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[ CAS No. 119-65-3 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 119-65-3
Chemical Structure| 119-65-3
Chemical Structure| 119-65-3
Structure of 119-65-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 119-65-3 ]

CAS No. :119-65-3 MDL No. :MFCD00006898
Formula : C9H7N Boiling Point : -
Linear Structure Formula :- InChI Key :AWJUIBRHMBBTKR-UHFFFAOYSA-N
M.W : 129.16 Pubchem ID :8405
Synonyms :

Calculated chemistry of [ 119-65-3 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 41.74
TPSA : 12.89 Ų

Pharmacokinetics

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) : -5.61 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.66
Log Po/w (XLOGP3) : 2.08
Log Po/w (WLOGP) : 2.23
Log Po/w (MLOGP) : 1.58
Log Po/w (SILICOS-IT) : 2.57
Consensus Log Po/w : 2.02

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.69
Solubility : 0.263 mg/ml ; 0.00204 mol/l
Class : Soluble
Log S (Ali) : -1.98
Solubility : 1.35 mg/ml ; 0.0105 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.66
Solubility : 0.0282 mg/ml ; 0.000218 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.0

Safety of [ 119-65-3 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P501-P273-P270-P264-P280-P337+P313-P305+P351+P338-P361+P364-P332+P313-P301+P312+P330-P302+P352+P312-P405 UN#:2811
Hazard Statements:H311-H302-H315-H319-H412 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 119-65-3 ]

* 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.

  • Upstream synthesis route of [ 119-65-3 ]
  • Downstream synthetic route of [ 119-65-3 ]

[ 119-65-3 ] Synthesis Path-Upstream   1~56

  • 1
  • [ 119-65-3 ]
  • [ 19493-44-8 ]
Reference: [1] Synthesis, 1983, # 10, p. 791 - 793
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1986, p. 1589 - 1592
[3] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 544[4] Chem. Zentralbl., 1923, vol. 94, # III, p. 1023
[5] Journal of the Chemical Society, 1934, p. 1905,1909
[6] Journal of the Chemical Society, 1934, p. 1905,1909
[7] Patent: US4656279, 1987, A,
[8] Patent: WO2013/92979, 2013, A1,
[9] Heterocycles, 2015, vol. 91, # 7, p. 1445 - 1454
[10] European Journal of Organic Chemistry, 2016, vol. 2016, # 8, p. 1606 - 1611
  • 2
  • [ 119-65-3 ]
  • [ 1984-23-2 ]
  • [ 19493-44-8 ]
Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 13, p. 2279 - 2282
  • 3
  • [ 119-65-3 ]
  • [ 112259-27-5 ]
  • [ 2439-04-5 ]
Reference: [1] Journal of the Chemical Society, Chemical Communications, 1987, p. 1722 - 1724
  • 4
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  • [ 2439-04-5 ]
Reference: [1] Patent: CN107778231, 2018, A,
  • 5
  • [ 119-65-3 ]
  • [ 3482-14-2 ]
  • [ 2439-04-5 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1993, # 9, p. 1065 - 1072
  • 6
  • [ 119-65-3 ]
  • [ 2439-04-5 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1993, # 9, p. 1065 - 1072
  • 7
  • [ 119-65-3 ]
  • [ 136918-14-4 ]
  • [ 491-30-5 ]
  • [ 2439-04-5 ]
  • [ 643-79-8 ]
Reference: [1] Journal of Physical Chemistry A, 1998, vol. 102, # 34, p. 6760 - 6765
  • 8
  • [ 119-65-3 ]
  • [ 80278-67-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3660 - 3668
  • 9
  • [ 7742-73-6 ]
  • [ 119-65-3 ]
  • [ 19493-45-9 ]
YieldReaction ConditionsOperation 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
  • 10
  • [ 119-65-3 ]
  • [ 34784-02-6 ]
YieldReaction ConditionsOperation in experiment
23.8% at 100℃; To a stirred solution of isoquinoline (24 g, 186 mmol) in AcOH (50 mL) was added NBS (36.2 g, 204.6 mmol) at RT and the reaction mixture was heated to 100° C. overnight. Then it was cooled to RT and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (5percent EtOAc:Hexanes) to furnish the title compound (9.2 g, 23.8percent) as an oil.
Reference: [1] Patent: US2013/178457, 2013, A1, . Location in patent: Paragraph 0219
  • 11
  • [ 119-65-3 ]
  • [ 20461-86-3 ]
  • [ 4494-18-2 ]
YieldReaction ConditionsOperation in experiment
73% With ammonium peroxydisulfate; caesium carbonate In dimethyl sulfoxide at 20℃; for 24 h; Inert atmosphere; Irradiation; Green chemistry General procedure: Heterocycle (0.10mmol,1equiv)ammonium persulfate (0.30 mmol, 3 equiv), Cs2CO3(0.20mmol,2 equiv)were placed in a dry glass tube.Then, anhydrous DMSO1 mL) and2,2-diethoxyacetic acid (0.7mmol7equiv), wereinjected into the tube by syringe under a N2atmosphere.The solution was then stirred at roomtemperature under the irradiation of 15W blueLEDs strip for 24h.After completion of the reaction,the mixture was quenched by addition of1.2mL of 3.0 M HCl, stirred for 20hthen saturated Na2CO3solution was added to adjust pH tobasicextract with CH2Cl2,the combined organic layers was washed with brine, then dry overanhydrous Na2SO4. The desired products were obtained in thecorresponding yields afterpurification by flashchromatography on silica gel eluting with petroleum and ethylacetate.
Reference: [1] Synlett, 2018, vol. 29, # 14, p. 1881 - 1886
  • 12
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  • [ 4494-18-2 ]
Reference: [1] Organic Letters, 2018, vol. 20, # 18, p. 5752 - 5756
  • 13
  • [ 110-88-3 ]
  • [ 119-65-3 ]
  • [ 4494-18-2 ]
Reference: [1] Journal of Organic Chemistry, 1986, vol. 51, # 4, p. 536 - 537
  • 14
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  • [ 23687-27-6 ]
Reference: [1] Patent: US2004/157849, 2004, A1,
  • 15
  • [ 119-65-3 ]
  • [ 3482-14-2 ]
  • [ 2439-04-5 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1993, # 9, p. 1065 - 1072
  • 16
  • [ 119-65-3 ]
  • [ 34784-07-1 ]
Reference: [1] Synthesis (Germany), 2018, vol. 50, # 11, p. 2181 - 2190
  • 17
  • [ 119-65-3 ]
  • [ 34784-07-1 ]
  • [ 91-21-4 ]
  • [ 75416-50-1 ]
Reference: [1] Synthesis (Germany), 2018, vol. 50, # 11, p. 2181 - 2190
  • 18
  • [ 119-65-3 ]
  • [ 1532-72-5 ]
YieldReaction ConditionsOperation in experiment
96% With dihydrogen peroxide In water for 0.25 h; Sonication In a 50 mL round bottom flask, quinoline 1.29 g, hydrogen peroxide (35percent mass fraction) 1.1 g, 5percent by mass were added in order.Number of perfluorosulfonic acid resin, 10 ml of water as a solvent, and the resulting mixture reacted for 15 minutes in a 30 W/20 KHz ultrasonic reactorbell. The resin catalyst in the reaction system is removed by filtration, the water in the reaction solvent is removed under reduced pressure, and finally recrystallized to obtain the correspondingQuinoline nitrogen oxide 1.39 g, yield 96percent.
