containing chopped ice and water and the resulting suspension was stirred for 1 h at 0° C. before it was filtered to afford Cap-144, step a (2.73 g, 81%) as a yellow solid which was used directly. Rt=2.01 min. (Cond.-D1); 95% homogenity index; LCMS: Anal. Calc. for [M+H]+ C9H5Cl2N2O2: 242.97; found: 242.92.
Stage #1: 1,3-dichloroisoquinoline With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.25h;
Stage #2: 1-iodo-2-methyl-2-propene In tetrahydrofuran at 20℃;
Stage #1: 1,3-dichloroisoquinoline With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2h;
Stage #2: With water-d2; hydrogen chloride In tetrahydrofuran
Stage #1: 1,3-dichloroisoquinoline With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.25h;
Stage #2: With iodine In tetrahydrofuran at 20℃;
With iodine; lithium diisopropyl amide In tetrahydrofuran at -78℃;
Stage #1: 1,3-dichloroisoquinoline With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.25h;
Stage #2: allyl iodid In tetrahydrofuran at 20℃;
Stage #1: 1,3-dichloroisoquinoline With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.25h;
Stage #2: benzoyl chloride In tetrahydrofuran at 20℃;
Stage #1: 1,3-dichloroisoquinoline With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.25h;
Stage #2: methyl trifluoromethanesulfonate In tetrahydrofuran at 20℃;
With N-Bromosuccinimide; sulfuric acid; In acetonitrile; at 20.0℃;
5-bromo-3-((4-fluorophenyl)sulfonyl)-N-(5-methyl-lH-pyrazol-3- vDisoq uinolin- 1-amine[00294] Step A: To 1,3-dichloroisoquinoline (5 g, 25.25 mmol) in acetonitrile(125 mL) were added concentrated sulfuric acid (5 mL) and N-bromosuccinimide (5.5 g. 29.41 mmol). The mixture was stirred at rt for 3 days, and then the solid precipitate was collected by filtration to afford 5-bromo-l,3-dichloroisoquinoline (2.8 g, 39%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-t ) delta ppm 7.54 (t, J=8.01 Hz, 1 H) 7.99 - 8.10 (m, 2 H) 8.32 (d, J=8.67 Hz, 1 H); LC-MS (ESI) m/z 278 (M+H)+.
With N-Bromosuccinimide; sulfuric acid; In acetonitrile; at 20.0℃; for 60.0h;
INTERMEDIATE 11 S-BROMO-l^-DIMETHOXYISOQUINOLINEStep A. 5-Brorno-l,3-dichloroisoquinolineTo a solution of 1,3-dichloroisoquinoline (1.0 g, 5.1 mmol) in CH3CN (25 mL) was added concentrated sulfuric acid ( 1.0 mL, 18 mmol), followed by N-bromosuccinimide (1.1 g, 6.1 mmol). The mixture was stirred at room temperature for 60 hours. The precipitate was collected by filtration, washed with water, then dried in air to afford the title compound: 1H15 NMR (500 MHz, CDCl3): delta 8.35 (d, J - 9.0 Hz, 1 H), 8.09 (s, 1 H), 8.08 (d, J = 9.0 Hz5 1 H), 7.57 (t, J - 8.0 Hz, 1 H). LC6: 3.74 min. (M+H): 278.
