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CAS No. : | 1745-07-9 | MDL No. : | MFCD00777849 |
Formula : | C11H15NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CEIXWJHURKEBMQ-UHFFFAOYSA-N |
M.W : | 193.24 | Pubchem ID : | 15623 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.45 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 58.77 |
TPSA : | 30.49 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.58 cm/s |
Log Po/w (iLOGP) : | 2.3 |
Log Po/w (XLOGP3) : | 1.27 |
Log Po/w (WLOGP) : | 0.82 |
Log Po/w (MLOGP) : | 1.12 |
Log Po/w (SILICOS-IT) : | 2.38 |
Consensus Log Po/w : | 1.58 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.02 |
Solubility : | 1.83 mg/ml ; 0.00948 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.51 |
Solubility : | 5.98 mg/ml ; 0.0309 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.54 |
Solubility : | 0.056 mg/ml ; 0.00029 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.78 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In neat (no solvent); at 100℃; for 0.133333h;Microwave irradiation; Green chemistry; | General procedure: Amine (1 mmol) and di-tert-butyl dicarbonate [(Boc)2O] (1.1 mmol) were placed in a microwave reaction vial. The LG microwave oven MG 555f was programmed to 300 W at 100 C. The reaction was monitored using TLC. After the reaction, ice water was added to the reaction mixture which resulted in the precipitation of the product. The solid product was merely filtered off and washed with excess cold water. The product was pure enough for all practical purposes. For characterization purpose, it was further purified by column chromatography (Neutral Alumina as adsorbent, solvent system: Hexane: Ethyl acetate (7.5:2.5)). |
85% | With triethylamine; In dichloromethane; at 20℃; | Compound 5 was prepared from <strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong> using the following four-step procedure: (1) Boc2O, Et3N, CH2Cl2, rt (85%); (2) sBuLi, THF, -78 C then allyl bromide, -78 C to rt (68%); (3) TFA, CH2Cl2, rt then aq NaOH (88%); (4) 2,3-dibromopropene, K2CO3, Et3N, DMF, rt (67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; | General procedure: To a stirred solution of 1,2,3,4-THIQ (1.0 equiv.) in CH2Cl2 (10.0 mL/mmol), triethylamine(1.2 equivalent) was added and then cooled to 0 C. Acyl chloride (1.2 equivalent), sulfonyl chloride(1.2 equivalent), or diethylcarbamoyl chloride (1.2 equivalent) was added slowly at 0 C. The resultingreaction mixture was stirred at room temperature for 2 h under an argon atmosphere and thenpoured onto water (10.0 mL/mmol) and the organic layer was separated. The aqueous layer wasextracted two times with CH2Cl2 (10.0 mL/mmol), and the combined organic layer was washed withbrine (5.0 mL/mmol), dried over sodium sulfate, filtered, and concentrated under reduced pressure.Purification of the crude residue by flash column chromatography on silica gel, using the appropriatemixture of eluents, provided the corresponding N-protected 1,2,3,4-tetrahydroisoquinoline. Spectral data(1H- and 13C-NMR) of compounds (5a, 5c, 5d, 5e, 5g, 5h, 5k, 5l, 5m, 5n, 5o, 5q, 5r) which were reportedpreviously were compared and found in agreement with literature data. Furthermore, references wererepresented in supporting information. The characterization of novel compounds is given. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide; In water; at 20℃; for 1h;Microwave irradiation; Inert atmosphere; | In a microwave vial filled with Ar gas, 6,7-dimethoxy-1,2,3,4-tetrahydroisoisoquinoline (<strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong>, 500mg, 2.18mmol) , Formula 10), methyl vinyl ketone (methyl vinyl ketone, 304.9mg, 4.35mmol, Formula 13) was dissolved in 2M NaOH (1.32ml) aqueous solution, and then stirred rapidly at room temperature for 1 hour. After confirming the reaction by TLC, water and DCM were added to divide the layer, followed by extraction with DCM (3 x 10 mL). The collected organic layer was dried with anhydrous MgSO4 and filtered. The filtered solution was vacuum-concentrated, and the obtained material was separated by flash column chromatography using KANTO neutral silica gel under a developing solvent condition of DCM/MeOH = 10:1, and a pale yellow compound 3g (545mg, 95%, Formula 23 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In ethanol; at 20℃; for 18h;Irradiation; | In the reactor, 100 mg of substrate <strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong> and 10 mg of boron nitride carbon photocatalyst Agent, 3ml of ethanol and 1.2 equivalents of potassium carbonate, the reaction was stirred at room temperature light 18h, after the reaction was extracted with ethyl acetate, The combined organic phases are dried, filtered and the solvent is evaporated under reduced pressure to give the crude product. The column eluant used is a 3: 1 volume of stone Oleyl ether: ethyl acetate mixed solvent, yield 82%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione; In dimethyl sulfoxide; at 20℃; for 1h; | In 2 ml DMSO, add <strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong>, compound 4 (0.1 g, 0.52mM) and 2-iodoxybenzoic acid (IBX, 0.15 g, 0.52 mM), react in DMSO at room temperature for 1 hour. After the reaction was completed, saturated NaCl was added and washed with water, extracted with ethyl acetate 3 times, and the ethyl acetate layer was evaporated to dryness to obtain 6,7-dimethoxy-3,4-2H isoquinoline, compound 5, as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sulfur; In N,N-dimethyl-formamide; at 170℃; for 0.25h;Microwave irradiation; | A mixture of 1.00 g of <strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong> (11, 5.17 mmol) and 0.33 g of sulfur (2 equiv., 10.34 mmol) in 20 cm3 of DMF was kept in a vial that was placed in the MW reactor and irradiated at 170 C for 15 min. The mixture was cooled and concentrated under reduced pressure. Purification by flash column chromatography afforded 0.73 g (63 %) 12. M.p.: 223-224 C (CHCl3-EtOH 1:3) (Ref. [37] 223 C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium tungstate (VI) dihydrate; dihydrogen peroxide; In methanol; water; at 20℃; for 3.5h;Cooling with ice; | In a 100 mL flask, equipped with a magnetic stirrer bar and a dropping funnel were placed<strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong> (1.93, 10.0 mmol), Na2WO4•2H2O (0.143 g, 0.43mmol), and methanol (25 mL). To the solution was added 30% aqueous hydrogen peroxide dropwisewith ice bath cooling over a period of 30 min. After the addition was completed, the reaction mixturewas stirred at room temperature for 3 h prior to the addition of 1M aqueous solution of NaHSO3 withice bath cooling to decompose excess of hydrogen peroxide. The mixture was extracted withdichloromethane (10 mL × 3), the combined organic layers were dried over MgSO4, and the solventwas removed under reduced pressure. The resulting crude product was purified by flash columnchromatography on silica gel using CH2Cl2-MeOH (49:1) as eluent to afford nitrone 1e as a whitesolid (1.523 g, 63%): 1H NMR (400 MHz, CDCl3) = 3.12 (t, J = 7.9 Hz, 2H, CH2CH2), 3.89 (s, 3H,OCH3), 3.91 (s, 3H, OCH3), 4.08 (t, J = 8.0 Hz, 2H, CH2N), 6.62 (s, 1H), 6.73 (s, 1H), 7.67 ppm (s,1H, CHN). The proton is in accordance with that described in the literature.2 |
