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CAS No. : | 23687-26-5 | MDL No. : | MFCD04114862 |
Formula : | C9H8N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NGFCTYXFMDWFRQ-UHFFFAOYSA-N |
M.W : | 144.17 | Pubchem ID : | 588991 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 46.15 |
TPSA : | 38.91 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.06 cm/s |
Log Po/w (iLOGP) : | 1.29 |
Log Po/w (XLOGP3) : | 1.57 |
Log Po/w (WLOGP) : | 1.82 |
Log Po/w (MLOGP) : | 0.92 |
Log Po/w (SILICOS-IT) : | 1.77 |
Consensus Log Po/w : | 1.47 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.4 |
Solubility : | 0.58 mg/ml ; 0.00402 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.0 |
Solubility : | 1.45 mg/ml ; 0.0101 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.32 |
Solubility : | 0.0693 mg/ml ; 0.000481 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.01 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H319 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | at 80℃; for 0.75 h; Microwave irradiation | A mixture of 1u (100 mg, 0.81 mmol), hydrazine hydrate (121.5mg, 2.43 mmol), and SS-Rh (370 mg, 2 molpercent Rh) were taken in an oven dried reaction tube equipped with screw cap. 0.5 ml of PEG-400 was added into the reaction mixture. The reaction was then irradiated in a microwave apparatus at 80°C , 80 W for 10 min with a pressure of 80 Psi. After cooling to ambient temperature in the microwave cavity the reaction mixture was extracted with ethyl acetate (3x2 ml) and water (1ml). The combined organic layer wasdried over anhydrous Na2SO4 and the solvent was removed under reduced pressure and after purificationwith silica gel column chromatography (hexane: EtOAc= 90:10) 2u asyellowish liquid (63 mg, 80percent).1H and 13C NMR spectra hasbeen compared with our previously reported study |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With ammonium hydroxide; copper(ll) sulfate pentahydrate In water at 190℃; for 6 h; | Reference Example 1 Synthesis of 6-aminoisoquinoline (Reference Compound 1) 6-bromoisoquinoline that weighed 17.2 g (see WO 2008/077553), 200 mL of 28percent ammonia water and 10.8 g of copper (II) sulfate pentahydrate were put into the autoclave and tightly sealed, and the mixture was then stirred at 190° C. for 6 hours. After cooling to room temperature, the reaction solution was poured into 250 mL of a 10percent aqueous sodium hydroxide solution, followed by extraction with ethyl acetate (100 mL*5). The extract was dried over anhydrous sodium sulfate, filtered, and then concentrated. The obtained crude product was suspended in dichloromethane and then filtered to obtain 10.2 g of the compound of interest as a light brown crystal (85percent). 1H-NMR spectrum (CDCl3, δ ppm): 5.54 (br s, 2H), 6.58 (s, 1H), 7.00 (d, J=9.0 Hz, 1H), 7.35 (d, J=5.5 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 8.32 (d, J=5.5 Hz, 1H), 8.98 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.4% | With tris-(dibenzylideneacetone)dipalladium(0) In dimethyl sulfoxide; ethyl acetate; Petroleum ether | Step 3. Synthesis of 6-amino isoquinoline (#E3). A solution of #A2 (4.0 g, 51.7 mmol), 6-bromoisoquinoline-1-carbonitrile #A3 (6.0 g, 25.9 mmol), BINAP (3.2 g, 5.2 mmol), Pd2(dba)3 (2.3 g, 2.6 mmol) and potassium phosphate (11.0 g, 51.7 mmol) in anhydrous DMSO (35 mL) was heated at 80° C. for 2 h. The complete disappearance of the 6-bromoisoquinoline-1-carbonitrile #A3 was observed on TLC. The reaction mixture was cooled to room temperature, filtered through Celite™ pad and the filtrate was diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL*3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude material which was purified by silica gel (100-200 mesh) column chromatography using 40percent EtOAc in petroleum ether as an eluting system to give #E3 as yellow solid (1.5 g, 25.4percent). Rf: 0.4 (60percent EtOAc in petroleum ether). LCMS m/z=227.9 (M+H); 1H NMR (400 MHz, d6-DMSO): δ 1.18 (d, J=6.8 Hz, 3H), 3.36-3.47 (m, 1H), 3.48-3.53 (m, 1H), 3.60-3.66 (m, 1H), 6.80-6.82 (m, 2H), 7.32 (dd, J=2.4 Hz, 8.8 Hz, 1H), 7.72 (d, J=5.6 Hz, 1H), 7.87 (d, J=9.6 Hz, 1H), 8.30 (d, J=5.6 Hz, 1H). |
