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Chemical Structure| 91-21-4
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Product Details of [ 91-21-4 ]

CAS No. :91-21-4 MDL No. :MFCD00006896
Formula : C9H11N Boiling Point : -
Linear Structure Formula :- InChI Key :UWYZHKAOTLEWKK-UHFFFAOYSA-N
M.W : 133.19 Pubchem ID :7046
Synonyms :

Calculated chemistry of [ 91-21-4 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.33
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 45.78
TPSA : 12.03 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.0 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.82
Log Po/w (XLOGP3) : 1.57
Log Po/w (WLOGP) : 0.8
Log Po/w (MLOGP) : 1.8
Log Po/w (SILICOS-IT) : 2.52
Consensus Log Po/w : 1.7

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.1
Solubility : 1.06 mg/ml ; 0.00796 mol/l
Class : Soluble
Log S (Ali) : -1.43
Solubility : 4.91 mg/ml ; 0.0369 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.24
Solubility : 0.0759 mg/ml ; 0.00057 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.21

Safety of [ 91-21-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 91-21-4 ]

* 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 [ 91-21-4 ]
  • Downstream synthetic route of [ 91-21-4 ]

[ 91-21-4 ] Synthesis Path-Upstream   1~35

  • 1
  • [ 91-21-4 ]
  • [ 23707-37-1 ]
Reference: [1] Journal of the American Chemical Society, 2011, vol. 133, # 20, p. 8014 - 8027
[2] Synlett, 2013, vol. 24, # 3, p. 301 - 304
[3] Synlett, 2013, vol. 24, # 3, p. 301 - 304
[4] Patent: US9138427, 2015, B2,
  • 2
  • [ 91-21-4 ]
  • [ 23687-26-5 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1958, vol. 6, p. 497,500
  • 3
  • [ 956003-79-5 ]
  • [ 34784-07-1 ]
  • [ 91-21-4 ]
  • [ 75416-50-1 ]
Reference: [1] Synthesis (Germany), 2018, vol. 50, # 11, p. 2181 - 2190
  • 4
  • [ 119-65-3 ]
  • [ 34784-07-1 ]
  • [ 91-21-4 ]
  • [ 75416-50-1 ]
Reference: [1] Synthesis (Germany), 2018, vol. 50, # 11, p. 2181 - 2190
  • 5
  • [ 34784-04-8 ]
  • [ 34784-07-1 ]
  • [ 91-21-4 ]
  • [ 75416-50-1 ]
Reference: [1] Synthesis (Germany), 2018, vol. 50, # 11, p. 2181 - 2190
  • 6
  • [ 91-21-4 ]
  • [ 1532-72-5 ]
  • [ 24423-87-8 ]
YieldReaction ConditionsOperation in experiment
63% With urea hydrogen peroxide adduct In methanol at 0 - 20℃; for 7 h; General procedure B. To a stirred solution of amine (0.3-0.8 mmol) in methanol (0.5 M) was added at 0 °C UHP (3 mol equiv) and catalyst 1 (2 mol percent). The mixture was stirred at room temperature for the necessary time (see Table 2). The reaction mixture developed a red-orange colour that disappeared at different times depending on the amine type. The reaction mixture, then, remained yellow and in some cases a white precipitate formed. After removal of the solvent under reduced pressure, dichloromethane was added and the slurry formed was filtered through Celite. The solvent was evaporated and the crude residue purified by flash column chromatography.
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 52, p. 7079 - 7082
  • 7
  • [ 91-21-4 ]
  • [ 119-65-3 ]
  • [ 1532-72-5 ]
Reference: [1] Polish Journal of Chemistry, 2003, vol. 77, # 11, p. 1579 - 1586
  • 8
  • [ 91-21-4 ]
  • [ 25939-81-5 ]
Reference: [1] Heterocycles, 1982, vol. 19, # 4, p. 653 - 656
  • 9
  • [ 91-21-4 ]
  • [ 75-03-6 ]
  • [ 25939-81-5 ]
Reference: [1] Tetrahedron, 1986, vol. 42, # 9, p. 2571 - 2574
  • 10
  • [ 91-21-4 ]
  • [ 591-50-4 ]
  • [ 3340-78-1 ]
YieldReaction ConditionsOperation in experiment
94% With potassium <i>tert</i>-butylate; palladium diacetate; CyJohnPhos In <i>tert</i>-butyl alcohol at 100℃; for 0.0833333 h; Microwave irradiation; Inert atmosphere General procedure: To a 2-mL Biotage microwave vial equipped with a stirrer bar was added Pd(OAc)2 (5.6 mg, 5 mol-percent), CyJohnPhos (9.6 mg, 5.5 mol-percent), KOt-Bu (78.4 mg, 1.4 equiv.), and aryl iodide (0.5 mmol, 1 equiv.) (if solid aryl iodide used). The vial was sealed with an aluminium crimp-top cap fitted with a septum and purged with argon. t-BuOH (1.0 mL) was added via syringe, followed by aryl iodide (0.5 mmol, 1 equiv.) (if liquid aryl iodide used) and then 1,2,3,4-tetrahydroisoquinoline (75 mL, 1.2 equiv.). The vial was irradiated at 100 °C for 5 min, then cooled to room temperature. The reaction mixture was diluted with EtOAc (10 mL), then filtered through Celite. The resulting filtrate was washed with saturated NaCl solution, dried over MgSO4 and concentrated under reduced pressure to yield the crude product.