90% With dihydrogen peroxide In ethanol; water at 20℃; for 24 h; {Mo132} 100 mg,Isoquinoline 1 mmol,30percent Hydrogen peroxide 5 mmol,Ethanol 2 ml and water 3 ml were mixed and stirred at room temperature,After the reaction for 24 hours, it was extracted with dichloromethane and then purified by distillation with organic phase dichloromethane to give the isoquinoline pyridine nitroxide in a yield of 90percent.
89.6% With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 18 h; To a stirred solution of isoquinoline (43-1) (2 g, 15.4 mmol) in dichloromethane (50 mL) at 0°C, was added mCPBA (3.77 g, 16.9 mmol) portionwise and the reaction mixture was stirred at RT for 18 h. After consumption of starting material as evident from TLC, the reaction mixture was quenched with a saturated solution of sodium sulphite, the organic layer was separated and washed with a saturated solution of sodium carbonate, brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford isoquinoline 2-oxide (43-2) (2.00 g, 13.7 mmol, 89.6 percent) as a white gummy solid. 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.12 (d, J = 6 Hz, 1H), 7.85-7.58 (m, 4H).
88% With K8[α-BHW11O39]*13H2O; dihydrogen peroxide In water at 65℃; for 6 h; Green chemistry General procedure: Catalyst (0.03 mmol), H2O (3 ml), substrate (4 mmol), and H2O2 (20 mmol, 30percent aq.) were charged in the reaction flask, which was first bathed in cold water (about 283 K). The mixture was then stirred at room temperature for 16–24 h. The reaction was detected by thin-layer chromatography (TLC). After the reaction, the system was concentrated by evaporation, and the catalyst precipitated from the mixture after the addition of anhydrous ethyl alcohol. The recovered catalyst, obtained by filtration, was washed with anhydrous ethyl alcohol and diethyl ether and then used for the next oxidation after drying. The filtrate was extracted with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4, and the pure products were obtained by evaporation or column chromatography. The products were analyzed by 1H NMR and 13C NMR.
86.8% at 40℃; for 24 h; step one,Tungsten-loaded titanium dioxide is used as a catalyst.50g isoquinoline,40mL 30percent hydrogen peroxide solution,5g of the catalyst prepared in step (a) was added to the three-necked flask;Step two,The mixture prepared in step 1 is stirred and reacted at 40° C. for 24 hours.After the reaction liquid is naturally cooled to room temperature, it is filtered, washed and concentrated.After the filtrate is concentrated, the yield of isoquinoline nitrogen oxide product is 86.8percent.The purity by HPLC was 94.8percent.
78% With 1,2-diphenyl-1,1,2,2-tetrahydroperoxyethane In acetonitrile at 20℃; for 0.216667 h; General procedure: To a solution of pyridine derivative 1 or tertiary amine 2(1 mmol) in acetonitrile (5 mL) was added 1,2-diphenyl-1,1,2,2-tetrahydroperoxyethane (1 g, 3 mmol). The resulting mixture was stirred at room temperature for an appropriate time (Table 2). After completion of the reaction as monitored by TLC, the reaction mixture was diluted with toluene (10 mL) and water (6 mL). The aqueous layer which contained the product was separated from theorganic layer and evaporated under reduced pressure toleave the product. The products were characterized on the basis of their melting points, elemental analysis and IR, 1HNMR and 13C NMR spectral analysis.
75% With dihydrogen peroxide; sodium hydrogencarbonate; trichloroacetonitrile In tetrahydrofuran; water at 0 - 25℃; for 12 h; General procedure: To a stirred solution of amine (1 mmol), trichloroacetonitrile (2 mmol), and NaHCO3 (0.5 mmol) inTHF (2 mL) was added an aqueous solution of 30percent (w/w) hydrogen peroxide(2 mmol, 0.2 mL) at 0 °C. The temperature was increased to 25 °C and the reaction continued. After completion of the reaction (monitored by TLC), the solvent was evaporated and MeCN (2 mL) was added. The mixture was cooled to 0 °C and filtered to remove the trichloroacetamide by-product. The filtrate was then concentrated under reduced pressure and purified by column chromatography. The products were identified by comparing their physical and spectral data with those of authentic samples reported in the literature.
64% With peracetic acid In ethyl acetate at 20℃; Add isoquinoline (500.00 g, 3.75 moles) and ethyl acetate (7.60 L, 77.62 moles) to a 22 L three- necked round-bottom flask in a water bath equipped with overhead stirrer, thermocoupler, nitrogen inlet/outlet, and addition funnel. Stir to dissolve. At room temperature add peracetic acid (1.25 L, 5.94 moles) dropwise over 0.5 ours. Stir at room temperature overnight. Chill the reaction flask in an ice-water bath, then quench the reaction by dropwise addition of dimethyl sulfide (525.00 mL, 7.14 moles) over 45 minutes. Stir overnight while warming to room temperature. Test the reaction mixture for peroxide.Combine two lots of the reaction mixture. Transfer the reaction mixtures to a 50 L separatory funnel and add water (2.00 L, 111.02 moles) and dichloromethane (12.00 L, 187.21 moles). Add sodium carbonate (2.07 kg, 19.53 moles) in portions, then separate layers. Extract the aqueous layer with dichloromethane ( 3 x 4 L), combine the organic layers and dry over sodium sulfate. Filter and remove solvent under reduced pressure to afford a crude dark red oil/liquid.Add ethyl acetate (8.00 L, 81.76 moles) to the crude dark red oil/liquid, then stir under reduced pressure until 6.8 L of ethyl acetate are removed. Filter the precipitated solid, wash with cold ethyl acetate (750.00 mL, 7.66 moles), then heptane (800.00 mL, 5.46 moles) wash. Dry the solid to afford isoquinoline- 2-oxide, 714.20 g (64percent) as a fine sand-like solid.As an alternative work-up, prior to the heptane wash, remove IL of solvent from the filtrate. Allow the filtrate to stand overnight. Filter the solid and wash with cold ethyl acetate (500.00 mL, 5.11 moles), followed by a heptane (500.00 mL, 3.41 moles) wash. The solid was dried to afford isoquinoline-2-oxide, 110.10 g (10percent) as a fine sand-like solid - cropNo.2 (total yield 74percent).