24.3% | With tris-(dibenzylideneacetone)dipalladium(0) In dimethyl sulfoxide | Step 3. Synthesis of 6-amino isoquinoline (#F3). A solution of #F2 (4.5 g, 51.7 mmol), 6-bromoisoquinoline-1-carbonitrile (6.0 g, 25.9 mmol), BINAP (3.2 g, 5.1 mmol), Pd2(dba)3 (2.3 g, 2.6 mmol) and potassium phosphate (11.0 g, 51.7 mmol) in anhydrous DMSO (35 mL) was heated at 80° C. for 2 h. The complete disappearance of the 6-bromoisoquinoline-1-carbonitrile was observed on TLC. The reaction mixture was cooled to room temperature, filtered through a Celite™ pad and the filtrate was diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL*3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude material. The product was purified by chromatography on silica gel (100-200 mesh) using 10percent MeOH in DCM as eluant to give racemic #F3 as yellow solid (1.5 g, 24.3percent). Rf: 0.4 (50percent EtOAc in petroleum ether). Chiral HPLC: two enantiomers (61.0percent, 39.0percent). LCMS m/z=240.1 (M+H). H NMR (400 MHz, d6-DMSO): δ 2.19-2.27 (m, 1H), 2.36-2.45 (m, 1H), 3.67-3.84 (m, 3H), 4.02-4.07 (m, 1H), 4.33-4.39 (m, 1H), 5.09 (t, J=4.8 Hz, 1H), 6.83 (d, J=1.6 Hz, 1H), 7.33 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 7.78 (d, J=6.4 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 8.36 (d, J=5.6 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With hydrazine hydrate; at 80℃; under 4137.29 Torr; for 0.75h;Microwave irradiation; | A mixture of 1u (100 mg, 0.81 mmol), hydrazine hydrate (121.5mg, 2.43 mmol), and SS-Rh (370 mg, 2 molpercent Rh) were taken in an oven dried reaction tube equipped with screw cap. 0.5 ml of PEG-400 was added into the reaction mixture. The reaction was then irradiated in a microwave apparatus at 80°C , 80 W for 10 min with a pressure of 80 Psi. After cooling to ambient temperature in the microwave cavity the reaction mixture was extracted with ethyl acetate (3x2 ml) and water (1ml). The combined organic layer wasdried over anhydrous Na2SO4 and the solvent was removed under reduced pressure and after purificationwith silica gel column chromatography (hexane: EtOAc= 90:10) 2u asyellowish liquid (63 mg, 80percent).1H and 13C NMR spectra hasbeen compared with our previously reported study |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In pyridine; water; | Preparation Example 21 6-(4-Toluenesulfonylamino) isoquinoline In pyridine (30 ml) was dissolved <strong>[23687-26-5]6-aminoisoquinoline</strong> (3.348 g, Synthesis, 733 (1975), and 4-toluenesulfonyl chloride (5.13 g) was added thereto, followed by stirring at room temperature overnight. Water was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was recrystallized from ethanol, to give the title compound (5.958 g, 85%) as pale yellow crystals. 1H-NMR (DMSO-d6) delta (ppm): 2.28 (3H, s), 7.32 (2H, d, J=8.2 Hz), 7.40 (1H, dd, J=1.6, 9.2 Hz), 7.55 (1H, brs), 7.67 (1H, d, J=5.6 Hz), 7.74 (2H, d, J=8.2 Hz), 7.97 (1H, d, J=9.2 Hz), 8.36 (1H, d, J=5.6 Hz), 9.10 (1H, s). |
85% | In pyridine; water; | Production Example 21b 6-(4-Toluenesulfonylamino)isoquinoline 6-Aminoisoquinoline (3.348 g, Synthesis, 733 (1975)) was dissolved in pyridine (30 ml). To the mixture was added 4-toluenesulfonyl chloride (5.13 g), followed by stirring at room temperature overnight. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was recrystallized from ethanol, to give the title compound (5.958 g, 85%) as pale yellow crystals. 1H-NMR (DMSO-d6) delta (ppm): 2.28(3H, s), 7.32(2H, d, J = 8.2 Hz), 7.40(1H, dd, J = 1.6, 9.2 Hz), 7.55(1H, brs), 7.67(1H, d, J = 5.6 Hz), 7.74(2H, d, J = 8.2 Hz), 7.97(1H, d, J = 9.2 Hz), 8.36(1H, d, J = 5.6 Hz), 9.10(1H, s). |
85% | In pyridine; water; | PRODUCTION EXAMPLE 21b 6-(4-Toluenesulfonylamino)isoquinoline 6-Aminoisoquinoline (3.348 g, Synthesis, 733 (1975)) was dissolved in pyridine (30 ml). To the mixture was added 4-toluenesulfonyl chloride (5.13 g), followed by stirring at room temperature overnight. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was recrystallized from ethanol, to give the title compound (5.958 g, 85%) as pale yellow crystals. 1H-NMR (DMSO-d6) delta (ppm): 2.28(3H, s), 7.32(2H, d, J=8.2 Hz), 7.40(1H, dd, J=1.6, 9.2 Hz), 7.55(1H, brs), 7.67(1H, d, J=5.6 Hz), 7.74(2H, d, J=8.2 Hz), 7.97(1H, d, J=9.2 Hz), 8.36(1H, d, J=5.6 Hz), 9.10(1H, s). |
2.2 g | With pyridine; at 20℃; for 12h; | Isoquinolin-6-amine B24 (2.00 g, 13.87 mmol) was dissolved in pyridine (20 mL), and 4- methylbenzenesulfonyl chloride (3.17 g, 16.64 mmol) was added. The reaction mixture was stirred at 20C for 12 hours. LCMS showed the reaction was completed. To the reaction mixture was added water (30 mL) under good stirring, the mixture was stirred at 20C for 0.5 hour, pale yellow solid precipitated out. The mixture was filtered and the solid was collected and washed with water (5 mL) to give compound B25 (2.2g) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-carbonyldiimidazole; In N-methyl-acetamide; dichloromethane; ethyl acetate; | EXAMPLE II N-(2-Hydroxyethyl)-N'-(isoquinolin-6-yl)-N-[4-[2-(methoxycarbonyl)ethyl]phenyl]-urea To 7.2 g of imidazole and 10.1 g of N,N'-carbonyldiimidazole in 100 ml of dimethylformamide are added dropwise, at a temperature of 0° to 10° C., 9.0 g of <strong>[23687-26-5]6-aminoisoquinoline</strong> in 70 ml of dimethylformamide. After 2 hours stirring at ambient temperature, 15.3 g of N-(2-hydroxyethyl)-4-[2-(methoxycarbonyl)ethyl]aniline