83% With copper(l) iodide In ethylene glycol; isopropyl alcohol at 85 - 90℃; for 24 h; Inert atmosphere Copper(I)iodide (39.8 mg, 0.21 mmol, 0.1 equiv.) and potas-sium phosphate (887.3 mg, 4.18 mmol, 2.09 equiv.) were weighedinto a round bottom flask which was evacuated and back filled with nitrogen for 3 times. 2-Propanol (2 ml), ethylene glycol(0.23 ml), iodobenzene (426.4 mg, 0.23 ml, 2.09 mmol, 1.05 equiv.)and 1,2,3,4-tetrahydroisoquinoline (0.27 g, 0.26 ml, 2.0 mmol, 1equiv.) were added via a syringe at room temperature. The reactionmixture was heated to 85–90C, stirred for 24 h and then allowedto cool to room temperature. Diethyl ether (5 ml) and water (5 ml)were then added to the reaction mixture. The organic layer wasextracted by diethyl ether (2 × 20 ml). The combined organic phaseswere washed with brine and dried over magnesium sulfate. Thesolvent was removed under vacuo and the crude mixture purifiedby column chromatography on silica gel (PE:EtOAc = 20:1). Com-pound 1 was obtained as light brown solid in 83percent yield (347 mg,1.66 mmol). M.p.: 43–46C;1H NMR (200 MHz, CDCl3) (ppm):3.01 (t,3J = 5.8 Hz, 2H), 3.59 (t,3J = 5.9 Hz, 2H), 4.44 (s, 2H), 6.85(t,3J = 7.2 Hz, 1H), 7.01 (d,3J = 7.9 Hz, 2H), 7.19–7.36 (m, 6H);13CNMR (50 MHz, CDCl3) (ppm): 29.83, 47.18, 51.41, 115.80, 119.34,126.51, 126.69, 127.00, 129.18, 129.83, 135.12, 135.51, 151.17
83% With potassium phosphate; copper(l) iodide In ethylene glycol; isopropyl alcohol at 90℃; for 24 h; Inert atmosphere Copper(I) iodide (39.8 mg, 0.21 mmol, 0.1 equiv.) and887.3 mg potassium phosphate (4.18 mmol, 2.09 equiv.)were weighed in a round flask which was evacuated andback filled with nitrogen three times. 2-Propanol (2 cm3),0.23 cm3 ethylene glycol, 426.4 mg iodobenzene(0.23 cm3, 2.09 mmol, 1.05 equiv.) and 0.27 g 1,2,3,4-tetrahydroisoquinoline (0.26 cm3, 2.0 mmol, 1 equiv.)were added via micro syringe at room temperature. Thereaction mixture was heated to 85–90 C, stirred for 24 hand then allowed to cool to room temperature. Diethylether (5 cm3) and 5 cm3 water were then added to thereaction mixture. The organic layer was extracted bydiethyl ether (2 9 20 cm3). The combined organic phaseswere washed with brine and dried over magnesium sulfate.The solvent was removed in vacuo and the crude mixturepurified by column chromatography on silica gel (PE:EtOAc= 20:1) to give 83percent (0.347 g, 1.66 mmol) of 1 as abeige solid. M.p.: 43–46 C (lit. m.p.: 45–46 C [27]);Rf = 0.69 (PE:EtOAc = 10:1).