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[4] Patent: CN108003098, 2018, A, . Location in patent: Paragraph 0085; 0086; 0087
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Reference: [1] Polish Journal of Chemistry, 2003, vol. 77, # 11, p. 1579 - 1586
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  • [ 394-67-2 ]
Reference: [1] Patent: JP2018/70562, 2018, A,
[2] Patent: JP2018/70562, 2018, A,
[3] Patent: JP2018/70562, 2018, A,
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  • 21
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  • [ 1532-97-4 ]
YieldReaction ConditionsOperation in experiment
23.8% at 100℃; lntermediate-12: 3-Bromoisoquinoline: To a stirred solution of isoquinoline (24 g, 186 mmol) in AcOH (50 mL) was added NBS (36.2 g, 204.6 mmol) at RT and the reaction mixture was heated to 100 2C overnight. Then it was cooled to RT and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (5percent EtOAc:Hexanes) to furnish the title compound (9.2 g, 23.8percent) as an oil.
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[8] Archiv der Pharmazie, 2003, vol. 336, # 4-5, p. 258 - 263
  • 22
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  • [ 5430-45-5 ]
  • [ 73075-59-9 ]
YieldReaction ConditionsOperation in experiment
45% at 0 - 10℃; for 24 h; To mechanically stirred concd H 2 SO 4 (100 mL), isoquinoline (1; 12.9 g,0.1 mol, 1.0 equiv) was slowly added at 0 °C. During intensive stirringTCCA (12.8 g, 55 mmol, 1.65 equiv) was then added in 4 portionswhile the reaction temperature was kept at 10 °C. The mixture wasthen stirred at 10 °C and followed by GC-MS. After 24 h the reactionmixture was poured onto crushed ice (ca. 200 g) and the precipitatewas filtered. The pH of the filtrate was adjusted to 2 with concd aqNH 3 solution with extensive cooling. The slurry was then filtered. Thefiltrate was extracted with toluene (6 × 75 mL) to remove the sideproduct, 5,8-dichloroisoquinoline (16). The aqueous phase was fur-ther basified with concd aq NH 3 solution until pH 6 was reached. Atthis point the precipitate was filtered, washed with H 2 O, and dried inair. Finally, the filtrate was recrystallized from methylcyclohexane toafford 15.Yield: 7.60 g (45percent); mp 70–72 °C.IR (ATR): 1580, 1489, 1371, 1267, 1204, 1140, 1065, 984, 822, 750,687, 628, 536 cm –1 .1 H NMR (400 MHz, CDCl 3 ): δ = 9.27 (s, 1 H), 8.64 (d, J = 6.0 Hz, 1 H),8.02 (d, J = 6.0 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 1 H), 7.77 (d, J = 7.5 Hz, 1 H),7.53 (t, J = 7.8 Hz, 1 H).13 C NMR (100 MHz, CDCl 3 ): δ = 152.4, 143.9, 133.7, 131.0, 130.3,129.4, 127.3, 126.7, 116.9.
Reference: [1] Synthesis (Germany), 2018, vol. 50, # 11, p. 2181 - 2190
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YieldReaction ConditionsOperation in experiment
81%
Stage #1: at -25 - 20℃;
Stage #2: With ammonia In water at 0℃;
Synthesis of 5-bromoisoquinoline
Into a 250 mL 3-necked round-bottom flask, was placed H2SO4 (150 mL).
To the above was added isoquinoline (17 g, 131.62 mmol) in several batches, while cooling to a temperature of 0° C.
To the above was added NBS (29.2 g, 164.04 mmol) in several batches, while cooling to a temperature of -25-22° C.
The resulting solution was allowed to react, with stirring, for 2 h while the temperature was maintained at -25° to -22° C.
The resulting solution was allowed to react with stirring overnight, while the temperature was maintained at room temperature.
The reaction progress was monitored by TLC (EtOAc/PE=1:5).
The reaction mixture was then quenched by the adding 1000 mL of H2O/ice.
Adjustment of the pH to 8-10 was accomplished by the addition of NH3.H2O (30percent).
The resulting solution was extracted four times with 500 mL of EtOAc and the organic layers combined and dried over Na2SO4.
The residue was purified by eluding through a column with a 1:5 EtOAc/PE solvent system.
This resulted in 22.24 g (81percent) of 5-bromoisoquinoline as a white solid.
81%
Stage #1: at -25 - 20℃; for 18 h;
Stage #2: With ammonia In water
Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 mL) at 0 °C. The reaction mixture was cooled at -25 °C and N-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was was diluted with 1000 mL of ice water (1000 <n="107"/>niL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4 x 500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5-bromoisoquinoline in 81percent yield as a white solid.
81%
Stage #1: With N-Bromosuccinimide; sulfuric acid In water at -25 - 20℃;
Stage #2: With ammonium hydroxide In water
Synthesis of 5-bromoisoquinoline
Into a 250 mL 3-necked round-bottom flask was placed H2SO4 (150 mL).
To the above was added isoquinoline (17 g, 131.62 mmol) in several batches, while cooling to a temperature of 0° C.
To the above was added NBS (29.2 g, 164.04 mmol) in several batches, while cooling to a temperature of -25-22° C.
The resulting solution was allowed to react, with stirring, for 2 hours while the temperature was maintained at -25-22° C.
The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature.
The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:5).
The reaction mixture was then quenched by the adding 1000 mL of H2O/ice.
Adjustment of the pH to 8-10 was accomplished by the addition of NH3. H2O (30percent).
The resulting solution was extracted four times with 500 mL of ethyl acetate and the organic layers combined and dried over Na2SO4.
The residue was purified by eluding through a column with a 1:5 ethyl acetate/petroleum ether solvent system.
This resulted in 22.24 g (81percent) of 5-bromoisoquinoline as a white solid.
81%
Stage #1: at 0℃;
Stage #2: at -25 - 20℃;
Stage #3: With ammonium hydroxide In waterCooling with ice
Intermediate 13: Synthesis of 2-methyl-1,2,3,4-tetrahydroisoquinoline-8-sulfonyl chloride; 1. Synthesis of 5-bromoisoquinoline; Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 mL) at 0° C. The reaction mixture was cooled at -25° C. and N-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was diluted with 1000 mL of ice water (1000 mL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4.x.500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5-bromoisoquinoline in 81percent yield as a white solid.
81%
Stage #1: at 0℃;
Stage #2: at -25 - 20℃;
Stage #3: With ammonia In water
Intermediate 19: Synthesis of 2-methyl-l,2,3,4-tetrahydroisoquinoline-8-sulfonyl chloride.1. Synthesis of 5-bromoisoquinoline.Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 niL) at O 0C. The reaction mixture was cooled at -25 0C and N-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was was diluted with 1000 mL of ice water (1000 mL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4 x 500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5- bromoisoquinoline in 81percent yield as a white solid.
81%
Stage #1: at -25 - 20℃;
Stage #2: With ammonia In water
Oxalyl chloride (157.6 mmol) was added dropwise at rt to a solution of 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonic acid (22.0 mmol) in dichloromethane (100 mL) and N,N-dimethylformamide (10 mL). The resulting solution was maintained for 2 h, then was diluted with iced water (200 mL). The resulting solution was extracted with dichloromethane (2.x.100 mL) and the combined organics were dried (sodium sulfate), filtered and concentrated. The residue was purified by Flash chromatography (1/4 ethyl acetate/petroleum ether) to afford 1-methyl-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride in 20percent yield as a yellow solid. 1H NMR (CDCl3) δ 7.69 (d, 1H), 7.51 (s, 1H), 6.54 (d, 1H), 3.57 (t, 2H), 3.02 (s, 3H), 2.78 (d, 2H), 1.98 (m, 2H).