With ethylenediaminetetraacetic acid; oxone||potassium monopersulfate triple salt; sodium hydrogencarbonate; In tetrahydrofuran; water; acetonitrile; at 5℃; for 2.33333h; | General procedure: To a solution of secondary amine (2.0 mmol) in a mixture ofMeCN-THF (3.5 mL, 4:1) was added EDTA aqueous solution (2.8 mL,0.01 M) and NaHCO3 (0.84 g, 10.0 mmol) at 5 C. Oxone (1.29 g,2.1 mmol) was added portionwise over 2 h under vigorous stirringto maintain the temperature at 5 C. The resulting mixture wasstirred for another 20 min at 5 C, and then diluted with ethyl acetate(10 mL). The two phases were separated, and the aqueouslayer was extracted with ethyl acetate (3 10 mL). The combinedorganic layer was washed with brine, dried over Na2SO4 andconcentrated under reduced pressure. The crude product wasdirectly used in the next reaction without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With formic acid; at 0 - 50℃; | 2-(3,4-Dimethoxyphenyl)ethan-1-amine (2.04 g, 11.26 mmol, 1.0 equiv) was cooled to 0 C and formic acid(4.8 mL) was added. After stirring for 5-10 min and dissolving the formed precipitate (sonic bath), paraformaldehyde (340.0 mg, 11.32 mmol, 1.0 equiv) was added, and the suspension was stirred at 50 C overnight. NaOH (first 2N, then conc.) was added to the solution, which was extracted three times with DCM (70 mLin total). The combined organic phases were washed with brine and dried over sodium sulphate. After evaporation of the solvent, 99% product (2.15 g, 11.14 mmol) were collected as off white solid, which was used without further purification. Spectroscopic data are in accordance with literature [12]. |
76% | In formic acid; at 50℃; for 12h; | 3,4-Dimethoxyphenylethylamine (52.00 g, 0.287 mol) was added dropwise to a solution of formic acid (130 mL), the mixture was stirred and the temperature was controlled under 50 C. Paraformaldehyde (8.70 g, 0.290 mol) was added and the solution was heated at 50 C for 12 h. The resulting mixture was poured into ice water (250 mL), NaOH pellets(about 150 g) was added slowly to adjusted the pH of the solution to 8-9 in ice bath, and the resulting mixture was extracted with dichloromethane (3 × 300 mL). The combined extracts were washed with brine and dried over anhydrous Na2SO4.The organic solvent was evaporated under vacuum, the resulting viscous oil was stirring vigorously in 300 mL petroleum ester (PE) for 0.5 h, the forming precipitation was filtrated under reduced pressure to give1a(42.05 g, 76%) as a pale yellow powder, Rf(dichloromethane /methanol, 15:1) = 0.24.1H NMR (CDCl3, 400 MHz) δ (ppm) 6.59 (s, 1 H), 6.51 (s, 1 H), 3.99 (s, 2 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.17 (t, J =5.8 Hz, 3 H), 2.77 (t, J = 5.8 Hz, 3 H). MS (EI-) m/z (%): 192.1 [M - H]-. (theoretical value: 192.1) |
76% | With formic acid; at 50℃; for 12h; | 3,4-Dimethoxyphenylethylamine (52.00 g, 0.287 mol) was added dropwise to a solution of formic acid (130 mL), the mixture was stirred and the temperature was controlled under 50 C. Paraformaldehyde (8.70 g, 0.290 mol) was added and the solution was heated at 50 C for 12 h. The resulting mixture was poured into ice water (250 mL), NaOH pellets (about 150 g) was added slowly to adjusted the pH of the solution to 8-9 in ice bath, and the resulting mixture was extracted with dichloromethane (DCM, 3×300 mL). The combined extracts were washed with brine and dried over anhydrous Na2SO4. The organic solvent was evaporated under vacuum, the resulting viscous oil was stirring vigorously in 300 mL petroleum ester (PE) for 0.5 h, the forming precipitation was filtrated under reduced pressure to give 2 (42.05 g, 76%) as a pale yellow powder, Rf (DCM /MeOH, 15:1) = 0.24. 1H NMR (CDCl3, 400 MHz) δ (ppm) 6.59 (s, 1 H), 6.51 (s, 1 H), 3.99 (s, 2 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.17 (t, J =5.8 Hz, 3 H), 2.77 (t, J = 5.8 Hz, 3 H). MS (EI-) m/z (%): 192.1 [M - H]-. |