75% With potassium phosphate; copper(l) iodide In ethylene glycol; isopropyl alcohol at 85 - 90℃; for 24 h; Schlenk technique; Inert atmosphere General procedure for the synthesis of 2-Phenyl-1,2,3,4-tetrahydroisoquinoline (1)[3] Copper (I) iodide (0.20 g, 1.0 mmol) and potassium phosphate (4.25 g, 20.0 mmol) were kept into a Schlenk tube. The tube was evacuated and back filled with nitrogen. 2-Propanol (10.0 mL), ethylene glycol (1.11 mL, 20.0 mmol), 1,2,3,4-tetrahydro-isoquinoline (2.0 mL, 15 mmol) and iodobenzene (1.12 mL, 10.0 mmol) were added successively by micro-syringe at room temperature. The reaction mixture was heated at 85-90 °C and kept for 24 h and allowed to cool to room temperature. Diethyl ether (20 mL) and water (20 mL) were added to the reaction mixture. The organic layer was extracted by diethyl ether (2 20 mL). The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed by rotary evaporation and purified by column chromatography on silica gel to give the desired product 1. 2-Phenyl-1,2,3,4-tetrahydroisoquinoline (1)[3] S4 Rf = 0.70 (SiO2, ethyl acetate-hexane, 1:20); yellow viscous liquid (75percent); 1H NMR (CDCl3, 400 MHz): δ 7.43 – 7.19 (m, 6H), 7.08 (d, J = 7.4 Hz, 2H), 6.92 (t, J = 6.5 Hz, 1H), 4.50 (s, 2H), 3.65 (d, J = 6.4 Hz, 2H), 3.08 (d, J = 5.7 Hz, 2H); 13C NMR (CDCl3, 101 MHz): δ 150.66, 134.99, 134.58, 129.32, 128.64, 126.66, 126.44, 126.14, 118.78, 115.26, 50.85, 46.65, 29.25; HRMS (ESI) m/z calcd. for C15H16N [M+H]+ 210.1277, found 210.1269; IR (KBr, Neat): ν = 3063, 3028, 2927, 2813, 1737, 1662, 1601, 1500, 1456, 1386, 1242, 1036, 931, 752, 695 cm-1.
60% With potassium phosphate; copper(l) iodide In ethylene glycol; isopropyl alcohol at 90℃; for 24 h; Inert atmosphere General procedure: Copper (I) iodide (0.21g, 1.13 mmol) and potassium phosphate (4.8 g, 22.6 mmol) were taken into the RB flask filled with nitrogen. 2-Propanol (10 mL), ethylene glycol (1.24 mL, 22.6 mmol), 1,2,3,4-tetrahydro-isoquinoline (2 g, 11.3 mmol) and iodobenzene (1.26 mL, 11.3 mmol) were added successively at room temperature. The reaction mixture was heated at 90 °C for 24 h and then allowed to cool to room temperature. The solvent was removed under vacuo, added water (20 mL) and extracted with dichloromethane (3x 30 mL). The organic layer was dried over sodium sulfate. The solvent was concentrated under reduced pressure and purified by column chromatography on silica gel (hexane/ethyl acetate=95:5), to give the desired product 4a with 30percent isolated yields.
60% With potassium dihydrogenphosphate; copper(l) iodide In isopropyl alcohol at 85 - 90℃; for 24 h; Schlenk technique Copper(I) iodide (200 mg, 1.0 mmol) and anhydrous potassium phosphate (4.25 g, 20.0 mmol) wereput into a Schlenk tube (No product was obtained when hydrated potassium phosphate was used). Thetube was evacuated and refilled with nitrogen. 2-Propanol (10 mL), ethylene glycol (1.11 mL, 20.0mmol), 1,2,3,4-tetrahydro-isoquinoline (2.0 mL, 15.0 mmol) and iodobenzene (1.12 mL, 10.0 mmol)were added successively using a syringe at room temperature. The reaction mixture was heated at85-90 °C and kept for 24 h. The reaction mixture was allowed to cool to ambient temperature, and thentransferred to a round-bottom flask. TLC, Rf = 0.2 (hexane); Rf = 0.7 (hexane/ethyl acetate = 20:1).Silica gel (3.0 g) was added, and the solvent was removed under reduced pressure to afford afree-flowing powder. This powder was then dryloaded onto a silica gel column and purified by flashchromatography using a petroleum ether/AcOEt mixture [from 50:1 to 20:1 (v/v)] as the eluent to givethe desired product in 60percent isolated yield.