81%
Stage #1: at -25 - 20℃;
Stage #2: With ammonium hydroxide In waterCooling with ice water
Intermediate 19: Synthesis of 2-methyl-l,2,3,4-tetrahydroisoquinoline-8-sulfonyl chloride.1. Synthesis of 5-bromoisoquinoline.Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 mL) at 0 0C. The reaction mixture was cooled at -25 0C and TV-bromosuccinamide (164 mmol) was added in portions and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h. The reaction mixture was was diluted with 1000 mL of ice water (1000 mL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide. The resulting solution was extracted with ethyl acetate (4 x 500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated. The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5- bromoisoquinoline in 81percent yield as a white solid.
81%
Stage #1: at -25 - 20℃;
Stage #2: With ammonia In water
Isoquinoline (132 mmol) was added in several batches to sulfuric acid (150 mL) at 0° C.
The reaction mixture was cooled at -25° C. and N-bromosuccinamide
(164 mmol) was added in portions and the reaction mixture was maintained for 2 h.
The reaction mixture was allowed to warm to rt and was maintained for an additional 16 h.
The reaction mixture was diluted with 1000 mL of ice water (1000 mL) and the pH of the solution was adjusted to 8-10 with concentrated ammonium hydroxide.
The resulting solution was extracted with ethyl acetate (4*500 mL) and the combined organic layers were dried (sodium sulfate) and concentrated.
The residue was purified by Flash chromatography (1/5 ethyl acetate/petroleum ether) to provide 5-bromoisoquinoline in 81percent yield as a white solid.
81%
Stage #1: at -25 - 20℃;
Stage #2: With ammonia In water
Into a 250 mL 3-necked round bottom flask was placed H2SO4 (150 mL). To the above was added isoquinoline (17 g, 131.62 mmol) in several batches, while cooling to a temperature of 0 0C. To the above was added NBS (29.2 g, 164.04 mmol) in several batches, while cooling to a temperature of -25 - -22 0C. The resulting solution was allowed to react, with stirring, for 2 hours while the temperature was maintained at -25 - -220C. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether = 1 :5). The reaction mixture was then quenched by the adding 1000 mL of H2O /ice. Adjustment of the pH to 8-10 was accomplished by the addition of NH3. H2O (30 percent). The resulting solution was extracted four times with 500 mL of ethyl acetate and the organic layers combined and dried over Na2SO4. The residue was purified by eluting through a column with a 1:5 ethyl acetate/petroleum ether solvent system. This resulted in 22.24 g (81percent) of 5- <n="129"/>bromoisoquinoline as a white solid.
79% at -25 - -18℃; for 4 h; To mechanically stirred concd H 2 SO 4 (170 mL), isoquinoline (1; 21.8 g,169.2 mmol, 1.0 equiv) was slowly added at 0 °C. The mixture wascooled to –25 °C and NBS (39.3 g, 220.5 mmol, 1.3 equiv) was added atsuch a rate that the reaction temperature was kept between at –25and –22 °C. The mixture was stirred between –25 and –20 °C for 2 hand at –18 °C for 2 h. It was then poured onto crushed ice (600 g) andmade alkaline (pH 8–9) by using concd aq NH 3 solution with intensivecooling. The alkaline slurry was extracted with Et 2 O (3 × 300 mL). Thecombined organic layer was washed with 1.0 M aq NaOH (2 × 300 mL)and H 2 O (300 mL), dried over anhyd Na 2 SO 4 , filtered, and evaporatedto give a brown oil. The crude product was purified by vacuum distil-lation (128–130 °C/2 Torr) to give 2 as a white powder.Yield: 27.8 g (79percent); mp 82–83 °C.IR (ATR): 1580, 1485, 1368, 1263, 1199, 1136, 962, 817, 750, 673, 627,525 cm –1 .1 H NMR (400 MHz, CDCl 3 ): δ = 9.23 (s, 1 H), 8.64 (d, J = 6.0 Hz, 1 H),7.99–7.94 (m, 3 H), 7.48 (t, J = 7.8 Hz, 1 H).13 C NMR (100 MHz, CDCl 3 ): δ = 152.7, 144.5, 135.2, 134.2, 129.8,127.9, 127.6, 121.7, 119.6.
77% at -10 - 25℃; for 24 h; Inert atmosphere (1) The reaction flask in 250mL three, -10 under nitrogen, was added isoquinoline (11g,85mmol) and concentrated sulfuric acid (100mL) Stir, then add N- bromosuccinimide (17.8g,100mmol) were mixed and the reaction warmed to 25 24h, to obtain a reaction solution. The reaction solution was addedInto ice water, followed by aqueous ammonia and ethyl acetate (50mL × 3) extraction, water (50mL × 3) wash,Saturated brine (100mL), dried over anhydrous sodium sulfate and concentrated to give 5-bromo - isoquinoline 14g,The yield was 77percent
71% With N-Bromosuccinimide; sulfuric acid In tetrahydrofuran at -25 - 25℃; for 26 h; Isoquinoline 38 (1156 mg, 8.95 mmol) was suspended in conc. H2SO4 (9.7 mL) at 0 °C. After cooling to -25 °C, NBS (1912 mg, 10.74 mmol) was added. The reaction mixture was stirred at -25 °C for 2 h and then at 25 °C for additional 24 h. Subsequently, ice was added and the mixture was treated with conc. NH4OH (10 mL) to pH = 8-10.
The resulting solution was extracted with EtOAc (3 * 10 mL).
The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated.
The residue was purified by flash chromatography on silica gel (20percent EtOAc in petroleum ether) to afford the title compound as a pale pink solid (71percent yield).
1H NMR (300 MHz, CDCl3) δ 9.24 (s, 1H), 8.65 (d, J = 5.9 Hz, 1H), 8.00-7.95 (m, 3H), 7.48 (t, J = 7.8 Hz, 1H); ESI-MS m/z 209.1 [M+H]+.
50%
Stage #1: at -30 - 0℃; for 5 h;
Stage #2: With ammonia In water
EXAMPLE 57A
5-bromoisoquinoline
Concentrated H2SO4 (260 mL) was cooled to -25° C. while stirring with a mechanical stirrer.
Isoquinoline (30 mL, 0.25 mol) was added slowly so the temperature did not exceed 0° C.
After the addition was complete.
the red solution was recooled to -25° C. and treated with N-bromosuccinimide (55.49 g, 0.31 mol) in small portions so that the temperature did not exceed -20° C.
The reaction mixture was stirred for 5 hours keeping the temperature between -30° C. and -18° C.
The reaction mixture was then allowed to warm to -10° C. and was poured carefully over 600 g of ice.
The resulting slurry was adjusted to pH 10 using 25percent NH4OH.