In tetrahydrofuran; n-heptane at 100℃; for 0.25h; Irradiation;
12.A
INTERMEDIATE 12 S-BROMO-S-METHOXY-l-METHYLISOQUINOLINE15Step A. 3-Chloro-l-methylisoquinolineA mixture of 1,3-dichloroisoquinoline (2.0 g. 10.1 mmol), trimethylaluminum 20 (2.0 M in heptane, 6.1 mL, 12.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (117 mg, 0.1 mmol) in THF (8 mL) was heated in a microwave reactor at 1000C for 15 min. After quenching by addition of water (30 mL), the mixture was extracted with EtOAc, The organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 10% EtOAc/hexanes to afford the title compound: 1H NMR (500 25 MHz, CDCl3): δ 8.12 (dd, J - 8.5, 0.5 Hz5 1 H); 7.76 (d, J - 8.0 Hz, 1 H); 7.10 (dt, J = 8.5, 0.5 Hz, 1 H), 7.62-7.60 (m, 2 H); 2.97 (s, 3H). LC6: 2.85 min, (M+H): 178. MRL DOB-0Q006
Stage #1: diethyl malonate With sodium hydride In 5,5-dimethyl-1,3-cyclohexadiene; mineral oil at 20 - 80℃; for 0.5h; Inert atmosphere;
Stage #2: 1,3-dichloroisoquinoline In 5,5-dimethyl-1,3-cyclohexadiene; mineral oil at 80 - 140℃; for 3h; Inert atmosphere;
10.A
Example 10Preparation of 3-(4-fluorophenylsulfonyl)-N-(5-methyl- lH-pyrazol-3- vDisoq uinolin- 1-amine[00249] Step A: To anhydrous MeOH (25 mL) was added portionwise sodium metal (436 mg, 18 mmol), and after the mixture was homogeneous, 1,3- dichloroisoquinoline (2.4 g, 12.1 mmol) in acetonitrile (20 mL) was added. The resulting mixture was heated at 65 °C for 1.5 h, and then concentrated under reduced pressure. The residue was partitioned between EtOAc and water and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over MgS04, filtered, and concentrated under reduced pressure to afford 3- chloro-l-methoxyisoquinoline as a pale yellow solid (2.2 g, 94%), which was used directly in the next step. JH NMR (300 MHz, DMSO-t/6) δ 8.16 (d, J= 9 Hz, 1H), 7.89 (d, J = 9 Hz, 1H), 7.81 (t, J= 7.0 Hz, 1H), 7.64 (t, J= 7.0 Hz, 1H), 7.57 (s, 1H), 4.08 (s, 3H); LC-MS (ESI) m/z 194 (M+H)+
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride In 1,2-dimethoxyethane at 90℃; regioselective reaction;
82%
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride In 1,2-dimethoxyethane Reflux;
81%
With tetrakis(triphenylphosphine) palladium(0) In 1,2-dimethoxyethane at 90℃; for 48h; regioselective reaction;
3 Method 1
Pd(PPh3)4 (0.80g, 0.67mmol) was added to a dry Schlenk tube containing anhydrous, degassed DME (100mL) followed by 1,3-dichloroisoquinoline 9 (4.45g, 22.5mmol) and the mixture stirred under nitrogen for 10min. Arylboronic acid 36 (4.6g, 25mmol) was then added as a solid followed by Cs2CO3 (7.5g, 50mmol). The mixture was then refluxed at 90°C for 2d after which time it was cooled to room temperature and water (100mL) and dichloromethane (100mL) were added. The organic layer was extracted and concentrated in vacuo to give a brown oil which was re-dissolved in dichloromethane (100mL), washed with water (30mL), brine (30mL), and then dried over Na2SO4. The solution was filtered and evaporated in vacuo to give an oil which was purified by column chromatography over silica gel (2:1, pentane:CH2Cl2) to yield the title compound 35 (5.54g, 81%). Rf=0.50, (3:1 pentane:EtOAc); m.p. 129-131°C; 1H NMR (300MHz; CDCl3) δ=7.91-7.83 (m, 4H), 7.68 (dt, 1H, J1=1.9Hz, J2=6.0Hz, J3=14.0Hz), 7.47-7.32 (m, 4H), 7.24 (dd, 1H, J1=7.0Hz, J2=8.2Hz), 6.98 (d, 1H, J=8.6Hz), 2.16 (s, 3H, CH3); 13C NMR (75MHz; CDCl3) 161.5 (4°), 145.2 (4°), 138.4 (4°), 134.5 (4°), 133.4 (4°), 132.7 (4°), 132.0 (4°), 131.3, 128.8, 128.6, 128.0, 127.7, 127.4, 127.2 (4°), 126.4, 126.3, 125.4, 125.1, 119.2, 20.2 (CH3); IR (KBr) νmax 3054, 1547, 1310, 1146, 1093, 965, 865, 812, and 742cm-1; HRMS (ES+): calculated for C20H14ClN, 304.0893, found 304.0892; C20H14ClN: calculated C, 79.07; H, 4.65; N, 4.61, found C, 78.79; H, 4.39; N, 4.53.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; In tetrahydrofuran; at 25℃; for 2.5h;Inert atmosphere;
General procedure: PdCl2(dppf), PdCl2(tbpf) and (A.caPhos)PdCl2. A mixture of the halogenated heterocycle (0.66 mmol) in anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes. Then, PdCl2(dppf) (27.0 mg, 0.033 mmol, 5.0 mol%), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature under argon for the proper time and then worked up as described above.