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[3] Advanced Synthesis and Catalysis, 2017, vol. 359, # 16, p. 2832 - 2846
[4] Journal of Molecular Catalysis A: Chemical, 2017, vol. 426, p. 398 - 406
[5] Monatshefte fur Chemie, 2017, vol. 148, # 1, p. 91 - 104
[6] Organic and Biomolecular Chemistry, 2018, vol. 16, # 11, p. 1971 - 1975
[7] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 1000 - 1010
[8] Tetrahedron Letters, 2016, vol. 57, # 40, p. 4480 - 4483
[9] Green Chemistry, 2018, vol. 20, # 18, p. 4217 - 4223
[10] Journal of the American Chemical Society, 2018,
[11] Advanced Synthesis and Catalysis, 2015, vol. 357, # 16-17, p. 3424 - 3428
[12] Chemical Communications, 2011, vol. 47, # 42, p. 11787 - 11789
[13] Organic and Biomolecular Chemistry, 2012, vol. 10, # 4, p. 835 - 842
[14] Tetrahedron Letters, 2012, vol. 53, # 12, p. 1456 - 1459
[15] Journal of Organic Chemistry, 2018, vol. 83, # 12, p. 6754 - 6761
[16] Synlett, 2018, vol. 29, # 20, p. 2697 - 2700
[17] Organic Letters, 2018, vol. 20, # 24, p. 7933 - 7936
[18] Organic Letters, 2014, vol. 16, # 9, p. 2346 - 2349
[19] European Journal of Organic Chemistry, 2017, vol. 2017, # 42, p. 6338 - 6348
[20] Journal of the American Chemical Society, 2005, vol. 127, # 19, p. 6968 - 6969
[21] Tetrahedron Asymmetry, 2006, vol. 17, # 4, p. 590 - 597
[22] Tetrahedron Letters, 2009, vol. 50, # 11, p. 1199 - 1202
[23] Organic Letters, 2008, vol. 10, # 17, p. 3661 - 3663
[24] Journal of Organic Chemistry, 2009, vol. 74, # 19, p. 7464 - 7469
[25] Organic and Biomolecular Chemistry, 2010, vol. 8, # 18, p. 4077 - 4079
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  • [ 108-86-1 ]
  • [ 3340-78-1 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With {(4,5-dihydro-2-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-4,4-dimethyl-oxazole)CdCl}2(μ-Cl)2; potassium hydroxide In dimethyl sulfoxide at 110℃; for 0.166667 h;
Stage #2: at 110℃; for 4 h;
General procedure: Bromobenzene derivatives (0.5mmol, 1.0equiv), 1 (19mg, 0.05mmol, 0.1equiv) and potassium hydroxide (19mg, 0.5mmol, 1.0equiv) were added in DMSO (0.5mL), then the mixture was stirred for 10min at 110°C before the addition of alkylamines (1.0mmol, 2.0equiv). Next the reaction was stirred at 110°C for several hours, after which the crude reaction mixture was loaded directly onto a column of silica gel and purified by column chromatography to give the corresponding products.
54 %Spectr. With potassium <i>tert</i>-butylate; palladium diacetate; CyJohnPhos In toluene at 100℃; for 0.166667 h; Microwave irradiation; Inert atmosphere General procedure: To a 2-mL Biotage microwave vial equipped with a stirrer bar was added Pd(OAc)2 (5.6 mg, 5 mol-percent), CyJohnPhos (9.6 mg, 5.5 mol-percent), KOt-Bu (78.4 mg, 1.4 equiv.), and aryl iodide (0.5 mmol, 1 equiv.) (if solid aryl iodide used). The vial was sealed with an aluminium crimp-top cap fitted with a septum and purged with argon. t-BuOH (1.0 mL) was added via syringe, followed by aryl iodide (0.5 mmol, 1 equiv.) (if liquid aryl iodide used) and then 1,2,3,4-tetrahydroisoquinoline (75 mL, 1.2 equiv.). The vial was irradiated at 100 °C for 5 min, then cooled to room temperature. The reaction mixture was diluted with EtOAc (10 mL), then filtered through Celite. The resulting filtrate was washed with saturated NaCl solution, dried over MgSO4 and concentrated under reduced pressure to yield the crude product.