The mixture was then extracted with diethyl ether (3*600 mL).
The ether fractions were combined, filtered through a celite plug and the filtrate concentrated under reduced pressure.
The residue was suspended in hot heptane (600 mL).
The heptane was decanted.
This procedure was repeated with hexane (2*200 mL).
The combined heptane and hexane fractions were concentrated under reduced pressure to give a mustard yellow solid.
The title compound was obtained by recrystallization from heptane (26.37 g, 50percent).
mp 78°-80° C.; MS (ESI+) m/z 209 (M+H)+; 1H NMR (DMSO, 300 MHz) δ 7.65 (t, J 7.9, 1H), 7.94 (d, J 8.1, 1H), 8.17 (dd, J 1.0, 7.4, 1H), 8.22 (d, J 8.1, 1H), 8.68 (d, J 6.1, 1H), 9.37 (s, 1H); Anal. Calcd for C9H6BrN: C, 51.96; H, 2.91; N, 6.73; Br, 38.41. Found: C, 51.24; H, 2.79; N, 6.52; Br, 38.81.
28%
Stage #1: With aluminum (III) chloride In dichloromethaneHeating / reflux
Stage #2: at 75 - 100℃; Neat (no solvent)
To a suspension of AIC13 (156.7 g, 1.18 mol) in CH2CI2 (500 mL), a solution of isoquinoline (605 mmol, 71 mL) in CH2CI2 (100 mL) was dropwise added at such rate that the reaction mixture was refluxed gently. After addition, CH2CI2 was removed by distillation. The blackish residue was melted at 120 C then the temperature was adjusted to 100 C. To the mixture, Br2 (31 mL, 605 mmol) was dropwise added over 2hrs at 100 C and stirred for 30min at same temperature, then was stirred at 75 C overnight. The mixture was cooled to RT then carefully poured into ice-water. The aqueous mixture was basified with NaOHaq. and extracted with ether. The organics was dried overNa2SO4 then evaporated. Sequence purification onSi02 column chromatography twice and recrystalisation (from hexane) gave the title compound (34.5 g, 28percent).
28%
Stage #1: With aluminum (III) chloride In dichloromethaneHeating / reflux
Stage #2: at 75 - 100℃; Neat (no solvent)
To a suspension of AICI3 (156.7 g, 1.18 mol) inCH2CI2 (500 mL), a solution of isoquinoline (1) (605 mmol, 71 mL) inCH2CI2 (100 mL) was dropwise added at such rate that the reaction mixture was refluxed gently. After addition,CH2CI2 was removed by distillation. The blackish residue was melted at120 C then the temperature was adjusted to100 C. To the mixture, Br2 (31 mL, 605mmol) was dropwise added over 2hrs at100 C and stirred for 30min at same temperature, then was stirred at75 C overnight. The mixture was cooled to room temperature then carefully poured into ice-water. The aqueous mixture was basified with NaOHaq. and extracted with ether. The organic layer was dried overNa2SO4 then evaporated. Sequence purification on Si02 column chromatography twice andrecrystallization from hexane gave the title compound (34.5g, 28 percent). MS (ESI) (M+H) + 208,210
26% at 75 - 85℃; for 5 h; 5-Bromoisoquinoline. The apparatus was a 500 mL three-necked flask equipped with a condenser, dropping funnel, and a stirrer terminating in a stiff, crescent-shaped Teflon polytetrafluroethylene paddle. To the isoquinoline (57.6 g, 447 mmol) in the flask was added AlCl3 (123 g, 920 mmol). The mixture was heated to 75-85°C. Bromine (48.0 g, 300 mmol) was added using a dropping funnel over a period of 4 hours. The resulting mixture was stirred for one hour at 75°C. The almost black mixture was poured into vigorously hand-stirred cracked ice. The cold mixture was treated with sodium hydroxide solution (10 N) to dissolve all the aluminum salts as sodium aluminate and the oily layer was extracted with ether. After being dried with Na2SO4 and concentrated, the ether extract was distilled at about 0.3 mm. A white solid (16.3 g, 78 mmol) from a fraction of about 1250C was obtained (26percent yield). The product was further purified by recrystallization (pentane or hexanes)
26% at 75 - 85℃; for 5 h; The apparatus was a 500 mL three-necked flask equipped with a condenser, dropping funnel, and a stirrer terminating in a stiff, crescent-shaped Teflon polytetrafluroethylene paddle. To the isoquinoline (57.6 g, 447 mmol) in the flask was added AiCl3 (123 g, 920 mmol). The mixture was heated to 75-85° C. Bromine (48.0 g, 300 mmol) was added using a dropping funnel over a period of 4 hours. The resulting mixture was stirred for one hour at 75° C. The almost black mixture was poured into vigorously hand-stirred cracked ice. The cold mixture was treated with sodium hydroxide solution (10 N) to dissolve all the aluminum salts as sodium aluminate and the oily layer was extracted with ether. After being dried with Na2SO4 and concentrated, the ether extract was distilled at about 0.3 mm. A white solid (16.3 g, 78 mmol) from a fraction of about 125° C. was obtained (26percent yield). The product was further purified by recrystallization (pentane or hexanes): mp 80-81° C.; 1H NMR (DMSO-d6) δ 9.34 (s, 1H), 8.63 (d, 1H, J=9.0 Hz), 8.17 (d, 1H, J=7,5 Hz), 8.11 (d, 1H, J=6.6 Hz), 7.90 (d, 1H, J=6.0 Hz), 7.60 (t, 1H, J=7.5 Hz); 13C NMR (DMSO-d6) δ 153.0, 144.7, 134.3, 134.0, 129.3, 128.5, 128.0, 120.3, and 118.6. Anal. Calcd. for C9H6BrN: C, 51.96; H, 2.91; N, 6.73. Found: C, 51.82; H, 2.91; N, 6.64.