(S)-tert-butyl 3-((3-chloroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester With sodium hydride In 1-methyl-pyrrolidin-2-one at 0℃; for 0.0833333h;
Stage #2: 1,3-dichloroisoquinoline In 1-methyl-pyrrolidin-2-one at 20 - 135℃; for 0.583333h; Microwave irradiation;
5.A Step A: (S)-tert-butyl 3-((3-chloroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate
To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.134 g, 6.06 mmol) in NMP (10 mL) at 0° C. was added NaH (60%) (202 mg, 5.05 mmol). The mixture was stirred for 5 minutes and 1,3-dichloroisoquinoline (1.000 g, 5.05 mmol) was added. The reaction mixture was stirred at RT for 5 minutes and then heated at 135° C. for 30 minutes in a microwave reactor. The mixture was diluted with water (400 mL) and extracted with EtOAc (3*125 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with a gradient of 25-50% EtOAc in hexane to give the title compound (5.29 g, 75%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, J=14.16 Hz, 9H), 2.12-2.34 (m, 2H), 3.42-3.58 (m, 3H), 3.69 (td, J=12.33, 4.64 Hz, 1H), 5.63-5.76 (m, 1H), 7.59 (s, 1H), 7.64 (ddd, J=8.30, 7.08, 1.22 Hz, 1H), 7.81 (td, J=7.57, 1.46 Hz, 1H), 7.87-7.92 (m, 1H), 8.11-8.19 (m, 1H); ESI-MS m/z [M+H-tert-butyl]+ 293.5.
75%
Stage #1: (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester With sodium hydride In 1-methyl-pyrrolidin-2-one at 0℃; for 0.0833333h;
Stage #2: 1,3-dichloroisoquinoline In 1-methyl-pyrrolidin-2-one at 20 - 135℃; for 0.583333h; Microwave irradiation;
tert-butyl trans-3-hydroxy-4-methylpyrrolidine-1-carboxylate[ No CAS ]
tert-butyl trans-3-((3-chloroisoquinolin-1-yl)oxy)-4-methylpyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.2%
Stage #1: tert-butyl trans-3-hydroxy-4-methylpyrrolidine-1-carboxylate With sodium hydride In 1-methyl-pyrrolidin-2-one; mineral oil at 0 - 20℃; for 0.25h; Inert atmosphere;
Stage #2: 1,3-dichloroisoquinoline In 1-methyl-pyrrolidin-2-one; mineral oil at 135℃; for 0.5h; Microwave irradiation;
19.A Step A: tert-butyl trans-3-((3-chloroisoquinolin-1-yl)oxy)-4-methylpyrrolidine-1-carboxylate
To a 25 mL microwave vial was added N-methyl-2-pyrrolidinone (10.00 mL) and tert-butyl trans-3-hydroxy-4-methylpyrrolidine-1-carboxylate (1.118 g, 5.55 mmol). The mixture was cooled to 0° C. under a nitrogen atmosphere. To this mixture was added portion-wise NaH (60% suspension in mineral oil, 0.202 g, 5.05 mmol). After 5 minutes the mixture was allowed to warm to RT and was stirred for 10 minutes. Next, 1,3-dichloroisoquinoline (1 g, 5.05 mmol) was added and the reaction mixture was heated in a microwave reactor at 135° C. for 30 minutes. The reaction mixture was subsequently diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated onto silica. The crude product was purified by flash column chromatography (SiO2) eluting with a gradient of 5-50% heptane in EtOAc to give the title compound as a white solid (1.066 g, 58.2%). 1H NMR (500 MHz, CDCl3) δ ppm 1.16 (d, 3H), 1.48 (s, 9H), 2.60 (br s, 1H), 3.23 (br s, 1H), 3.49 (br s, 1H), 3.74 (br s, 1H), 3.94 (br s, 1H), 5.38 (br s, 1H), 7.23-7.32 (m, 1H), 7.51 (ddd, 1H), 7.61-7.71 (m, 2H), 8.17 (d, 1H); ESI-MS m/z [M+H]+ 307.6.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 90℃; for 12.0h;
10.0 g (50.5 mmol) of 1,3-dichloroisoquinoline, 31.2 g (111.1 mmol) of <strong>[929203-04-3]3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine</strong> and 2.9 g (2.5 mmol) of tetrakis(triphenylphosphine)palladium [Pd(PPh3)4] were dissolvedin 200 ml of tetrahydrofuran (THF) as a solvent, a solution obtained by dissolving 27.9 g (201.9 mmol) of potassiumcarbonate (K2CO3) in 100 ml of water, and the mixture was reacted at 90 C for 12 hours. After removing the solventunder a reduced pressure, the obtained reactant was washed with water and methanol. The residue was recrystallizedwith toluene, and the precipitated crystal was separated with a filter, washed with methanol and dried, obtaining 14.0 gof a white solid compound (a yield: 64 %). (calculation value: 435.52, measurement value: MS[M+1] 435.87)