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[2] Inorganica Chimica Acta, 2015, vol. 427, p. 226 - 231
[3] Chemistry - A European Journal, 2017, vol. 23, # 39, p. 9313 - 9318
[4] Chemistry - A European Journal, 2018, vol. 24, # 37, p. 9269 - 9273
[5] Chemical Communications, 2014, vol. 51, # 2, p. 334 - 337
[6] Journal of Organic Chemistry, 2004, vol. 69, # 19, p. 6504 - 6506
[7] Synthetic Communications, 2001, vol. 31, # 7, p. 987 - 992
[8] Journal of Organometallic Chemistry, 2012, vol. 720, p. 7 - 18,12
[9] Journal of Chemical Research, 2013, vol. 37, # 2, p. 99 - 101
[10] Australian Journal of Chemistry, 2015, vol. 68, # 12, p. 1890 - 1893
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Reference: [1] Organic Letters, 2003, vol. 5, # 23, p. 4397 - 4400
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  • [ 98-80-6 ]
  • [ 3340-78-1 ]
Reference: [1] Organic Letters, 2003, vol. 5, # 23, p. 4397 - 4400
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  • [ 930-68-7 ]
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Reference: [1] Organic Letters, 2012, vol. 14, # 21, p. 5606 - 5609,4
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  • [ 88284-48-4 ]
  • [ 3340-78-1 ]
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  • [ 325723-04-4 ]
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  • [ 66003-78-9 ]
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  • [ 603-33-8 ]
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  • [ 3076-54-8 ]
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Reference: [1] Tetrahedron Letters, 1987, vol. 28, # 27, p. 3111 - 3114
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  • [ 42923-79-5 ]
YieldReaction ConditionsOperation in experiment
80% With P2O5/silica gel; nitric acid In water at 20℃; for 0.333333 h; In a mortar 2 g of P2O5/silica gel (65percent w/w)1 (10 mmol) and 1,2,3,4-tetrahydroisoquinoline (10 mmol, 1.33 g) was triturated for 30 s, and then 5 ml of HNO3 65percent was added drop-wise and the mixture was further triturated with a pestle at room temperature for 20 min until a deep-yellow color appeared, at which point TLC (n-hexane:EtOAc 70:30) showed complete disappearance of 1,2,3,4-tetrahydroisoquinoline (30 min). To the reaction mixture was added diethyl ether (50 ml) and the solid was separated through a short pad of silica gel and washed with diethyl ether (2 .x. 15 ml). The filtrate was washed with NaHCO3 10percent (20 ml) and dried (MgSO4). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (n-Hexane:EtOAc, 2:1), 7-nitro-1,2,3,4-tetrahydroisoquinoline (2b) was obtained (8 mmol, 1.4 g 80percent) as a yellow solid, mp 121 °C. 1H NMR, δ: 8.05 (m, 2H), 7.60 (m, 1H,), 3.82 (s, 2H), 3.38 (t, 2H, J = 7.4 Hz), 3.12 (t, 2H, J = 7.4 Hz), 2.83 (s, 1H). 13C NMR, δ: 150.6, 145.0, 140.3, 129.6, 122.6, 121.4, 46.9, 44.1, 28.1. EMS [M+H+] for C9H10N2O2, Calcd 179.0740. Found, 179.1121.
50%
Stage #1: at 0 - 20℃;
Stage #2: With ammonia In water
Stage #3: With hydrogenchloride In water
An ice-cold solution of 12 (10.8g, 80mmol) in concentrated sulfuric acid (40mL) is treated with potassium nitrate (8.8g, 87mmol) in small portions, keeping the temperature below 5 °C. The reaction is left overnight at room temperature and poured onto ice. The resulting solution is basified WITH NH3. H20, extracted with CH2Cl2 and concentrated to dryness. The crude product obtained is converted to the hydrochloride salt. Crystallization from methanol gave 8. 5g of the hydrochloride (yield 50 percent), which is basified to give compound 8.APOS;H NMR (300MHz, CDCl3) 6 7.98 (1H, d, H-6), 7.91 (1H, s, H-8), 7.24 (1H, d, H-5), 4.10 (2H, s, H-1), 3.17 (2H, t, H-3), 2.89 (2H, t, H-4).
41% at 5 - 20℃; for 27 h; Synthesis of 7-nitro-1,2,3,4-tetrahydroisoquinoline (31-2)
1,2,3,4-Tetrahydroisoquinoline (4.0 g, 30.0 mmol) was dissolved in 10 N of sulfuric acid (6 mL, 30.0 mmol) and then evaporated to dryness to afford a solid residual.
This sulfate was added slowly to a solution of potassium nitrate (3.34 g, 33.0 mmol) in sulfuric acid (15 mL), taking care that the temperature of the reaction mixture did not rise above 5° C.
After being stirred at room temperature for a further 27 h, the reaction mixture was slowly poured into a con. ammonium solution (ca. 100 mL) under ice cooling.
The resulted solution was extracted with dichloromethane (100 mL*3).
The combined organic phase was washed with brine (150 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (DCM:MeOH=100:1) to afford 31-2 as a brown solid (2.24 g, yield 41percent).