Reference: [1] Patent: US2008/318941, 2008, A1, . Location in patent: Page/Page column 22
[2] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 105-106
[3] Patent: US2008/200471, 2008, A1, . Location in patent: Page/Page column 45; 45-46
[4] Patent: US2010/16297, 2010, A1, . Location in patent: Page/Page column 25
[5] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 68
[6] Patent: US2010/29629, 2010, A1, . Location in patent: Page/Page column 52
[7] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 86; 87
[8] Patent: US2010/22581, 2010, A1, . Location in patent: Page/Page column 35; 36
[9] Patent: WO2007/98418, 2007, A1, . Location in patent: Page/Page column 127-128
[10] Synthesis (Germany), 2018, vol. 50, # 11, p. 2181 - 2190
[11] Patent: CN105669547, 2016, A, . Location in patent: Paragraph 0076; 0077
[12] European Journal of Medicinal Chemistry, 2019, p. 290 - 320
[13] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 24, p. 5567 - 5573
[14] Organic Letters, 2017, vol. 19, # 1, p. 262 - 265
[15] Patent: US2005/113576, 2005, A1, . Location in patent: Page/Page column 29
[16] Organic Syntheses, 2005, vol. 81, p. 96 - 104
[17] Patent: WO2005/49576, 2005, A1, . Location in patent: Page/Page column 27
[18] Patent: WO2005/49577, 2005, A1, . Location in patent: Page/Page column 28
[19] Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3660 - 3668
[20] Patent: WO2006/12640, 2006, A2, . Location in patent: Page/Page column 52
[21] Patent: US2007/155720, 2007, A1, . Location in patent: Page/Page column 24
[22] Phosphorus, Sulfur and Silicon and Related Elements, 2000, vol. 164, p. 131 - 143
[23] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 22, p. 2623 - 2628
[24] Journal of Medicinal Chemistry, 2005, vol. 48, # 15, p. 4972 - 4982
[25] Patent: US2003/158188, 2003, A1,
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[30] Inorganic Chemistry, 2016, vol. 55, # 15, p. 7388 - 7395
[31] Patent: US2004/157849, 2004, A1,
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[2] Helvetica Chimica Acta, 1985, vol. 68, p. 1828 - 1834
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 3, p. 744 - 752
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YieldReaction ConditionsOperation in experiment
15.2 g (59 % from 97% isoquinoline) With N-Bromosuccinimide; sulfuric acid In hexane; n-heptane 5-Bromoisoquinoline.
Isoquinoline (15 ml; 128 mmol) was slowly added to a mechanically stirred solution of concentrated H2SO4 (130 ml) (Note 1) at -20° C., at such a speed that the temperature did not exceed +8° C.
The reaction mixture was then re-cooled to -20° C., and solid N-bromosuccinimide (27.29 g; 153 mmol) (Note 2 and 3) was added at such a speed that the reaction temperature did not exceed -15°C. (Note 4).
The reaction mixture was stirred at -20° C. until all isoquinoline was consumed (Note 5).
The reaction was then allowed to warm to -9° C. over 20 min.
The reaction mixture was poured onto 300 g of crushed ice and pH adjusted to 10 using 25percent NH3 (aq.), while the temperature was kept below 50-60° C.
Extraction with diethyl ether (2*250 ml) filtration through celite and evaporation to dryness gave a red-brown oil which crystalized upon cooling.
The precipitate was suspended in boiling heptane (300 ml) under rapid stirring and decanted while warm.
This procedure was repeated with hexane (2*100 ml).
The combined organic fractions was evaporated to dryness to give 18.2 g crude product as a slightly yellow powder.
Recrystalization from heptane gave 15.2 g (59 percent from 97percent isoquinoline) of pure product as a slightly yellow powder.
M.p. 82-83° C. (Litt. 82-83° C.4, 79.5-80.5° C.1, 82-84° C.3,9, 83.0-83.5° C.2, 83-85° C.5); 1H-NMR (DMSO-d6): δ 9.38 (d, J=0.9 Hz); 8.67 (d, J=5.9 Hz); 8.21 (d, J=8.2 Hz); 8.16 (dd, JA=0.9 Hz, JB=7.5 Hz); 7.94 (d, J=5.9 Hz); 7.64 (t.dagger., J=7.8 Hz).
.dagger.A dd with JA=8.2 Hz and JB=7.5 Hz was expected.
Reference: [1] Patent: US6500954, 2002, B1,
  • 26
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  • [ 63927-22-0 ]
  • [ 81045-39-8 ]
Reference: [1] Synthesis, 2002, # 1, p. 83 - 86
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  • [ 1532-84-9 ]
Reference: [1] Journal of the American Chemical Society, 2016, vol. 138, # 29, p. 9166 - 9171
[2] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 544[3] Chem. Zentralbl., 1923, vol. 94, # III, p. 1023
[4] Journal of Organic Chemistry, 1937, vol. 2, p. 411,427[5] Justus Liebigs Annalen der Chemie, 1935, vol. 515, p. 34,37
[6] Pharmaceutical Bulletin, 1957, vol. 5, p. 606,609
[7] Journal of Organic Chemistry, 1946, vol. 11, p. 239,242
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  • [ 108-88-3 ]
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Reference: [1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 544[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1023
  • 29
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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1937, vol. 56, p. 699,706
[2] Heterocycles, 2015, vol. 91, # 7, p. 1445 - 1454
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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1937, vol. 56, p. 699,706
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Reference: [1] Archiv der Pharmazie, 2003, vol. 336, # 4-5, p. 258 - 263
[2] Patent: US2013/178457, 2013, A1,
[3] Patent: WO2013/5168, 2013, A2,
  • 32
  • [ 119-65-3 ]
  • [ 127-17-3 ]
  • [ 58022-21-2 ]
YieldReaction ConditionsOperation in experiment
76% With ammonium peroxydisulfate; [Ir(2-(2,4-difluorophenyl)-5-methylpyridine)24,4′-di-tert-butyl-2,2′-bipyridine]PF6 In dimethyl sulfoxide at 20℃; for 12 h; Inert atmosphere; Irradiation; Green chemistry General procedure: Heterocycle (0.10mmol, 1 equiv)ammonium persulfate (0.20 mmol, 2equiv),[Ir{dF(CF3ppy)}2(dtbbpy)]PF6 ( 0.2 molpercent),α-keto acids(1.0mmol10equiv)wereplaced in a dry glass tube.Then, anhydrous DMSO1mLwereinjected into the tubeby syringe under a N2 atmosphere.The solution was then stirred at roomtemperatureunder the irradiation of 15W blue LEDs strip for 12h.After completion of thereaction,then saturated Na2CO3solution was added to adjust pH to basic.Thecombined organic layer was washed with brine and then dried overanhydrousNa2SO4.The desired products were obtained in thecorresponding yields afterpurification by flashchromatography on silica gel eluting with petroleum andethylacetate.
70% With dipotassium peroxodisulfate In water at 100℃; Sealed tube General procedure: To a solution of isoquinoline 1a (0.5 mmol) in water (2 mL) was added keto acid 2a (1.25 mmol), followed by K2S2O8 (1.5 mmol). The reaction mixture contained in a sealed tube was heated at 100 °C for 4-6 h. The contents were then cooled in an ice-bath and quenched with the saturated solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (2 × 10 mL) The organic phase was washed with water, dried over anhydrous sodium sulphate and evaporated under diminished pressure to afford the crude residue. The residue was finally purified by column chromatography to obtain the pure acylated product 3a.
