* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With 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
[2] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 329 - 331
[3] Journal of Medicinal Chemistry, 2003, vol. 46, # 5, p. 831 - 837
[4] Patent: WO2004/60902, 2004, A2, . Location in patent: Page/Page column 15
[5] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 307
[6] Organic Letters, 2013, vol. 15, # 23, p. 5928 - 5931
[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
[12] Journal of Medicinal Chemistry, 1997, vol. 40, # 25, p. 3997 - 4005
[13] Journal of Medicinal Chemistry, 1998, vol. 41, # 21, p. 4036 - 4052
[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
[17] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 3, p. 633 - 637
[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
3
[ 181514-37-4 ]
[ 42923-79-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 23, p. 4583 - 4591
[2] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 8, p. 2085 - 2094
[3] Patent: WO2006/12374, 2006, A1, . Location in patent: Page/Page column 226-227
[4] Patent: WO2007/48070, 2007, A2, . Location in patent: Page/Page column 117
Synthesis of 7-nitroisoquinoline (31-3) Under refluxing, a solution of iodine (4.0 g, 15.9 mmol) in ethanol (56 mL) was added dropwise to a stirred solution of 31-2 (2.0 g, 9.34 mmol) in ethanol (24 mL) during 5 h. Then the resulted mixture was stirred for a further 66 h. The solvent was removed and the residual was loaded onto a silica gel chromatography column (PE:EA=6:1) to give 31-3 as a brown dark solid (602 mg, yield 36%).
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1h;
Acetyl chloride (1.3 g, 16.6 mmol) was slowly added to a solution of 7-nitro-1,2,3,4- tetrahydroisoquinoline (33.1) (2.0 g, 11.2 mmol) and triethylamine (2.3 g, 22.4 mmol) in THF (20 mL) at 0 C, and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated to afford the crude product. The crude product was purified by column chromatography (DCM/MeOH: 20/1) to afford 1-(7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (49.1) as a brown solid (2.4 g, 97%). [00696] LCMS: 221.2 [M+1]+.
96%
With triethylamine; In tetrahydrofuran; at 0℃; for 0.5h;
To a slurry containing 710 mg (3.3 mmol) of 7-NITRO-1, 2,3, 4-TETRAHYDROISOQUINOLINE and 10 mL of THF at 0C was added 1.15 mL (8.3 MMOL) of triethylamine, followed by 0.25 mL (3.5 MMOL) of acetyl chloride. The reaction mixture was allowed to stir for 30 min, then diluted with ethyl acetate, washed with water and brine, and dried over MGS04. The solvents were removed under reduced pressure to give the title compound as a brown oil (700mg, 96%).'H NMR (300 MHz, CDCI3) A 2.19 (s, 1.8H), 2.20 (s, 1.2H), 2.94 (t, 0.8H, J = 5.7 Hz), 3.00 (t, 1.2H, J = 5.7 Hz), 3.72 (t, 0.8H, J = 6.0 Hz), 3.86 (t, 1.2H, J = 6.0 Hz), 4.71 (s, 0.8H), 4.82 (s, 1.2H), 7.32 (dd, 1 H, J = 8.4 Hz), and 8.01-8. 07 (m, 2H); ESIMS : 221.0 (M+H) +
50%
To a stined solution of <strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydroisoquinoline</strong> (1 g, 5.62 mmol) in THF (15 mL) was added Et3N (1.6 mL, 14.04) at 0 C. After 5 mm, acetyl chloride (0.35 mL, 5.62 mmol) was added at 0 C, and the reaction was stined at RT for 2 h. The reaction was diluted with water (15 mL) and extracted with EA (2 x 50 mL). The combined organic layers were washed with water (15 mL), brine (25 mL), dried (Na2SO4) and concentrated in vacuo. The crude mixture was triturated with pentane to afford 1 -(7-nitro- 3,4-dihydroisoquinolin-2(1H)-yl)ethanone (600 mg, 50%) as a pale yellow solid. MS (ESI) mlz 221.2 [M+H].