34% at 5 - 20℃; for 18 h; To ice cold concentrated sulfuric acid was added in a dropwise manner 1,2, 3,4- tetrahydroisoquinoline (23 mL, 170 MMOL), followed by potassium nitrate (18.8 g, 186 mmol) at such a rate that the temperature did not rise above 5 °C. After complete addition the mixture was stirred at room temperature for 18 h then poured onto a stirred mixture of ice (700 g) and NH40H (150 ML). The mixture was extracted with CHC13 (3 x 300 mL). The combined CHCl3 layers were washed with saturated NaCl (200 ML), dried over NA2SO4, filtered and concentrated in vacuo. The residue was dissolved in ethanol (130 mL) and cooled in an ice bath as concentrated hydrochloric acid (22 mL) was added. The formed precipitate was removed by filtration and recrystallized from methanol to give the product (12.45 g, 34 percent) ; H NMR 500MHZ (DMSO-d6) No. = 3,. 13 (2H, t, J = 6. 2 Hz), 3.35 (2H, t, J = 6. 2 Hz), 4.35 (2H, s), 7.50 (LH, d, J=8. 5HZ), 8.07 (1H, dd, J=2. 3and8. 5Hz), 8.19 (1H, d, J=2. 3Hz) 10.02 (2H, br S).
34% at 5 - 20℃; for 18 h; EXAMPLE 110; Step A; To ice cold concentrated sulfuric acid was added in a dropwise manner 1,2,3,4-tetrahydroisoquinoline (23 mL, 170 mmol), followed by potassium nitrate (18.8 g, 186 mmol) at such a rate that the temperature did not rise above 5° C. After complete addition the mixture was stirred at room temperature for 18 h then poured onto a stirred mixture of ice (700 g) and NH4OH (150 mL). The mixture was extracted with CHCl3 (3.x.300 mL). The combined CHCl3 layers were washed with saturated NaCl (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in ethanol (130 mL) and cooled in an ice bath as concentrated hydrochloric acid (22 mL) was added. The formed precipitate was removed by filtration and recrystallized from methanol to give the product (12.45 g, 34percent); 1H NMR 500 MHz (DMSO-d6) δ=3.13 (2H, t, J=6.2 Hz), 3.35 (2H, t, J=6.2 Hz), 4.35 (2H, s), 7.50 (1H, d, J=8.5 Hz), 8.07 (1H, dd, J=2.3 and 8.5 Hz), 8.19 (1H, d, J=2.3 Hz) 10.02 (2H, br s).

Reference: [1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 24, p. 7435 - 7440
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[3] Journal of Medicinal Chemistry, 2003, vol. 46, # 5, p. 831 - 837
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[5] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 307
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[7] Patent: WO2004/94371, 2004, A2, . Location in patent: Page 140
[8] Patent: US2008/81803, 2008, A1, . Location in patent: Page/Page column 69-70
[9] Chemical and Pharmaceutical Bulletin, 1958, vol. 6, p. 497,500
[10] Journal of the Chemical Society, 1951, p. 2851
[11] Chemical and Pharmaceutical Bulletin, 1958, vol. 6, p. 497,500
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[14] Patent: EP1200375, 2004, B1, . Location in patent: Page 7
[15] Patent: US5936089, 1999, A,
[16] Patent: WO2007/42806, 2007, A1, . Location in patent: Page/Page column 58
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[18] Patent: WO2005/108367, 2005, A1, . Location in patent: Page/Page column 13; 27-28
[19] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 2, p. 786 - 789
[20] Patent: WO2012/6203, 2012, A1, . Location in patent: Page/Page column 67-68
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Reference: [1] Synthesis (Germany), 2018, vol. 50, # 11, p. 2181 - 2190
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  • [ 99365-69-2 ]
YieldReaction ConditionsOperation in experiment
52.3%
Stage #1: at 0℃; for 2 h;
Stage #2: at 25℃;
Stage #3: With hydrogenchloride In isopropyl alcohol at 0℃;
1,2,3,4-Tetrahydroisoquinoline (50 g; 1 equiv.) was added at 0° C., in the course of 90 minutes, to 185 ml of sulfuric acid, and the reaction mixture was stirred for 30 minutes at 0° C. Potassium nitrate (40.7 g; 1.2 equiv.) was then added in portions, and stirring was carried out for 15 hours at room temperature. When the conversion was complete, the reaction mixture was shaken on 500 g of ice and adjusted to pH 8-9 with ammonia solution. Extraction with chloroform was then carried out 3 times, and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in IPA (500 ml) and cooled to 0° C., and hydrochloric acid (2 equiv.) was added. The resulting solid was filtered out and recrystallised from methanol. 7-Nitro-1,2,3,4-tetrahydroisoquinoline (35 g; 52.3percent) was obtained in the form of a white solid.
48%
Stage #1: With sulfuric acid; potassium nitrate In ethanol at 5 - 20℃;
Stage #2: With hydrogenchloride In ethanol
7-Nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride
This compound is described in the literature for Buolamwini et al. J. Med. Chem.