Reference: [1] Organic Letters, 2017, vol. 19, # 21, p. 5772 - 5775
[2] Synlett, 2018, vol. 29, # 14, p. 1881 - 1886
[3] Tetrahedron Letters, 2017, vol. 58, # 24, p. 2347 - 2350
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  • [ 75-07-0 ]
  • [ 58022-21-2 ]
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  • [ 64-17-5 ]
  • [ 58022-21-2 ]
Reference: [1] Russian Journal of Organic Chemistry, 2010, vol. 46, # 9, p. 1399 - 1402
  • 35
  • [ 119-65-3 ]
  • [ 58022-21-2 ]
Reference: [1] Journal of the American Chemical Society, 1945, vol. 67, p. 1268
[2] Journal of the American Chemical Society, 1945, vol. 67, p. 1268
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  • [ 56-23-5 ]
  • [ 64-17-5 ]
  • [ 58022-21-2 ]
  • [ 1258282-74-4 ]
Reference: [1] Russian Journal of Organic Chemistry, 2010, vol. 46, # 9, p. 1399 - 1402
  • 37
  • [ 67123-97-1 ]
  • [ 119-65-3 ]
  • [ 6624-49-3 ]
Reference: [1] Journal of the American Chemical Society, 1981, vol. 103, # 15, p. 4642 - 4643
[2] Journal of the American Chemical Society, 1981, vol. 103, # 15, p. 4642 - 4643
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Reference: [1] Journal of the American Chemical Society, 1945, vol. 67, p. 1268
[2] Journal of the American Chemical Society, 1945, vol. 67, p. 1268
[3] Chemische Berichte, 1905, vol. 38, p. 3432
  • 39
  • [ 119-65-3 ]
  • [ 7159-36-6 ]
Reference: [1] Patent: US2013/178457, 2013, A1,
[2] Patent: WO2013/5168, 2013, A2,
  • 40
  • [ 119-65-3 ]
  • [ 607-32-9 ]
YieldReaction ConditionsOperation in experiment
100% at -15 - 20℃; for 3.3 h; General procedure for the preparation of isoquinolin-5-amine (6)
To a solution of isoquinoline (3.0 g, 23.2 mmol) in 40 mL H2SO4 at -15 °C was added solid KNO3 (2.8 g, 27.8 mmol) in four successive equal portions in 30 min.
The reaction mixture was warmed to room temperature and stirred for 3 h, then poured into ice-water (100 mL).
The pH of the mixture was adjusted to 8-10 with a few drops of ammonia.
The precipitated solids were collected by filtration, washed with methyl-tert-butyl ether (100 mL * 2) and dried to provide 5 (4.0 g, 100percent yield) as a yellow solid.
To compound 5 (2.5 g, 14.4 mmol) in MeOH (50 mL) was added 10percent Pd/C (300 mg), and the mixture was stirred under an atmosphere of hydrogen at room temperature for 3 h.
The mixture was filtered and the filtrate was concentrated under vacuum to give the 6 (0.85 g, 41percent yield) as a tan solid.
94%
Stage #1: at -15 - 20℃;
Stage #2: With ammonium hydroxide In water at 0℃;
To a solution of isoquinoline (120g, 0.929 mol) in H2S04 (1 L) was added KN03 (1 12.6g, 1 .1 15mol) at -15 °C (portionwise). The mixture was stirred at room temperature for 2 hours. TLC (petroleum ether: ethyl acetate= 2: 1 ) showed the reaction was complete. The mixture was added to water (3L) at 0 °C. The mixture was adjusted to pH 8 by the addition of NH4OH and filtered. The filter cake was washed with methyl tertbutyl ether (1 L x 2) and concentrated in vacuo to give 5-nitro- isoquinoline (160g, 94percent) as a yellow solid.
94% at -15 - 20℃; for 2 h; To a solution of isoquinoline (120 g, 0.929 mol) in H2SO4 (10 was added KNO3 (112.6 g, 1.115 mol) at -15° C. (portionwise).
The mixture was stirred at room temperature for 2 hours. TLC (petroleum ether: ethyl acetate=2: 1) showed the reaction was complete.
The mixture was added to water (3 L) at 0° C.
The mixture was adjusted to pH 8 by the addition of NH4OH and filtered.
The filter cake was washed with methyl tertbutyl ether (1 L*2) and concentrated in vacuo to give 5-nitro-isoquinoline (160 g, 94percent) as a yellow solid.
94% at -15 - 20℃; for 2 h; To a solution of isoquinoline (120 g, 0.929 mol) in H2S04 (1 L) was added KNO3 (112.6 g, 1.115 mol) at -15°C (dropwise). The mixture was stirred at room temperature for 2 hours. TLC (petroleum ether: ethyl acetate= 2: 1) showed complete conversion. The mixture was added to water (3 L) at 0°C. The mixture was adjusted to pH 8 by the addition of NH4OH and filtered. The filter cake was washed with methyl tertbutyl ether (1 L x 2) and concentrated under vacuum to give 5-nitro- isoquinoline (160 g, 94percent) as a yellow solid.
66.76% at 0℃; for 2 h; A solution of potassium nitrate (0.04 mol, 4.05 g) in conc. sulphuric acid (23 mL) was added drop-wise to a solution of isoquinoline 1 (0.04 mol, 5 g) in 23 mL of conc. sulphuric acid, with a continual stirring at 0°C for 2 hr. After complete addition, the reaction mixture was poured into crushed ice, and neutralized by ~ 150 mL of ammonia solution. The obtained green precipitate was then filtered off. After drying, a crude pale green solid of 2 was obtained which was purified by recrystallization from toluene, giving dark green needles (4.5 g, 66.76percent).

Reference: [1] Bioorganic Chemistry, 2019, vol. 82, p. 100 - 108
[2] Patent: WO2012/146724, 2012, A2, . Location in patent: Page/Page column 49
[3] Patent: US2014/57942, 2014, A1, . Location in patent: Paragraph 0337-0338
[4] Patent: WO2014/68035, 2014, A1, . Location in patent: Page/Page column 35
[5] Journal of Organic Chemistry, 1986, vol. 51, # 11, p. 2011 - 2021
[6] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53, # 8, p. 1098 - 1109
[7] Organic Letters, 2017, vol. 19, # 1, p. 262 - 265
[8] Archiv der Pharmazie, 2015, vol. 348, # 5, p. 347 - 352
[9] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 8, p. 4617 - 4625
[10] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 22, p. 2623 - 2628
[11] Angewandte Chemie - International Edition, 2018, vol. 57, # 34, p. 11025 - 11029[12] Angew. Chem., 2018, vol. 130, p. 11191 - 11195,5
  • 41
  • [ 119-65-3 ]
  • [ 7664-93-9 ]
  • [ 7697-37-2 ]
  • [ 607-32-9 ]
  • [ 7473-12-3 ]
Reference: [1] Journal of the Chemical Society, 1957, p. 2521,2527
  • 42
  • [ 119-65-3 ]
  • [ 27655-40-9 ]
YieldReaction ConditionsOperation in experiment
60% at 20℃; Cooling with ice Isoquinoline 1a (47.5 mL, 405 mmol) was slowly added to 22 mL concentrated sulfuric acid, and stirred into small pieces.
Then the resulting mixture was added slowly in 20percent fuming sulfuric acid (200 mL).
The resulting clear solution was allowed to stand for 2 days at room temperature before being poured onto crushed ice (700 g).
The mixture was stood overnight.
The precipitate was collected by filtration, the cake was washed by water (100 mL*2) and dried in oven to give isoquinoline-5-sulfonic acid 1b (50 g, yield: 60percent), used in next step directly.