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 90℃; for 12h;
4 Synthesis of Compound B-2
8.0 g (40.4 mmol) of 1,3-dichloroisoquinoline, 29.4 g (88.9 mmol) of 8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinoline and 2.3 g (2.0 mmol) of tetrakis(triphenylphosphine)palladium [Pd(PPh3)4] were dissolved in200 ml of tetrahydrofuran (THF) as a solvent, a solution obtained by dissolving 22.3 g (161.6 mmol) of potassiumcarbonate (K2CO3) in 100 ml of water was added thereto, and the mixture was reacted at 90 ° C for 12 hours. Afterremoving the solvent under a reduced pressure, the obtained reactant was washed with water and methanol. The residuewas recrystallized with toluene, and the precipitated crystal was separated with a filter, washed with methanol and dried,obtaining 15.0 g of a white solid compound (a yield: 69 %).
Stage #1: 1,3-dichloroisoquinoline With (diphenylphosphin)ferrocene; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0) In 1,4-dioxane at 23℃; for 0.0833333h; Inert atmosphere; Sealed tube;
Stage #2: 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-[1,3,2]dioxaborolane In 1,4-dioxane; water at 100℃; for 48h; Inert atmosphere; Sealed tube;
Stage #1: 1,3-dichloroisoquinoline With (diphenylphosphin)ferrocene; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0) In 1,4-dioxane at 23℃; for 0.0833333h; Inert atmosphere; Sealed tube;
Stage #2: 4,4,5,5-tetramethyl-2-(3-phenylpropyl)-[1,3,2]dioxaborolane In 1,4-dioxane; water at 100℃; for 18h; Inert atmosphere; Sealed tube;
Stage #3: phenylboronic acid In 1,4-dioxane; water at 100℃; for 18h; Inert atmosphere; Sealed tube;
N-[2-(1-adamantyloxy)ethyl]-3-chloroisoquinolin-1-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 24h; Inert atmosphere;
N-(Heteroaryl)-substituted adamantane-containing amines 16-46 (general procedure).
General procedure: A corresponding chloro-substitutedeteroarene (0.2-0.5 mmol), finely powdered K2CO3 (173 mg,1.25 mmol), DMF (1 mL), and a corresponding adamantane-containing amine (0.2-0.5 mmol) were placed into a one-neckflask equipped with a magnetic stirrer and reflux condenser and filled with dry argon, and the reaction mixture was stirred for 24 h at 140 °C. When the reaction was carried out with diamines 13 and 14 (0.5 mmol), 2,6-dichloropyrazine (186 mg, 1.25 mmol) and K2CO3 (345 mg, 2.5 mmol) were used. On the reaction completion, the mixture was cooled to room temperature, dichloromethane (5 mL) was added, a precipitate was filtered off and additionally washed with dichloromethane (5 mL), the commbined organic fractions were concentrated in vacuo, the residues were analyzed by NMR spectroscopy. If necessary, the products were purified by chromatography on silica gel, using the followwing sequence of eluents: light petroleum ether-CH2Cl2 (4 : 1 →1 : 4), CH2Cl2, CH2Cl2-MeOH (500 : 1 → 3 : 1). The target products were obtained as faintly colored or colorless dense oils or crystalline powders. The spectral data of compound 15 arer eported in the work.20
89%
With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 24h;
3.1. N-(Heteroaryl)-Substituted Adamantane-Containing Amines 5-7 (General Procedure)
General procedure: 3.1. N-(Heteroaryl)-Substituted Adamantane-Containing Amines 5-7 (General Procedure)A corresponding chlorosubstituted heteroarene (0.5-2 mmol), finely powdered anhydrousK2CO3 (1.25-8 mmol), DMF (1-4 mL), and a corresponding adamantane-containingamine 4 (0.5-2 mmol) were placed into a glass vial equipped with a magnetic stirrer andscrew tap, and the reaction mixture was stirred for 24 h at 140 °C. On the reaction completion,the mixture was cooled to room temperature, dichloromethane (5 mL) was added, aninorganic precipitate was filtered off and additionally washed with dichloromethane (5 mL),the combined organic filtrates were concentrated in vacuo, and the residues were analyzedby NMR spectroscopy. The products were purified by chromatography on silica gel, usingthe following sequence of eluents: hexanes-CH2Cl2 (4:1-1:4), CH2Cl2, CH2Cl2-MeOH(200:1-50:1).