in 20 ml of dimethylformamide are added dropwise and the mixture is stirred for 21/2 days at ambient temperature. The mixture is diluted with 750 ml of ethyl acetate and extracted twice with water and saturated saline solution. The organic phase is separated off, dried and evaporated down. The residue is purified by chromatography over a silica gel column using ethyl acetate/methylene chloride/methanol=70:30:10. Yield: 4.8 g (19percent of theory), Rf value: 0.48 (silica gel; methylene chloride/methanol/ethyl acetate=20:1:1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2h; | To a mixture of Intermediate 25.2 (0.054 mmol) in 1 mL CH3CN at rt, were added DIEA (14 muL, 0.082 mmol) and <strong>[23687-26-5]6-aminoisoquinoline</strong> (15.7 mg, 0.109 mmol). The mixture was stirred at rt for 2 h, then was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100percent EtOAc/hexanes gradient) to afford 22.5 mg of Intermediate 25.3 as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With pyridine; In dichloromethane; | (e) Benzenesulphonyl chloride (4.9 g, 0.028M) in CH2 Cl2 (15 ml) was added dropwise over 10 minutes to a cooled stirred mixture of <strong>[23687-26-5]6-aminoisoquinoline</strong> (4.0 g, 0.028M) and pyridine (2.37 g, 0.03M) in CH2 Cl2 (150 ml). The reaction mixture was stirred overnight at room temperature and was then washed with H2 O. The CH2 Cl2 solution was dried over MgSO4 and was then chromatographed on a silica gel column. After evaporation the residue was recrystallized from isopropanol to yield 6-phenylsulphonamidoisoquinoline (2.28 g, 33percent), m.p. 204°-6° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In chloroform; | Synthetic Example 84b 6-(4-Chlorobenzenesulfonylamino)-1-cyanoisoquinoline The compound obtained using <strong>[23687-26-5]6-aminoisoquinoline</strong> (0.5 g, Synthesis, 733 (1975)) and 4-chlorobenzenesulfonyl chloride (0.88 g) in the same method as in Synthetic Example 1b was dissolved in chloroform (150 ml). Under ice-cooling, m-chloroperbenzoicacid (0.9 g) was added theterto, followed by stirring at room temperature overnight. The solvent was evaporated, and the resulting crystals were washed with diethyl ether, collected by filtration and dried, to give 6-(4-chlorobenzenesulfonylamino)isoquinoline-N-oxide (1.072 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With lithium diisopropyl amide; In tetrahydrofuran; at -78 - 20℃; for 0.5h; | Step 1: Synthesis of 2-Chloro-7V-isoquinolin-6-yl-acetamide: A 2.0- mL vial equipped with a stirrer bar was charged with <strong>[23687-26-5]6-aminoisoquinoline</strong> (100 mg, 0.7 mmol) in THF (1.0 niL) and cooled to -78 °C. Lithium diisopropylamine (40 muL, 0.35 mmol) was added to the reaction at -78 °C followed by dropwise addition of chloroacetylchloride (62 muL, 0.7 mmol). The reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was concentrated in vacuo then the solid was triturated with cold methanol. The solid was collected by filtration to afford 2-chloro-iV-isoquinolin-6-yl-acetamide (58 mg, 38percent). 1H NMR (400 MHz, DMSCW6) delta ppm 3.14 (s, 2H) 8.01 (dd, J=9.08, 1.66 Hz, IH) 8.45 (d, J-8.98 Hz, 2H) 8.66 (d, J=1.56 Hz, IH) 11.46 (s, IH); LCMS: 221 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 40℃; | To a solution of <strong>[23687-26-5]6-aminoisoquinoline</strong> (25 mg, 0.17 mmol) in DMF (1.0 mL) was added indoline-2-carboxylic acid (30 mg, 0.17 mmol), HATU (70 mg, 0.19 mmol), diisopropylethylamine (35 muL, 0.19 mmol) and stirred overnight at 40 °C. The reaction mixture was concentrated and purified by prep-HP LC to afford the titled compound (3.0 mg): 1H NMR (400 MHz, METHANOL-^) delta ppm 3.18 (dd, J=16.11, 8.30 Hz, IH) 3.56 (dd, J=16.20, 10.54 Hz, IH) 4.52 (dd, J-10.54, 8.40 Hz, IH) 6.70 - 6.81 (m, 2H) 6.99 - 7.10 (m, 3H) 7.73 (d, J=6.05 Hz, IH) 7.81 (dd, J=8.88, 2.05 Hz, IH) 8.05 (d, J=8.98 Hz, IH) 8.35 (d, J=5.86 Hz, IH) 8.40 (d, J-1.95 Hz, IH) 9.11 (s, IH); LCMS: 290 (M+H).[00178] This isoquinoline was also tested using the luciferase biochemical assay. The maximum inhibition was 110percent for GRK-2. The results in Ki (nM) using the scale above were as follows: GRK-2 - ++ GRK-3 - ++ GRK-5 - + EPO <DP n="39"/>GRK-6 - +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 2 Preparation of N-(isoquinolin-6-yl)-3-phenylpropanamide (E2) To <strong>[23687-26-5]6-aminoisoquinoline</strong> in DMF cooled to 0° C. was added NaH and the solution was stirred for 30 minutes at 0° C. Then hydrocinnamoyl chloride was added and the mixture was stirred for 4 hours at room temperature. The mixture was diluted with EtOAc, extracted with NaHCO3(sat), dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 10percent hexanes/EtOAc) gave N-(isoquilin-6-yl)-3-phenylpropanamide (E2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In N,N-dimethyl-formamide; at 20℃; for 4h; | EXAMPLE 88 Preparation of 1-benzyl-3-(isoquinolin-6-yl)urea (E88) To <strong>[23687-26-5]6-aminoisoquinoline</strong> in DMF is added DMAP and benzyl isocyanate and the solution was stirred at room temperature for 4 hours. The mixture was poured into NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Flash chromatography (SiO2, 5percent MeOH/CH2Cl2) provided 1-benzyl-3-(isoquinolin-6-yl) urea (E88). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 8h; | EXAMPLE 39 Preparation of tert-butyl 2-(isoquinolin-6-ylamino)-2-oxoethyl carbamate (F39) To N-Boc-glycine in DMF was added EDC, HOBT and <strong>[23687-26-5]6-aminoisoquinoline</strong>. This mixture was stirred for 8 hours. The reaction was washed with NaHCO3(sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, MeOH/CH2Cl2) gave tert-butyl 2-(isoquinolin-6-ylamino)-2-oxoethyl carbamate (E39). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 87 Preparation of benzylisoquinolin-6-ylcarbamate (E87) To <strong>[23687-26-5]6-aminoisoquinoline</strong> in DMF at -40° C. was added NaH and solution was warmed to 0° C. for 30 minutes. Then benzylchloroformate was added and the reaction stirred at 0° C. for 2 hours. The solution was quenched with AcOH, poured into NaHCO3(sat) and extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Flash chromatography (SiO2 90percent EtOAc/Hex) gave benzylisoquinolin-6-ylcarbamate. (E87). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 4h; | EXAMPLE 1 Preparation of 2-chloro-N-(isoquinolin-6-yl) acetamide (E1) To chloroacetic acid in DMF was added EDC, DMAP and <strong>[23687-26-5]6-aminoisoquinoline</strong>. This mixture was stirred for 4 hours. The reaction was washed with NaHCO3(sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5percent MeOH/CH2Cl2) gave 2-chloro-N-(isoquinolin-6-yl)acetamide (E1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h; | The intermediate acid (0.14 mmol) was dissolved in 0.8 ml anhydrous DMF under nitrogen. 1.6 Eq. EDC was added followed by 0.08 eq. DMAP and 1.3 eq. <strong>[23687-26-5]6-aminoisoquinoline</strong> and the reaction left at room temperature for 3 hours. The reaction was poured into water and extracted with EtOAc. The combined organic layers were washed once with water, dried over Na2SO4, filtered and concentrated. The compound was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To <strong>[23687-26-5]6-aminoisoquinoline</strong> in DMF at 0° C. is added NaH. After 30 min, chlorosulfonyl chloride is added to the reaction. After 2-4 hours at rt or when TLC indicates completion, the reaction is quenched by the addition of water and extracted with EtOAc. The combined organics are washed with brine and dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5percent MeOH/CH2Cl2) gives 1-chloro-N-(isoquinolin-6-yl) methanesulfonamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; | The intermediate acid was dissolved in 1 mL anhydrous DMF under nitrogen. 1.6 eq. EDC was added followed by 0.08 eq. DMAP and 1.3 eq. <strong>[23687-26-5]6-aminoisoquinoline</strong> and the reaction left at room temperature over night. Reaction was poured into water and extracted with EtOAc. The combined organic layers were washed once with water, dried over MgSO4, filtered and concentrated. The final compound E117d was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 118 Synthesis of 4-(2-(isoquinolin-6-ylcarbamoyl) cyclopropyl)-N-(pyridin-4-yl)benzamide (E118) Using the procedures in Example 117, Intermediate 118a was prepared. 1.2 Eq. of <strong>[23687-26-5]6-aminoisoquinoline</strong> was suspended in 0.5 ml toluene in a dry flask under nitrogen. 1.2 eq of 2.0M trimethylaluminum in heptane was added dropwise. After one hour all the suspended material has dissolved. This solution was added to 0.1 mmol of intermediate 118a suspended in 0.5 ml toluene under nitrogen. The reaction is heated at 80° C. overnight. Sat. aq. Rochelle's salt was added to the reaction and this was stirred vigorously for 30 minutes. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried over MgSO4, filtered and concentrated. The compound E118b was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; | A 5 mL microwave reaction vial was charged with methyl 2-(4-ethynylphenoxy)acetate, 1-(azidomethyl)-4-chlorobenzene, t-BuOH, copper turnings and copper sulfate. The reaction was heated under microwave conditions at 125° C. for 25 minutes. The reaction was cooled to room temperature and poured into water. The reaction was extracted with CH2Cl2. The combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated. Flash chromatography (SiO2, Hexanes/EtOAc) gave 2-(4-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenoxy)-N-(isoquinolin-6-yl)-acetamide (E148). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; | A solution of methyl 2-(4-(2H-tetrazol-5-yl)phenoxy)acetate in acetone was treated with triethylamine and stirred at room temperature for 20 minutes. Benzyl bromide was added and stirred for 18 hours at 60° C. The solvent was removed and the residue was purified by reverse phase preparative HPLC to give 2-(4-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenoxy)-N-(isoquinolin-6-yl)-acetamide (E149). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h; | The intermediate acid (0.12 mmol) was dissolved in anhydrous DMF under nitrogen. 1.6 eq. EDC was added followed by 0.08 eq. DMAP and 1.3 eq. <strong>[23687-26-5]6-aminoisoquinoline</strong> and the reaction left at room temperature for 3 hours. Reaction was poured into water and extracted with EtOAc. The combined organic layers were washed once with water, dried over MgSO4, filtered and concentrated. The compound E206b was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; | The intermediate acid was dissolved in anhydrous DMF under nitrogen. 1.6 eq. EDC was added followed by 0.08 eq. DMAP and 1.3 eq. <strong>[23687-26-5]6-aminoisoquinoline</strong> and the reaction left at room temperature over night. Reaction was poured into water and extracted with EtOAc. The combined organic layers were washed once with water, dried over MgSO4, filtered and concentrated. The compound (E208b) was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; | Scheme 20 describes an example for the preparation of a parallel synthesis library of polyamine EPIs. Thus the carboxylic acid CXXXII was coupled using standard methods with a variety of CAP amines CXXXIII to give the polyamine EPI CXXXIV. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 4h; | Example 7 Preparation of (R)-tert-butyl 2-(isoquinolin-6-ylamino)-2-oxo-1-phenylethyl(methyl)carbamate (E7) To (R)-2-(tert-butoxycarbonyl(methyl)amino)-2-phenylacetate (E6) in DMF was added EDC, DMAP and <strong>[23687-26-5]6-aminoisoquinoline</strong>. This mixture was stirred for 4 hours and the reaction was washed with NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, Hexanes/EtOAc) gave pure (R)-tert-butyl 2-(isoquinolin-6-ylamino)-2-oxo-1-phenylethyl(methyl)carbamate (E7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 4h; | Example 1 Preparation of (R)-tert-butyl-2-(isoquinolin-6-ylamino)-2-oxo-1 phenyl-ethylcarbamate (E1) To (R)-2-Boc-2-phenylacetic acid in DMF was added EDC, dimethyl aminopyridine ("DMAP") and <strong>[23687-26-5]6-aminoisoquinoline</strong>. This mixture was stirred for 4 hours and the reaction was washed with NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, Hexanes/EtOAc) gave pure (R)-tert-butyl-2-(isoquinolin-6-ylamino)-2-oxo-1 phenyl-ethylcarbamate (E1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 50 Preparation of N-(isoquinolin-6-yl)cyclohexylamino phenylmethanesulfonamide. (E50) To <strong>[23687-26-5]6-aminoisoquinoline</strong> in DMF at 0° C. is added NaH. After 30 min, chloro(phenyl)methylsulfonyl chloride is added to the reaction. After 2-4 hours at rt or when TLC indicates completion, the reaction is quenched by the addition of water and extracted with EtOAc. The combined organics are washed with brine and dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5percent MeOH/CH2Cl2) gives 1-chloro-N-(isoquinolin-6-yl)phenylmethanesulfonamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 105℃; for 18h;Inert atmosphere; | Intermediate 6 (50 mg, 0.148 mmol), Isoquinolin-6-ylamine (26 mg, 0.178 mmol), tris(dibenzylideneacetone)dipalladium(0) (8 mg, 0.009 mmol), xantphos (7 mg, 0.012 mmol) and <n="148"/>sodium tert-butoxide (43 mg, 0.44 mmol) were combined with dioxane (3 ml), sealed and then purged with nitrogen gas. The reaction mixture was heated at 1050C for 18 h, evaporated and purified through a silica plug, eluting with 0 to 10percent methanol/DCM. Further purification by preparative LCMS (high pH buffer) gave the desired product as a white solid (15 mg, 23percent). 1H NMR (400 MHz, DMSO-^6) delta ppm 0.42 - 0.50 (m, 2 H), 0.78 - 0.86 (m, 2 H), 1.41 - 1.52 (m, 1 H), 1.71 - 1.81 (m, 2 H), 3.24 - 3.31 (m, 2 H), 3.36 - 3.45 (m, 2 H), 6.81 - 6.89 (m, 1 H), 7.13 (dd, 7=4.8, 3.9 Hz, 1 H), 7.54 - 7.63 (m, 2 H), 7.70 - 7.76 (m, 3 H), 8.02 (d, /=6.4 Hz, 1 H), 8.24 (dd, /=7.8, 0.9 Hz, 1 H), 8.43 (d, /=6.0 Hz, 1 H), 8.48 - 8.55 (m, 1 H), 8.90 (s, 1 H), 9.23 (s, 1 H); m/z (ES+APCI)+: 445 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; | (E48) To 3-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)propanoic acid (E47) in pyridine was added EDC, DMAP, and <strong>[23687-26-5]6-aminoisoquinoline</strong>. The solution was stirred overnight at room temperature. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 3percent MeOH/CH2Cl2) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(thiophen-3-yl) propylcarbamate (E48). | |