51% | At 0 C, formic acid (5.6 mL, 100 mmol) was added dropwise to 3,4-dimethoxyphenethylamine (2.2 mL, 11.0 mmol). The solution was stirred at 0 C for 10 minutes. Paraformaldehyde (336 mg, 11.0 mmol) was added, and the resulting reaction mixture was stirred at 50 C for 13 h. Excess formic acid was removed under reduced pressure, and the resulting viscous oil was diluted with 10 mL ice water to which 50 mL 1 M NaOH solution saturated with NaCl was added. The crude product was extracted with CH2Cl2 (3 x 40 mL), dried over MgSO4 and concentrated in vacuo. The product was purified by silica gel column chromatography using CH2Cl2 /MeOH, 70:30 (Rf = 0.15) to afford 6 (1.087 g, 51%) as a white solid. 1H NMR (400 MHz, CDCl3): δ = 2.80 (t, J = 6.3 Hz, 2H) 3.19 (t, J = 6.3 Hz, 2H); 3.71 (s, 3H) 3.85 (s, 3H) 3.86 (s, 2H) 4.01 (s, 2H) 6.52 (s, 1H) 6.59 (s, 1H). 13C NMR (100.5 MHz, CDCl3): δ = 26.19, 42.33, 45.18, 55.96, 56.01, 109.07, 111.65, 121.88, 124.43, 148.06, 148.44. Lit.[2] 1H NMR (300 MHz, CDCl3): δ = 2.71 (t, J = 5.8 Hz, 2H), 3.12 (t, J = 5.8 Hz, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 3.94 (s, 2 H), 6.51 (s, 1H), 6.58 (s, 1H). 13C NMR (75 MHz, CDCl3): δ = 28.5, 43.7, 47.7, 55.9 (2 C), 109.1, 111.1, 126.4, 127.4, 147.3, 147.4. | |
General procedure: The amine (1.35 g, 8.18 mmol) obtained in previous step was added to formic acid (3.5 mL) at 0 C and stirred for 10 min at same temperature until complete dissolution of amine. Then paraformaldehyde (0.25 g, 8.18 mmol) was added and stirred at 50 C for 24h, added saturated NaOH solution and extracted with DCM. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. Then purified by column chromatography on silica gel using MeOH/ CHCl3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; | General procedure: To a stirred solution of 1,2,3,4-THIQ (1.0 equiv.) in CH2Cl2 (10.0 mL/mmol), triethylamine(1.2 equivalent) was added and then cooled to 0 C. Acyl chloride (1.2 equivalent), sulfonyl chloride(1.2 equivalent), or diethylcarbamoyl chloride (1.2 equivalent) was added slowly at 0 C. The resultingreaction mixture was stirred at room temperature for 2 h under an argon atmosphere and thenpoured onto water (10.0 mL/mmol) and the organic layer was separated. The aqueous layer wasextracted two times with CH2Cl2 (10.0 mL/mmol), and the combined organic layer was washed withbrine (5.0 mL/mmol), dried over sodium sulfate, filtered, and concentrated under reduced pressure.Purification of the crude residue by flash column chromatography on silica gel, using the appropriatemixture of eluents, provided the corresponding N-protected 1,2,3,4-tetrahydroisoquinoline. Spectral data(1H- and 13C-NMR) of compounds (5a, 5c, 5d, 5e, 5g, 5h, 5k, 5l, 5m, 5n, 5o, 5q, 5r) which were reportedpreviously were compared and found in agreement with literature data. Furthermore, references wererepresented in supporting information. The characterization of novel compounds is given. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6, 7-Dimethoxy-1, 2,3, 4-tetrahydroisoquinoline (5.0 g, 25.9 mmol) and 3- hydroxybenzaldehyde (3.16 g, 25.9 mmol) are dissolved in 100 mL of anhydrous DCE under N2 atmosphere. Solid NaBH (OAc) 3 (8.22 g, 38.8 mmol) is added, followed by addition of acetic acid (5 mL). The reaction is stirred for 16 hours at room temperature. The resulting reaction mixture is taken to basic pH by addition of aqueous NaOH (200 mL, 1M). A solid precipitates from solution and is subsequently filtered. The precipitate is washed with H20 (50 mL) and then EtOAc (100 mL) to afford the desired product as a white solid. H-1 NMR (DMSO-d6) : 7. 08 (1H, t), 6. 52-6.74 (5H, m), 3.68 (3H, s), 3.64 (3H, s), 3. 48 (2H, s), 3.36 (2H, s), 2.44-2. 72 (4H, m). LC/MS m/z: (M+H) + calcd for C18H21NO3 300, found 300. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6, 7-Dimethoxy-1, 2,3, 4-tetrahydroisoquinoline (84 mg, 0.44 mmol) and 3-(4-test- butylphenoxy) benzaldehyde (113 uL, 0.44 mmol) are dissolved in 2 mL of anhydrous 1,2- dichloroethane under a N2 atmosphere. Solid NaBH (OAc) 3 (129 mg, 0.61 mmol) is added, followed by addition of acetic acid (100 I1L). The resulting suspension is stirred for 16 hours at room temperature. The reaction mixture is taken to basic pH by addition of aqueous NaOH (2 mL, 1M). The product is extracted with CH2CI2 (3 x 2 mL) and the combined organic fractions washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product is dissolved in a minimal amount of methanol and loaded onto an SCX SPE cartridge (Applied Separations). Non-basic impurities are eluted with methanol (4 mL). The desired product is collected with NH3 (1M in methanol, 4 mL). Solvent removal under reduced pressure affords the title compound as a colorless oil. H-1 NMR (CDC13) : 7.34 (2H, d), 7. 