N-[2-(1-adamantyl)ethyl]-3-chloroisoquinolin-1-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 24h; Inert atmosphere;
N-(Heteroaryl)-substituted adamantane-containing amines 16-46 (general procedure).
General procedure: A corresponding chloro-substitutedeteroarene (0.2-0.5 mmol), finely powdered K2CO3 (173 mg,1.25 mmol), DMF (1 mL), and a corresponding adamantane-containing amine (0.2-0.5 mmol) were placed into a one-neckflask equipped with a magnetic stirrer and reflux condenser and filled with dry argon, and the reaction mixture was stirred for 24 h at 140 °C. When the reaction was carried out with diamines 13 and 14 (0.5 mmol), 2,6-dichloropyrazine (186 mg, 1.25 mmol) and K2CO3 (345 mg, 2.5 mmol) were used. On the reaction completion, the mixture was cooled to room temperature, dichloromethane (5 mL) was added, a precipitate was filtered off and additionally washed with dichloromethane (5 mL), the commbined organic fractions were concentrated in vacuo, the residues were analyzed by NMR spectroscopy. If necessary, the products were purified by chromatography on silica gel, using the followwing sequence of eluents: light petroleum ether-CH2Cl2 (4 : 1 →1 : 4), CH2Cl2, CH2Cl2-MeOH (500 : 1 → 3 : 1). The target products were obtained as faintly colored or colorless dense oils or crystalline powders. The spectral data of compound 15 arer eported in the work.20
N-(1-adamantylmethyl)-3-chloroisoquinolin-1-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 24h;Inert atmosphere;
General procedure: A corresponding chloro-substitutedeteroarene (0.2-0.5 mmol), finely powdered K2CO3 (173 mg,1.25 mmol), DMF (1 mL), and a corresponding adamantane-containing amine (0.2-0.5 mmol) were placed into a one-neckflask equipped with a magnetic stirrer and reflux condenser and filled with dry argon, and the reaction mixture was stirred for 24 h at 140 C. When the reaction was carried out with diamines 13 and 14 (0.5 mmol), 2,6-dichloropyrazine (186 mg, 1.25 mmol) and K2CO3 (345 mg, 2.5 mmol) were used. On the reaction completion, the mixture was cooled to room temperature, dichloromethane (5 mL) was added, a precipitate was filtered off and additionally washed with dichloromethane (5 mL), the commbined organic fractions were concentrated in vacuo, the residues were analyzed by NMR spectroscopy. If necessary, the products were purified by chromatography on silica gel, using the followwing sequence of eluents: light petroleum ether-CH2Cl2 (4 : 1 ?1 : 4), CH2Cl2, CH2Cl2-MeOH (500 : 1 ? 3 : 1). The target products were obtained as faintly colored or colorless dense oils or crystalline powders. The spectral data of compound 15 arer eported in the work.20
With potassium <i>tert</i>-butylate; palladium diacetate; triphenylphosphine; potassium thioacetate In dimethyl sulfoxide at 120℃; Inert atmosphere;
30 Example 30
Under a nitrogen atmosphere,The substrate 1,3-dichloroisoquinoline 1u (0.2 mmol, 39.2 mg) was added to a 25 mL test tube reactor, KSAc(0.6mmol,68.4mg),DMC(1.0mmol,90mg),Pd(OAc)2(0.01mmol,2.3mg),PPh3 (0.02mmol,5.9mg),tBuOK(0.6mmol,69.2mg),and DMSO(2.0mL).The reaction was heated to 120 ° C to carry out the reaction.After the TLC detection reaction was completed,The system was cooled to room temperature.The reaction was quenched with saturated aqueous ammonium chloride,And extracted with ethyl acetate (3 * 10 mL)The product was purified by column chromatography to give product 2u 37.1 mg (51%).