With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃;Product distribution / selectivity; | 7e/t-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(thiophen-3-yl)propylcarbamate (E432) was prepared from E431 according to the below:To 3-(terf-butoxycarbonylamino)-2-(thiophen-3-yl)propanoic acid (E431 ) in pyridine was added was added EDC, DMAP, and <strong>[23687-26-5]6-aminoisoquinoline</strong>, and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(Sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 3percentMeOH/CH2CI2) gave pure te/t-butyl 3-(isoquinolin-6-ylamino)-3- oxo-2-(thiophen-3-yl) propylcarbamate (E432). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 10h; | (E5) To 3-(tert-butyoxcarbonylamino)-3-(thiophen-3-yl)propanoic acid (E4) in pyridine was added EDC, DMAP, and <strong>[23687-26-5]6-aminoisoquinoline</strong>. The solution was stirred for 10 hours at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5percent MeOH/CH2Cl2) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-1-(thiophen-3-yl)propylcarbamate (E5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 44 Preparation of 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E44) To 3-(dimethylamino)-2-(thiophen-3-yl)propanoic acid (E43) in pyridine was added EDC, DMAP, and <strong>[23687-26-5]6-aminoisoquinoline</strong>. The solution was stirred overnight at room temperature. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5-20percent MeOH/CH2Cl2) gave pure 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide. The pure compound was taken up in CH2Cl2 and HCl was added. The solvents were evaporated to give pure 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E44). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 10h; | Preparation of tert-butyl 4-(isoquinolin-6-ylamino)-4-oxo-1-(thiophen-3-yl)butylcarbamate (E73E) To 4-(tert-butyoxcarbonylamino)-4-(thiophen-3-yl)butanoic acid (E73D) in pyridine is added EDC, DMAP and <strong>[23687-26-5]6-aminoisoquinoline</strong> and the solution is stirred for 10 hours at room temperature. The mixture is poured into NaHCO3 (sat) and extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5percent MeOH/CH2Cl2) gives pure tert-butyl 4-(isoquinolin-6-ylamino)-4-oxo-1-(thiophen-3-yl)butylcarbamate (E73E). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;Inert atmosphere; | To 2-(2-carboxy-2-(4-(triisopropylsilyloxy)phenyl)ethylcarbamoyl) benzoic acid (E4) in pyridine was added EDC, DMAP, and <strong>[23687-26-5]6-aminoisoquinoline</strong>, and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into EtOAc/NaHCO3(Sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography 5percent MeOH/CH2CI2 gave pure 3-(1 ,3- dioxoisoindolin-2-yl)-Lambda/-(isoquinolin-6-yl)-2-(4-(triisopropylsilyloxy phenyl) propanamide (E5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;Inert atmosphere; | N-(isoquinolin-6-yl)-2-phenyl-3-(triisopropylsilyloxy)propanamide (E401 ) was prepared from E400 according to the below:To 2-phenyl-3-(triisopropylsilyloxy)propanoic acid (E400) in pyridine was added EDC, DMAP, and <strong>[23687-26-5]6-aminoisoquinoline</strong>, and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into NaHCO3(Sat) and extracted with EtOAC. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (3-4percent MeOH/CH2CI2) gave pure N-(isoquinolin-6-yl)-2-phenyl-3-(triisopropylsilyloxy)propanamide (E401 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;Inert atmosphere; | 3-(1 ,3-dioxoisoindolin-2-yl)-N-(isoquinolin-6-yl)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanamide (E136) was prepared from E135 according to the below: To 2-(2-carboxy-2-(4-((triisopropylsilyloxy)methyl)phenyl)ethylcarbamoyl)benzoic acid (E135) in pyridine was added EDC, DMAP and <strong>[23687-26-5]6-aminoisoquinoline</strong> and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 5percent MeOH/CH2CI2) gave pure 3- (1 ,3-dioxoisoindolin-2-yl)-N-(isoquinolin-6-yl)-2-(4- ((triisopropylsilyloxy)methyl)phenyl)propanamide (E136). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; | 7e/t-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-((triisopropylsilyloxy)methyl)phenyl)propyl(methyl)carbamate (E205) was prepared from E204 according to the below:To 3-(ferf-butoxycarbonyl(methyl)amino)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoic acid (E204) in pyridine was added was added EDC, DMAP, and <strong>[23687-26-5]6-aminoisoquinoline</strong>, and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-6percentMeOH/CH2CI2 gradient) gave pure tert- butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-((triisopropylsilyloxy)methyl)phenyl)propyl(methyl)carbamate (E205). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;Inert atmosphere; | 2-(2-(5-(te/t-butyldimethylsilyloxy)methyl)thiophen-2-yl)-3-(1 ,3-dioxoisoindolin- 2-yl)-N-(isoquinolin-6-yl)propanamide (E235) was prepared from E234 according to the below:To 2-(2-(5-(fe/t-butyldimethylsilyloxy)methyl)thiophen-2-yl)-2-carboxyethylcarbamoyl)benzoic acid (E234) in pyridine was added EDC, DMAP, and <strong>[23687-26-5]6-aminoisoquinoline</strong>, and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 4percent MeOH/CH2CI2) gave pure 2-(2-(5-(/e/t-butyldimethylsilyloxy)methyl)thiophen-2-yl)-3-(1 ,3- dioxoisoindolin-2-yl)-N-(isoquinolin-6-yl)propanamide (E235). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With ammonium hydroxide; copper(ll) sulfate pentahydrate; In water; at 190℃; for 6h; | Reference Example 1Synthesis of 6-aminoisoquinoline (Reference Compound 1)6-bromoisoquinoline that weighed 17.2 g (see WO 2008/077553), 200 mL of 28percent ammonia water and 10.8 g of copper (II) sulfate pentahydrate were put into the autoclave and tightly sealed, and the mixture was then stirred at 190° C. for 6 hours.After cooling to room temperature, the reaction solution was poured into 250 mL of a 10percent aqueous sodium hydroxide solution, followed by extraction with ethyl acetate (100 mL*5).The extract was dried over anhydrous sodium sulfate, filtered, and then concentrated.The obtained crude product was suspended in dichloromethane and then filtered to obtain 10.2 g of the compound of interest as a light brown crystal (85percent).1H-NMR spectrum (CDCl3, delta ppm): 5.54 (br s, 2H), 6.58 (s, 1H), 7.00 (d, J=9.0 Hz, 1H), 7.35 (d, J=5.5 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 8.32 (d, J=5.5 Hz, 1H), 8.98 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reference Example 2Synthesis of 6-chlorosulfonylisoquinoline (Reference Compound 2)4.0 g of <strong>[23687-26-5]6-aminoisoquinoline</strong> (Reference Compound 1) was suspended at 0° C. in 40 mL of concentrated hydrochloric acid (35percent).To the suspension, 4.0 g of sodium nitrite was added in small portions, and the mixture was stirred for 30 minutes.This reaction solution was added dropwise at 0° C. to a mixed solution of 20 mL of acetic acid saturated with sulfite gas generated from sodium bisulfite and sulfuric acid, and 298 mg of copper chloride, and the mixture was stirred for 1 hour.The mixture was neutralized by the addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane (100 mL*2).The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate.The obtained dichloromethane solution was used in the next reaction without being further purified because the compound of interest was unstable. | ||
Reference Example 1 Isoquinoline-6-sulfonyl chloride 4.0 g of commercially available <strong>[23687-26-5]6-aminoisoquinoline</strong> was suspended in 40 mL of concentrated hydrochloric acid (35percent) with cooling at 0° C. To the suspension, 4.0 g of sodium nitrite was added in small portions, and the mixture was stirred for 30 minutes. This reaction solution was added dropwise at 0° C. to a mixed solution of 20 mL of acetic acid saturated with sulfite gas generated from sodium bisulfite and sulfuric acid, and 298 mg of copper chloride, and the mixture was stirred for 1 hour. The mixture was neutralized by the addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane (100 mL*2). The obtained organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. A dichloromethane solution obtained by filtration was used in the next reaction without being further purified because the compound of interest was unstable. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine; In dichloromethane; acetonitrile; at 0 - 20℃; | General procedure: Procedure A: The isothiocyanate compound (1 equiv) was added to the solution of amine (1 equiv) in 5 ml of a mixture of dichloromethane and acetonitrile (1:1, v/v). The mixture was cooled to 0°C. Then, triethylamine (2 equiv) was added gradually. The mixture was stirred at 0°C for 15 min, after which stirring was continued at room temperature for 2?10 h. The reaction mixture was concentrated, extracted with dichloromethane, and washed with brine.The organic layer was dried over MgSO4 and purified by column chromatography (MeOH/CH2Cl2) or by preparative TLC (MeOH/CH2Cl2) to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium phenoxide; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 110℃; under 760.051 Torr; for 20h;Inert atmosphere; | A mixture of tert-butyl (1S,2R)-2-(5-bromo-6-cyanopyridin-3··ylanilino)cyclohexylcarbamate (90 mg, 0,227 mmol), <strong>[23687-26-5]6-aminoisoquinoline</strong> (40 mg, 0.277 mmol), NaOPh trihydrate (50 mg, 0.294 mmol), xantphos (30 rng, 0.051 mmol) and Pd2dba3 (18 mg, 0.019 mmol) in dioxane (3 mL) was degassed with Ar, then was