1H NMR (400 MHz, D2O): δ 9.66 (s, 1H), 8.94-8.92 (m, 1H), 8.62-8.60 (m, 2H), 8.58-8.56 (m, 1H), 8.50-8.48 (m, 1H), 7.99-7.95 (m, 1H).
MS-ESI cal. [M+H]+ 210, found 210.
24 g at 120℃; for 5 h; Add 20g isoquinoline to 300ml fuming sulfuric acid, heat to 120°C, stir for 5 hours, cool to room temperature,Pour slowly into ice water to precipitate a white solid which was filtered, washed with water and dried to give 24 g of 5-sulfonic acid isoquinoline.
Reference: [1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 9, p. 2317 - 2333
[2] Patent: US2017/37050, 2017, A1, . Location in patent: Paragraph 0064-0067
[3] Acta Poloniae Pharmaceutica, 1994, vol. 51, # 6, p. 479 - 482
[4] Patent: CN107778231, 2018, A, . Location in patent: Paragraph 0021; 0022
  • 43
  • [ 119-65-3 ]
  • [ 58142-46-4 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1891, vol. &lt;2&gt; 43, p. 199
  • 44
  • [ 119-65-3 ]
  • [ 63927-23-1 ]
YieldReaction ConditionsOperation in experiment
43%
Stage #1: at 20 - 25℃; for 22.25 h;
Stage #2: for 1.16667 h;
jV-Bromosuccinimide (17.80 g, 100 mmol) was added in portions over 15 min to a solution of isoquinoline (11.00 g, 85 mmol) in H2SO4 (cone, 100 mL) cooled to -25 °C. After stirring at rt for 22 h, KNO3 (11.12 g, 110 mmol) was added and the mixture was stirred for 70 min. The mixture was poured onto crushed ice and neutralised with NH3 (aq, sat, 100 mL). The precipitate was filtered off, washed with water and dried. Crystallisation from MeOH gave the sub-title product (9.27 g, 43percent) as a dark brown solid.1H NMR (DMSO-^6, 400 MHz) δ 10.01 (s, IH), 8.84 (d, IH), 8.19 (d, IH), 8.15 (d, IH), 8.11 (d, IH).
Reference: [1] Organic Syntheses, 2005, vol. 81, p. 96 - 104
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 3, p. 744 - 752
[3] Patent: WO2006/32851, 2006, A1, . Location in patent: Page/Page column 49
[4] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 22, p. 2623 - 2628
[5] Patent: WO2007/115408, 2007, A1, . Location in patent: Page/Page column 138
[6] ChemMedChem, 2014, vol. 9, # 1, p. 129 - 150
[7] Patent: CN105669547, 2016, A,
[8] Patent: US2004/157849, 2004, A1,
[9] Patent: WO2008/144931, 2008, A1, . Location in patent: Page/Page column 85
  • 45
  • [ 119-65-3 ]
  • [ 63927-23-1 ]
Reference: [1] Patent: US6500954, 2002, B1,
  • 46
  • [ 119-65-3 ]
  • [ 59139-93-4 ]
Reference: [1] Patent: WO2013/92979, 2013, A1,
  • 47
  • [ 119-65-3 ]
  • [ 34784-04-8 ]
  • [ 63927-22-0 ]
  • [ 81045-39-8 ]
Reference: [1] Synthesis, 2002, # 1, p. 83 - 86
  • 48
  • [ 119-65-3 ]
  • [ 55270-33-2 ]
Reference: [1] Chemical Communications, 2015, vol. 51, # 82, p. 15129 - 15132
[2] Organic Letters, 2015, vol. 17, # 18, p. 4408 - 4411
[3] Chemical Communications, 2015, vol. 51, # 100, p. 17744 - 17747
[4] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 5, p. 492 - 497
  • 49
  • [ 119-65-3 ]
  • [ 81045-39-8 ]
YieldReaction ConditionsOperation in experiment
56%
Stage #1: at 0℃;
Stage #2: at -25 - 20℃;
Stage #3: at 0℃; for 1 h;
Isoquinoline ( 13a) (1.83 ml, 15.50 mmol) was added slowly to concentrated H2SO4 ( 17 ml) at 0°C under stirring. The mixture was cooled at -25°C and sodium borohydride (6.34 g, 35.65 mmol) was added at a rate such that the reaction temperature was maintained between -25°C to -20°C. The resulting reaction was continued for 1 hour at the said temperature and then allowed to reach at room temperature. The reaction mixture was poured into crushed ice and the pH was adjusted to 7.0 using concentrated aqueous N¾. The resulting slurry was stirred for 1 hour at 0°C after which it was filtered and washed with ice-cold water. The crude product so obtained was air dried and purified by column chromatography to afford (2.5 g, 56percent) 5,8-dibromoisoquinoline (13b). MS (EI) rn/z: 286 (M+l). Ή NMR (400 MHz, DMSO-d6): 8 9.48 (s, 1H), 8.78 (d, J = 6 Hz, 1H), 8.06 (d, J = 8 Hz, 1H), 7.98 (dd, J = 6 Hz, J = 8 Hz, 2H).
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[2] Journal of Materials Chemistry C, 2015, vol. 3, # 22, p. 5835 - 5843
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 16, p. 4026 - 4030
[4] Patent: WO2013/5157, 2013, A1, . Location in patent: Page/Page column 36; 37
[5] Polymer, 2011, vol. 52, # 26, p. 6029 - 6036
[6] Reactive and Functional Polymers, 2011, vol. 71, # 8, p. 849 - 856
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  • [ 81045-39-8 ]
Reference: [1] Helvetica Chimica Acta, 1985, vol. 68, p. 1828 - 1834
[2] Helvetica Chimica Acta, 1985, vol. 68, p. 1828 - 1834
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 3, p. 744 - 752
  • 51
  • [ 119-65-3 ]
  • [ 34784-04-8 ]
  • [ 63927-22-0 ]
  • [ 81045-39-8 ]
Reference: [1] Synthesis, 2002, # 1, p. 83 - 86
  • 52
  • [ 32313-57-8 ]
  • [ 119-65-3 ]
  • [ 486-25-9 ]
  • [ 746-47-4 ]
  • [ 1940-57-4 ]
Reference: [1] Zeitschrift fuer Chemie (Stuttgart, Germany), 1985, vol. 25, # 12, p. 438
  • 53
  • [ 119-65-3 ]
  • [ 34784-07-1 ]
  • [ 91-21-4 ]
  • [ 75416-50-1 ]
Reference: [1] Synthesis (Germany), 2018, vol. 50, # 11, p. 2181 - 2190
  • 54
  • [ 119-65-3 ]
  • [ 84468-15-5 ]
Reference: [1] Patent: US2017/37050, 2017, A1,
  • 55
  • [ 119-65-3 ]
  • [ 205055-63-6 ]
Reference: [1] Patent: US2003/187026, 2003, A1,
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  • [ 119-65-3 ]
  • [ 77278-40-1 ]
  • [ 205264-33-1 ]
Reference: [1] Journal of the American Chemical Society, 2017, vol. 139, # 33, p. 11622 - 11628
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