2003, 46, 831-837, which are hereby incorporated by reference and form part of the disclosure.
A cold solution of 1,2,3,4-tetrahydroisoquinoline (13.3 g, 0.1 mol) in concentrated sulfuric acid (50 mL) was treated with potassium nitrate (11.12 g, 1.1 mol) in small portions, keeping the temperature below 5° C.
The reaction was left overnight at room temperature and poured onto ice.
The resulting solution was basified with ammonium hydroxide, extracted with CH2Cl2, dried and evaporated to dryness in vacuo.
The crude was dissolved in 100 mL ethanol.
A 2.8 M solution of hydrogen chloride in ethanol (40 mL) was then added.
The precipitate formed was collected by filtration and crystallized from methanol to give the product (10.30 g, 48percent yield) as a white solid.
Melting point: 268-270° C.
IR cm-1(KBr): 2944, 2764, 1589, 1523, 1429, 1345, 1090.
1H NMR (300 MHz, DMSO-d6) d ppm: 3.13 (t, f-6.15 Hz, 2H), 3.35 (t, J=6.22 Hz, 2H), 4.35 (s, 2H), 7.50 (d, J=8.49 Hz, 1H), 8.08 (dd, J=8.49, 2.49 Hz, 1H), 8.19 (d, J=2.34 Hz, 1H), 9.96 (s, 2H)
42%
Stage #1: at 20℃; Cooling with ice
To 11 mL of 9 concentrated sulfuric acid in an ice bath was added 0 1,2,3,4-tetrahydroisoquinoline (2.9 g, 21 mmol), and 0 potassium nitrate (2.4 g, 24 mmol) was added slowly. The mixture was allowed to increase to room temperature and react overnight. Then the reaction liquid was poured into ice water, and pH was adjusted to around 10 with concentrated aqueous ammonia. After extraction with DCM three times, organic layers were combined and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure to obtain oil. The oil was dissolved in 16 mL of ethanol in an ice bath, and 3 mL of concentrated HCl was added to generate plenty of solid, which was subjected to suction filtration and drying. After recrystallization with methanol, 1.9 g of beige solid was obtained with a yield of 42percent.
42%
Stage #1: at 0℃; for 0.166667 h;
Stage #2: at 20℃; for 16 h;
Stage #3: With hydrogenchloride In ethyl acetate
1,2,3,4-tetrahydroisoquinoline (2.5 mL, 2.0 mmol) is dripped to H2SO4 (10 mL, 18.0 mmol) at 0 °C in 10 min, after that potassium nitrate (2.16 g, 2.14 mmol) is added in batches, and the temperature is increased to room temperate, then the mixture continues to react for 16 hrs.
And then the reaction mixture is poured into ice water (50 mL), washed with ethyl acetate (30 mL * 2), and pH of the aqueous layer is adjusted to approximately 9∼10 with ammonium hydroxide, then the aqueous layer is extracted with ethyl acetate (50 mL * 2), dried with anhydrous Na2SO4 and rotated to dryness.
The resulted product is dissolved in ethyl acetate (20 mL) and its pH is adjusted to approximately 4∼5 with HCl dissolved in ethyl acetate solution, then the mixture is filtered and washed, dried, to obtain a yellow solid of 1.8 g, that is 7-nitro-1,2,3,4-tetrahydroiso-quinoline hydrochloride with a yield of 42percent.
Spectrum is: 1H NMR (400 MHz, DMSO) δ: 9.91(s, 2H), 8.20(d, J = 1.6 Hz, 1H), 8.10(dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.52(d, J = 8.4 Hz, 1H), 4.37(s, 2H), 3.38(t, J = 6.0 Hz, 2H), 3.15(t, J = 6.0 Hz, 2H).
39% With hydrogenchloride; potassium nitrate In concentrated H2 SO4; ethanol (a)
1,2,3,4-Tetrahydroisoquinoline (50 g, 0.376M) was dissolved in concentrated H2 SO4 (180 ml) with cooling.
Solid potassium nitrate (40.4 g, 0.4M) was added in portions, keeping the temperature below 5° C., over 4 hours.
The reaction mixture was allowed to stand overnight at room temperature and was then poured onto ice, basified with NH4 OH and was then extracted with CHCl3.
After evaporation, the residue was dissolved in ethanol and concentrated HCl was added.
The resulting precipitated hydrochloride salt was filtered off and recrystallized from methanol to yield 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (31.5 g, 39percent), m.p. 268°-269° C.