To a suspension of the product from Step A (12 g, 58 MMOL), and pyridine (23.7 mL, 293 mmol) in anhydrous CHZCIZ (50 mL) cooled at 0 C was added in a dropwise manner trifluoroacetic anhydride (12 ML, 87 MMOL), and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was poured onto ice (500 g) and extracted with CH2CI2 (4 x 150 mL). The combined CH2CI2 layers were washed with 1 N HCl (4 x 100 ML), saturated NaCl (100 mL), dried over NA2SO4, filtered and evaporated IN VACUO to give the product (15.92 g, 89 %) ; H NMR 500MHZ (CDCl3) 8 = 3.07 (2H, m), 3.91 and 3.94 (2H, t, J = 6. 2 HZ), 4. 85 and 4.88 (2H, s), 7.36 (1H, dd, J = 8.7 and 11.9 Hz), 8.07 (1H, dd, J=2. 3AND 8.5 Hz), 8.01-8. 08 (2H m).
89%
With triethylamine; In dichloromethane; at 0 - 20℃; for 18h;
Step B; To a suspension of the product from Step A (12 g, 58 mmol), and pyridine (23.7 mL, 293 mmol) in anhydrous CH2Cl2 (50 ml) cooled at 0 C. was added in a dropwise manner trifluoroacetic anhydride (12 mL, 87 mmol), and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was poured onto ice (500 g) and extracted with CH2Cl2 (4×150 mL). The combined CH2Cl2 layers were washed with 1 N HCl (4×100 mL), saturated NaCl (100 mL), dried over Na2SO4, filtered and evaporated in vacuo to give the product (15.92 g, 89%); 1H NMR 500 MHz (CDCl3) delta=3.07 (2H, m), 3.91 and 3.94 (2H, t, J=6.2 Hz), 4.85 and 4.88 (2H, s), 7.36 (1H, dd, J=8.7 and 11.9 Hz), 8.07 (1H, dd, J=2.3 and 8.5 Hz), 8.01-8.08 (2H m).
1,2,3,4-tetrahydroiosquinoline (Aldrich Tl,300-5, 100 gm) (11.6 g, 84.8 mmol) is added dropwise with care to stirred ice-cold concentrated H2S04 (42.0 mL). Potassium nitrate (9.40 g. , 93 mmol) is then added in small portions, taking care that the temperature of the reaction mixture does not rise above 5 °C. After stirring overnight at room temperature the dark brown reaction mixture is added carefully to a stirred ice-cold concentrated NH40H solution. The basic red reaction mixture is extracted with chloroform (three times), and the combined chloroform extracts is washed with brine and dried over anhydrous Na2S04. Evaporation of the solvent gives a dark brown oil (14.6 g) which was taken up in EtOH (65 mL) and cooled in an ice bath. Treatment of this reddish solution with concentrated HCI (11 mL) yields a viscous yellow precipitate of the hydrochloride salt which is filtered and crystallized from methanol (250 mL) to yield the product compound (2) as a solid (5.36 g, ~30percent yield). Alternatively, flash chromatography may be used to purify the crude reaction mixture before crystallization.
palladium 10% on activated carbon; In diethylene glycol; at 220℃; for 0.416667h;Microwave radiation;
A mixture of 7-nitro-l,2,3,4-tetrahydro-isoquinoline(1.5g, 8.38 mmole) and 10% Pd/C (300 mg) in diethyleneglycol (5 mL) was reacted in a Smith Synthesizer undermicrowave radiation at 220 2C for 25 min. The resultingmixture was diluted with MeOH and filtered. The filtrate wasconcentrated and diluted with CH2C12, washed with sat. aq.NH4C1 and dried over Na2S04. After filtration andconcentration, the title compound was isolated through flashchromatography (eluted with CH2Cl2:MeOH 9:1) as an orangesolid. MS: (ES+) 145(M+H). Calc'd. for C9H8N2 - 144.07.
With hydrogen;palladium 10% on activated carbon; In diethylene glycol; at 220℃; for 0.416667h;microwave radiation;
The mixture of 7-Nitro- 1,2,3, 4-tetrahydro-isoquinoline (1.5 g, 8.38 mmole) and 10% Pd/C (300 mg) in diethyleneglycol (5 mL) was submitted to Smith Synthesizer under microwave radiation at 220 C for 25 min. The resulting mixture was diluted with MeOH arid filtered. The filtrate was concentrated and diluted with CH2Cl2, washed with sat'a'q. ' NH4CI and dried over Na2SO4. After filtration and concentration, the desired compound was isolated through flash chromatography (eluted with CH2Cl2:Me0H 9: 1) as an orange solid. MS: (ES+) 145(M+H). Calc'd. for C9H8N2 - 144.07.