51%
With potassium <i>tert</i>-butylate; palladium diacetate; triphenylphosphine; potassium thioacetate In dimethyl sulfoxide at 120℃; Schlenk technique; Inert atmosphere;
(S)-tert-butyl ((3-chloroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester With sodium hydride In 1-methyl-pyrrolidin-2-one at 0℃; for 0.0833333h;
Stage #2: 1,3-dichloroisoquinoline In 1-methyl-pyrrolidin-2-one at 135℃; for 0.5h; Microwave irradiation;
1.A STEP A: (^-tert-butyl -((3-chloroisoquinolin-l-yl)oxy)pyrrolidine-l-carboxylate
[0109] STEP A: (^-tert-butyl -((3-chloroisoquinolin-l-yl)oxy)pyrrolidine-l-carboxylate (0153) (0154) [0110] To {S)-tert-buty 3-hydroxypyrrolidine-l-carboxylate (1.134 g, 6.06 mmol) in MP (10 mL) at 0°C was added NaH (60%) (202 mg, 5.05 mmol). The mixture was stirred for 5 minutes and 1,3-dichloroisoquinoline (1.000 g, 5.05 mmol) was added. The reaction mixture was stirred at RT for 5 minutes and then heated at 135°C for 30 minutes in a microwave reactor. The mixture was diluted with water (400 mL) and extracted with EtOAc (3 x 125 mL). The organic layers were combined, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with a gradient of 25-50% EtOAc in hexane to give the title compound (5.29 g, 75%) 1H NMR (500 MHz, DMSO-i) δ ppm 1.40 (d, J=14.16 Hz, 9 H), 2.12-2.34 (m, 2 H), 3.42- 3.58 (m, 3 H), 3.69 (td, J=12.33, 4.64 Hz, 1 H), 5.63-5.76 (m, 1 H), 7.59 (s, 1 H), 7.64 (ddd, J=8.30, 7.08, 1.22 Hz, 1 H), 7.81 (td, J=7.57, 1.46 Hz, 1 H), 7.87-7.92 (m, 1 H), 8.11-8.19 (m, 1 H); ESI-MS m/z [M+H-tert-butyl]+ 293.5.
3-chloro-N-(pyridin-3-ylmethyl)-isoquinolin-1-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
In 1,4-dioxane at 100℃;
6 <Example 6> 3-Chloro -N- (pyridin-3-ylmethyl)-isoquinolin-1-amine
According to Scheme 6, 1,3-dichloroisoquinoline(100 mg, 0.505 mmol) was dissolved in 1,4-dioxane (1.5 ml) 3- (Aminomethyl) pyridine (0.0566 ml, 0.555 mmol) was added and the reaction was carried out according to the general preparation procedure 6 above.The intermediate was obtained by column chromatography. (24 mg, yield: 18%).
ethyl 2‐(1,3‐dichloroisoquinolin‐4‐yl)‐2‐hydroxyacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
322 mg
Stage #1: 1,3-dichloroisoquinoline With iodine; lithium diisopropyl amide In tetrahydrofuran at -78℃;
Stage #2: Ethyl oxalyl chloride With copper(I) bromide dimethylsulfide complex; isopropylmagnesium chloride In tetrahydrofuran at -15 - -10℃; for 0.5h;
Stage #3: With sodium tetrahydroborate; ethanol In tetrahydrofuran at 0℃; for 0.166667h;
Stage #1: 1,3-dichloroisoquinoline; C30H15F8N5O2Pd In dichloromethane at 20℃; for 0.0833333h;
Stage #2: o-iodo-methyl-benzoic acid With methyl bicyclo[2.2.1]hept-2-ene-2-carboxylate; silver(I) acetate; palladium diacetate; silver carbonate; N-acetylglycine at 80℃; for 18h; Sealed tube; regioselective reaction;
General procedure for the remote site-selective arylation of benzoazines. A
General procedure: reaction vial (8 ml) was charged with benzoazine (0.10 mmol, 1.0 equiv.), template-MeCN (0.10 mmol, 1.0 equiv.) and 0.2 ml dichloromethane. The mixture was stirred for 5 min at room temperature, and then concentrated in vacuo. Pd(OAc)2 (2.2 mg,10 μmol, 10 mol%), Ac-Gly-OH (2.3 mg, 20 μmol, 20 mol%), aryl iodide (0.3 mmol,3 equiv.), AgOAc (50 mg, 0.30 mmol, 3.0 equiv.), Ag2CO3 (27.6 mg, 0.1 mmol,1.0 equiv.), NBE-CO2Me (22.8 mg, 0.15 mmol, 1.5 equiv.) and HFIP (1.5 ml) were added. The reaction vial was sealed and allowed to stir at 80 °C for 18 h. The reaction mixture was cooled to room temperature. Then a solution of