23%
Stage #1: at -5 - 0℃;
Stage #2: With hydrogenchloride In ethanolCooling with ice
1,2,3,4-Tetrahydroisoquinoline (6.3 mL, 50.0 mmol) was added dropwise to a stirred ice-cold solution of concentrated H2SO4 (25 mL). KNO3 (5.6 g, 55.0 mmol) was added portionwise while maintaining the temperature below 5° C.
The mixture was stirred at room temperature overnight, carefully poured into an ice-cold solution of concentrated NH4OH, and then extracted three times with CHCl3.
The combined organic layers were washed with brine, dried over Na2SO4 and concentrated.
The resulting dark brown oil was taken up into EtOH, cooled in an ice bath and treated with concentrated HCl.
The yellow precipitate was collected via filtration and recrystallized from methanol to give 1,2,3,4-tetrahydro-7-nitroisoquinoline hydrochloride as yellow solid (2.5 g, 23percent).
1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 2H), 8.22 (d, J=1.6 Hz, 1H), 8.11 (dd, J=8.5, 2.2 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 4.38 (s, 2H), 3.38 (s, 2H), 3.17-3.14 (m, 2H); HPLC ret. time 0.51 min, 10-99percent CH3CN, 5 min run; ESI-MS 179.0 m/z (MH+).
23%
Stage #1: at 0 - 20℃;
Stage #2: With ammonium hydroxide In water at 20℃; Cooling
Stage #3: With hydrogenchloride In ethanol; water
Concentrated sulfuric acid (70 mL) was cooled in an ice-salt bath to 00C. 1,2,3,4- <n="109"/>Tetrahydroisoquinoline (96percent, 19.6 g, 141 mmol) was added dropwise in portions over 35 minutes, with the temperature mostly staying below 200C, but occasional brief excursions as high as 400C. The resulting mixture was again cooled in an ice-salt bath to 00C and solid potassium nitrate (15.7 g, 155 mmol) was added in portions over 60 minutes, keeping the temperature mostly below 5°C with occasional brief excursions as high as 7°C. Following completion of addition, the bath was removed and the resulting mixture was allowed to stir overnight at ambient temperature. The mixture was added carefully in small portions over 2 hours to concentrated ammonium hydroxide (200 mL), cooled initially in an ice-salt bath to - 2°C. The resulting mixture was diluted with chloroform (400 mL) and the mixture stirred overnight at ambient temperature. Additional concentrated ammonium hydroxide was added to bring the pH to about 11. The mixture was transferred to a separatory funnel and the organic layer was dried over sodium sulfate and evaporated to give about 25 g of dark red oil. This oil was redissolved in ethanol (100 mL), and to the resulting stirred solution was added concentrated hydrochloric acid (10 mL). The mixture immediately formed a hard solid. Additional ethanol (100 mL) and concentrated hydrochloric acid (10 mL) were added, and after stirring for a few minutes, the resulting precipitate was collected by filtration, washed with ethanol, and air-dried. The precipitate was heated to boiling with methanol (200 mL), and the mixture was allowed to cool to ambient temperature and stand overnight. The precipitate was collected by filtration, washed with methanol, and dried under vacuum to afford 7-nitro-l,2,3,4-tetrahydroisoquinoline hydrochloride as an off-white solid (7.05 g, 23percent yield).

Reference: [1] Patent: US2010/234340, 2010, A1, . Location in patent: Page/Page column 21
[2] Patent: US2006/40978, 2006, A1, . Location in patent: Page/Page column 9
[3] Chemistry - A European Journal, 2009, vol. 15, # 4, p. 885 - 900
[4] Patent: EP3363803, 2018, A1, . Location in patent: Paragraph 0153
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YieldReaction ConditionsOperation in experiment
22% With hydrogenchloride; sodium hydroxide; sulfuric acid; nitric acid In ethanol Step 1
Conc. sulfuric acid (80 ml) was added by small portions to tetrahydroisoquinoline (24.4 g, 183 mmol) under ice-cooling for dissolution.
Then, 60percent nitric acid (18 ml) was added dropwise from a funnel and the mixture was stirred under ice-cooling for 3 hr.
The mixture was stirred at room temperature for 18 hr.
The reaction mixture was diluted with water under ice-cooling, and 35percent aqueous sodium hydroxide solution was added to adjust the solution to pH 12.
After extraction with chloroform, the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was dissolved in ethanol (180 ml) and conc. hydrochloric acid (20 ml) was added under ice-cooling.
The precipitated brown crystals were collected by filtration with suction to give 7-nitrotetrahydroisoquinoline hydrochloride (7.18 g, 22percent).
Reference: [1] Patent: US6410561, 2002, B1,
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