2-(4,5-Dihydro-1H-imidazol-2-yl)-7-nitro-1,2,3,4-tetrahydroisoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In methanol; diethyl ether; water;
Step 1 2-(4,5-Dihydro-1H-imidazol-2-yl)-<strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydroisoquinoline</strong> A mixture of 10 g of <strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydroisoquinoline</strong>, 13.7 g of 2-methylsulphanyl-4,5-dihydro-1H-imidazole hydriodide and 100 ml of methanol is heated at reflux for 12 hours. The addition of diethyl ether causes the separation of a precipitate, which is taken up in water, neutralised using sodium hydroxide and extracted with dichloromethane.
7-Nitro-2-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-1,2,3,4-tetrahydroisoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
STR52 7-Nitro-2-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-1,2,3,4-tetrahydroisoquinoline Following the procedure described for Example 1, Step 6 but using <strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydroisoquinoline</strong>, the title compound was obtained (after treatment with HCl in ether) as a white solid.
2-[(4-cyanophenyl)-acetyl]-7-nitro-1,2,3,4-tetrahydro-isoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; ethyl acetate; chlorobenzene;
a. 2-[(4-cyanophenyl)-acetyl]-<strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydro-isoquinoline</strong> 4.0 g (22.5 mmol) of <strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydro-isoquinoline</strong> are dissolved in 100 ml of chlorobenzene, mixed with 4.24 g (25 mmol) of 4-cyanophenylacetic acid chloride and refluxed for 2 hours. After cooling to ambient temperature the mixture is diluted with 11 of petroleum ether and filtered. The residue is dissolved in ethyl acetate and chromatographed on silica gel, eluding first with methylene chloride, later with methylene chloride/ethanol (50:1 and 25:1). The desired fractions are combined and evaporated down. Yield: 3.80 g (53% of theory), Rf -value: 0.50 (silica gel; methylene chloride/ethanol=19:1).
a) 7-nitro-1,2,3,4-tetrahydro-isoquinoline. To a mixture of 7-nitro-1,2,3,4-tetrahydroisoquinolinone (1.50 g, 7.8 mmol) in THF (15 mL) was added 2M borane methylsulfide in THF (9.0 mL, 18 mmol) dropwise. After addition was complete, the clear solution was heated to reflux for 4 h. The solution was s cooled to RT, and dry hydrogen chloride was bubbled into the solution to pH 2. The solution was heated to reflux for 1.5 h, cooled to 0 C. and diluted with ether. The resulting white solid was filtered and dried in vacuo to yield the title compound (1.62 g, 76%). MS(ES) m/e 179 [M+H]+.
ethyl 7-nitro-1,2,3,4-tetrahydro-isoquinoline-2-acetate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; triethylamine; In 1,4-dioxane; ethanol;
(12-1) The raw material <strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydroisoquinoline</strong> was prepared according to Heterocyclic Chemistry,22, 329 (1985). In 20 ml of ethanol, 2.89 g of <strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydroisoquinoline</strong> was dissolved, 3.9 ml of triethylamine and 2.25 g of ethyl bromoacetate were added, and the mixture was refluxed by heating for an hour. After 1 hour, most of the solvent was distilled off under reduced pressure. The concentrated residue was extracted with ethyl acetate and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The crude product obtained was purified by silica gel column chromatography using a mixture, ethyl acetate:n-hexane=1:3, as a developer and successively treated with a hydrochloric acid/dioxane solution to give 2.14 g of ethyl <strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydroisoquinoline</strong>-2-acetate hydrochloride.