DMAP (36.7 mg, 0.3 mmol, 3 equiv.) in toluene (1.5 ml) was added. The mixture was stirred at 80 °C for 15 min. The reaction mixture was cooled to room temperatureand diluted with EtOAc. The mixture was filtered through a short pad of celite and eluted with EtOAc (2 × 2 ml). The filtrate was evaporated under reduced pressure. (If the product release was not complete, a solution of DMAP (18.4 mg,0.15 mmol, 1.5 equiv.) in toluene (1.5 ml) was added; the solution was then stirredat 80 °C for 15 min and then concentrated.) Purification by preparative thin-layer chromatography afforded the title compound
methyl 1,3-dichloroisoquinoline-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: 1,3-dichloroisoquinoline With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: methyl chloroformate In tetrahydrofuran at -78℃; for 1h;
130.130A Preparation 130A: Methyl l,3-dichloroisoquinoline-4-carboxylate
To a solution of 1,3-dichloroisoquinoline (2 g, 10.10 mmol) in THF (40 mL) at - 78 °C was added LDA (5.55 mL, 11.11 mmol) dropwise. After stirring for 30 minutes at this temperature, methyl carbonochloridate (1.017 mL, 13.13 mmol) was added. The mixture was stirred for an additional hour and then slowly warmed to room temperature. The reaction was quenched with ice-water. The reaction mixture was diluted with EtOAc. The organic layer was separated, washed with brine and dried with sodium sulfate. The solvents were removed under reduced pressure and the residue was purified using an 80 gram silica gel column by ISCO eluting with 5-100% DCM/hexanes to afford Preparation 130A (2.34 g, 9.14 mmol, 90 % yield). NMR (400 MHz, CHLOROFORM-d) d 8.41 (d, J= 8.2 Hz, 1H), 7.90-7.82 (m, 2H), 7.79-7.74 (m, 1H), 4.11 (s, 3H).
1.1 The first step:
Compound 1a (39.4 g, 200.0 mmol), compound 1b (31.8 g, 200.0 mmol), cesium carbonate (129.6 g, 400.0 mmol) were dissolved in N,N-dimethylformamide (300 mL), The temperature was raised to 80°C, and the reaction was monitored by TLC. After the reaction was completed, water (300 mL) was added to quench the reaction, extracted with ethyl acetate (300 mL×2), the organic layers were combined, the organic layers were dried, concentrated, and separated by column chromatography to obtain a pale yellow solid ( Intermediate 1c) 43.5 g. Wherein, the structural formula of compound 1a is shown in formula 1a, and the others are deduced by analogy.
3-chloro-1-(3,5-dimethylphenyl)isoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With tetrakis-(triphenylphosphine)-palladium; caesium fluoride In 1,2-dimethoxyethane at 80℃; for 19h; Inert atmosphere;
IV.1 Step 1: 3-Chloro-1-(3,5-dimethylphenyl)isoquinoline
A pressure tube was charged with 1,3-dichloroisoquinoline (200 mg, 1.010 mmol), (3,5-dimethylphenyl)boronic acid (200 mg, 1.333 mmol), Pd(PPh3)4 (47 mg, 0.04067 mmol), CsF (338 mg, 2.225 mmol), and 1,2-dimethoxyethane (1.5 mL). The mixture was degassed by flow of nitrogen and heated at 80 °C for 19 h. EtOAc and water were added to the reaction and the two layers were separated. The organic layer was washed with brine (x 2), dried over Na2SO4, filtered through a plug of Celite and concentrated. The crude product was purified on 24 g of silica gel utilizing a gradient of 0-15% ethyl acetate in hexane to yield 3-chloro-1-(3,5- dimethylphenyl)isoquinoline (230 mg, 85%) as a colorless viscous liquid. ESI-MS m/z calc. 267.08148, found 268.1 (M+1)+; Retention time: 2.17 minutes (LC method A).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
120K+ Compounds
Competitive Price
1-2 Day Shipping