stirred at 110 °C for 20 h. The mixture was concentrakd in vacuo. The residue was then dissolved in trifluoroacetic acid (5 mL). The solution was allowed to stand for 30 min. Excess of trifluoroacetie acid vvas removed in vacuo. The residue was purified by HPLC to give 5-((1R,2S)-2-aminocyclohexylamino)-3-(isoquinolin-6-ylamino)picolinonitrile (85 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium phenoxide; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 110℃; under 760.051 Torr; for 20h;Inert atmosphere; | A mixture of (R)-2-(5-bromo-6-cyanopyridin-3-ylamino)-4-methylpentanamide (80 mg, 0.257 mmol), <strong>[23687-26-5]6-aminoisoquinoline</strong> (40 mg, 0.277 mrnol), NaOPh trihydrate (55 mg, 0.323 mmol), xantphos (30 mg, 0.051 mmoi) and Pd2dba3 (18 mg, 0.019 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 °C for 20 h. The mixture was concentrated in vacuo. The residue was purifled by HPLC to give (R)-2-(6·cyano-5-(isoquinolin-6-ylamino)pyridin-3-ylamino)-4-methylpentanarnide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.4% | With tris-(dibenzylideneacetone)dipalladium(0); In dimethyl sulfoxide; ethyl acetate; Petroleum ether; | Step 3. Synthesis of 6-amino isoquinoline (#E3). A solution of #A2 (4.0 g, 51.7 mmol), 6-bromoisoquinoline-1-carbonitrile #A3 (6.0 g, 25.9 mmol), BINAP (3.2 g, 5.2 mmol), Pd2(dba)3 (2.3 g, 2.6 mmol) and potassium phosphate (11.0 g, 51.7 mmol) in anhydrous DMSO (35 mL) was heated at 80° C. for 2 h. The complete disappearance of the 6-bromoisoquinoline-1-carbonitrile #A3 was observed on TLC. The reaction mixture was cooled to room temperature, filtered through Celite? pad and the filtrate was diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL*3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude material which was purified by silica gel (100-200 mesh) column chromatography using 40percent EtOAc in petroleum ether as an eluting system to give #E3 as yellow solid (1.5 g, 25.4percent). Rf: 0.4 (60percent EtOAc in petroleum ether). LCMS m/z=227.9 (M+H); 1H NMR (400 MHz, d6-DMSO): delta 1.18 (d, J=6.8 Hz, 3H), 3.36-3.47 (m, 1H), 3.48-3.53 (m, 1H), 3.60-3.66 (m, 1H), 6.80-6.82 (m, 2H), 7.32 (dd, J=2.4 Hz, 8.8 Hz, 1H), 7.72 (d, J=5.6 Hz, 1H), 7.87 (d, J=9.6 Hz, 1H), 8.30 (d, J=5.6 Hz, 1H). |
24.3% | With tris-(dibenzylideneacetone)dipalladium(0); In dimethyl sulfoxide; | Step 3. Synthesis of 6-amino isoquinoline (#F3). A solution of #F2 (4.5 g, 51.7 mmol), 6-bromoisoquinoline-1-carbonitrile (6.0 g, 25.9 mmol), BINAP (3.2 g, 5.1 mmol), Pd2(dba)3 (2.3 g, 2.6 mmol) and potassium phosphate (11.0 g, 51.7 mmol) in anhydrous DMSO (35 mL) was heated at 80° C. for 2 h. The complete disappearance of the 6-bromoisoquinoline-1-carbonitrile was observed on TLC. The reaction mixture was cooled to room temperature, filtered through a Celite? pad and the filtrate was diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL*3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude material. The product was purified by chromatography on silica gel (100-200 mesh) using 10percent MeOH in DCM as eluant to give racemic #F3 as yellow solid (1.5 g, 24.3percent). Rf: 0.4 (50percent EtOAc in petroleum ether). Chiral HPLC: two enantiomers (61.0percent, 39.0percent). LCMS m/z=240.1 (M+H). H NMR (400 MHz, d6-DMSO): delta 2.19-2.27 (m, 1H), 2.36-2.45 (m, 1H), 3.67-3.84 (m, 3H), 4.02-4.07 (m, 1H), 4.33-4.39 (m, 1H), 5.09 (t, J=4.8 Hz, 1H), 6.83 (d, J=1.6 Hz, 1H), 7.33 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 7.78 (d, J=6.4 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 8.36 (d, J=5.6 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With 2,4,6-trimethyl-pyridine; 2,2,2-trichloro-1,1-dimethylethoxychloroformate; In N,N-dimethyl-formamide; at 0℃; for 2h; | [00246] To (5)-3-(fert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (28) (8.5 g, 28.4 mmol) in DMF cooled to 0 °C was added 2,4,6-trimethylpyridine and 2,2,2-trichloro-l,l- dimethylethyl chloro formate in DMF. Then, <strong>[23687-26-5]6-aminoisoquinoline</strong> in DMF was added and the solution stirred for 2 h at 0 °C. The mixture was poured into NaHC03 (sat) and extracted with EtOAc. The organic layers were washed with H20, dried (Na2S04), filtered and evaporated to give crude 29. Column chromatography (30percent EtOAc-Hexanes) and recrystallization (EtOAc/Hexanes) gave pure {S)-tert- vXy\ 2-(4-chlorophenyl)-3-(isoquinolin-6-ylamino)-3- oxopropylcarbamate (29, 7.8 g, 64percent, >99percent> S enantiomer). |
Tags: 23687-26-5 synthesis path| 23687-26-5 SDS| 23687-26-5 COA| 23687-26-5 purity| 23687-26-5 application| 23687-26-5 NMR| 23687-26-5 COA| 23687-26-5 structure
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P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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