With hydrogenchloride; triethylamine; In 1,4-dioxane; ethanol;
(5-1) The raw material <strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydroisoquinoline</strong> was prepared according to Heterocyclic Chemistry, 22, 329 (1985). 7-Nitro-1,2,3,4-tetrahydroisoquinoline (5.78 g) was dissolved in ethanol (400 ml), triethylamine (7.8 ml) and ethyl bromoacetate (4.5 g) were added, and the mixture was heated and refluxed for 1 hour. Most of the solvent was distilled off under reduced pressure, concentrated residue was extracted with ethyl acetate and the extracted solution was dried with anhydrous magnesium sulfate. The solvent distilled off under reduced pressure and the crude product obtained was purified by silica gel column chromatography using a solvent mixture, ethyl acetate:n-hexane=1:3, as a developer. The compound obtained was treated with a hydrochloric acid/dioxane solution to obtain ethyl <strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydro-isoquinoline</strong>-2-acetate hydrochloride (4.2 g).
With hydrogenchloride; triethylamine; In 1,4-dioxane; ethanol;
(5-1) The raw material <strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydroisoquinoline</strong> was prepared according to Heterocyclic Chemistry, 22 , 329 (1985). 7-Nitro-1,2,3,4-tetrahydroisoquinoline (5.78g) was dissolved in ethanol (400ml), triethylamine (7.8ml) and ethyl bromoacetate (4.5g) were added, and the mixture was heated and refluxed for 1 hour. Most of the solvent was distilled off under reduced pressure, the concentrated residue was extracted with ethyl acetate and the extracted solution was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the crude product obtained was purified by silica gel column chromatography using a solvent mixture, ethyl acetate : n-hexane = 1: 3, as a developer. The compound obtained was treated with a hydrochloric acid/dioxane solution to obtain ethyl <strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydro-isoquinoline</strong>-2-acetate hydrochloride (4.2g).
2-Methyl-<strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydroisoquinoline</strong> (252). Formic acid (9.4 mL, 250 mmol) was added dropwise to Ac2O (19 mL, 202 mmol) at 0 0C. The solution was stirred at 50 0C for 45 min, then cooled to -18 0C, diluted with THF (100 mL) and a solution of 7-nitro- 1 ,2,3,4-tetrahydroisoquinoline [(a) Tercel, M.; et al., J. Med. Chem. 1996, 39, 1084-1094; (b) Zhu, Z., et al., J. Med. Chem. 2003, 46, 831-837] (251) (13.8 g, 5.0 mmol) in THF (100 mL) was added and stirred at -15 to -18 0C for 30 min. The solution was warmed to 20 0C, the solvent evaporated and the residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL). The aqueous fraction was extracted with EtOAc (3 x 250 mL), dried and the solvent evaporated. The residue was dissolved in THF (200 mL), EPO <DP n="159"/>cooled to 10 0C and BH3 DMS solution (10 M, 19.4 mL, 194 mmol) was added. The solution was stirred at 20 0C for 1 h, diluted with MeOH (30 mL) and acidified with HCI solution (1 M, 45 mL). The solution was stirred at 40 0C for 15 min, the solvent evaporated and the residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL). The aqueous fraction was extracted with EtOAc (3 x 250 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give isoquinoline 252 (12.6 g, 85%) as an orange solid: 1H NMR delta 8.09 (dd, J = 8.4, 2.3 Hz, 1 H, H-6), 7.95 (d, J = 2.3 Hz, 1 H, H-8), 7.37 (d, J = 8.4 Hz, 1 H, H-5), 4.27 (d, J = 16.1 Hz1 1 H, H-1), 3.94 (d, J = 16.1 Hz, 1 H, H-1), 3.23-3.34 (m, 2 H, CH2), 2.99-3.18 (m, 2 H, CH2), 2.17 (s, 3 H, NCH3); MS (APCI) m/z 193 (MH+, 100%).
To a stined solution of 7-nitro-2 ,3-dihydro- 1 H-spiro[cyclopropane- 1,4- isoquinoline] (500 mg, 2.45 mmol) in DMF (5 mL) was added K2C03 (1.55 g, 11.23 mmol) at 0 C. After 5 mins, methanesulfonyl chloride (0.4 mL, 5.62 mmol) was added at 0 C, and the reaction was stined at RT for 3 h. The reaction was diluted with water and extracted with EA (2 x 30 mL). The combined organic layers were washed with water (15 mL), dried (Na2SO4), and concentrated. The crude was triturated with pentane to afford 2- (methylsulfonyl)-<strong>[42923-79-5]7-nitro-1,2,3,4-tetrahydroisoquinoline</strong> (505 mg, 70%) as a pale yellow solid. MS (ESI) mlz 257.3 [M+H].
With triethylamine; In dichloromethane; at 20℃;
2-Methanesulfonyl-l52,354-tetrahydro-isoquinolin-7-ylamine was prepared as follows: A solution of l5253,4-tetrahydro-isoquinolin-7-ylamine (1.255g)[ prepared from 1,2,3,4-tetrahydroisoquinoline according to J. Med. Chem., 2003, 46(5), pp831- 7.], NEt3 (l.lmL) and methanesulfonylchloride (0.6mL) in dry CH2Cl2 (2OmL) was stiired at R.T. overnight. Aqueous work-up followed by purification on silica gave 2- methanesulfonyl-7-nitro-l,25354-tetrahydro-isoquinoline (1.435g).
1,2,3,4-tetrahydroisoquinolin (10. Og, 75.1mmol, 1 equiv) was dissolved in 40ml of concentrated sulfuric acid (exothermic reaction) and potassium nitrate (8.4g, 83.0mmol,1.1 equiv) was added in portions over lhour whilst stirring at O0C. The reaction mixture was then warmed up to room temperature and stirred for 2hrs. The reaction was poured in ice-water (100ml) and basified to pH 10 with ammonia solution (100ml). The mixture was then extracted with chloroform (2 x 250ml). The combined extracts were washed with brine, dried over magnesium sulfate and concentrated to give a dark red oil. The residue was purified by column chromatography using DCM/MeOH/NH4OH:95/5/0.5 to give the title mixture of isomers as a solid (7g, 52%).1H NMR (CDCl3, 400MHz) delta= 7.99 (m, IH), 7.92 (s, IH), 7.28 (m, IH), 7.26 (m, IH), 4.1 (s, 2H), 3.17 (m, 2H), 2.9 (m, 2H).
With iron; ammonium chloride; In ethanol; water; at 60℃; for 24h;
The mixture of 7-nitro-l,2,3,4-tetrahydroisoquinoline and 6-nitro-l,2,3,4- tetrahydroisoquinoline (1.Og, 5.6mmol, 1 equiv) was dissolved in a mixture of aqueous ammonium chloride [(2.4g, 44.8mmol, 8 equiv) in 6 ml of water] and ethanol (4ml). Iron powder (1.3g, 23.3mmol, 4 equiv) was added and the reaction mixture was stirred at 60C for 24hrs. The mixture was cooled down to room temperature and then filtered throughCelite. The filter cake was washed with ethanol (50ml). The orange solution was filtered again to remove any inorganics, concentrated in vacuum and azeotroped with toluene. The residue was stirred in ethanol (50ml) at 40C and filtered. The filtrate was concentrated to give the title mixture as a yellow solid ( 0.85g, 100%).1H NMR (MeOD, 400MHz) delta= 6.95 (m, IH), 6.66 (m, IH), 6.63 (m, IH), 4.2 (m, 2H), 3.4 (m, 2H), 3.0 (m, 2H).
tert-Butyl 3,4-dihydro-7-nitroisoquinoline-2(1H)-carboxylate A mixture of 1,2,3,4-Tetrahydro-7-nitroisoquinoline (2.5 g, 11.6 mmol), 1,4-dioxane (24 mL), H2O (12 mL) and 1N NaOH (12 mL) was cooled in an ice-bath, and Boc2O (2.8 g, 12.8 mmol) was added. The mixture was stirred at room temperature for 2.5 h, acidified with a 5% KHSO4 solution to pH 2-3, and then extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give tert-butyl 3,4-dihydro-7-nitroisoquinoline-2(1H)-carboxylate (3.3 g, quant.), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) delta 8.13 (d, J=2.3 Hz, 1H), 8.03 (dd, J=8.4, 2.5 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 4.63 (s, 2H), 3.60-3.57 (m, 2H), 2.90 (t, J=5.9 Hz, 2H), 1.44 (s, 9H); HPLC ret. time 3.51 min, 10-99% CH3CN, 5 min run; ESI-MS 279.2 m/z (MH+).
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