30 (1H, d), 7.12 (1H, d), 7.08 (1H, d), 6.94 (2H, d), 6.94 (1H, t), 6.58 (1H, s), 6.48 (1H, s), 3.84 (3H, s), 3.82 (3H, s), 3. 72 (2H, s), 3.62 (2H, s), 2.80 (4H, m); LC/MS m/z : (M+H) + calcd for C28H33NO3 432, found 432. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dicyclohexyl-carbodiimide;dmap; In dichloromethane; at 20℃; for 2h; | DCC (2.16 g, 0.011 mol), a catalytic amount of DMAP (0.098 g, 8 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.04 g, 0.009 mol) were added to a solution of 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.31 g, 0.008 mol) in dichloromethane (30 ml). The clear solution soon deposited a white solid corresponding to the cyclohexyl urea formation. The crude was stirred for 2 hours at room temperature. The solid was filtered and the crude was washed with water and dried over Na2SO4. The solvent was vacuum concentrated and the residue was purified by flash chromatography using a gradient consisting of different mixtures of dichloromethane/methanol to give pure tert-Butyl-4-(<strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong>-2-carbonyl)piperidine-1-carboxylate as yellow solid (3.8 g, 85% yield). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.45 (s, 9 H) 1.62 (m, 4 H) 1.70 (m, 4 H) 2.78 (m, 3 H) 3.72 (m, 1 H) 3.86 (s, 6 H) 4.16 (m, 2 H) 4.64 (s, 1 H) 6.62 (s, 2 H) MS (APCI (M+H)+): 405 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium phosphate; copper(l) iodide; ethylene glycol; In isopropyl alcohol; at 80℃; for 24h; | General procedure: CuI (10 mol %) and K3PO4 (2.0 equiv) were placed in a Schlenk tube, and the flask put under argon. Then, ethylene glycol (2.0 equiv) and isopropanol (amount calculated for a 1.1 M solution based on the aryliodide) were added, and the solution degassed. Then, aryl iodide (1.0 equiv) and the 1,2,3,4-tetrahydroisoquinoline derivative (1.4 equiv) were added in this order, and the mixture was stirred at 80 Cfor 24 h. The reaction was quenched by adding water and 3.5 M NH3 until the tetraamminecopper complex hads formed. The aqueous phase was extracted three times with Et2O. The combined organic phases were washed with a small portion of water and brine. After drying over sodium sulphate, the crude material was purified by column chromatography using LP/EA as the eluent. |
30% | With potassium phosphate; copper(l) iodide; In ethylene glycol; isopropyl alcohol; at 90℃; for 24h;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 30% isolated yields. |
With potassium phosphate; copper(l) iodide; ethylene glycol; In isopropyl alcohol; at 20℃;Inert atmosphere; | General procedure: A mixture of CuI (10 mmol%) and K3PO4 (3.0 equiv.) was taken in a two necked round bottom flask evacuated and backfilled with nitrogen and fitted on oil bath. 2-Propanol (10 mL), ethylene glycol (1.1 mL), 1,2,3,4-tetrahydroisoqunoline (15 mmol, 2.0mL) and aryl iodide (10 mmol, 1.12 mL) were added successively by microsyring at rt. The reaction mixture was heated at 80-90 oC with stirring for 24-36 h. After the completion of the reaction was allowed to cool at rt. Diethyl ether (20 mL) and water (20 mL) was added to reaction mixture. The organic layer was extracted by diethyl ether (2 × 20mL). The combined organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed by rotary evaporator and the crude product was purified by column chromatography on silica gel with a mixture of hexane/ethyl acetate as eluent to afford an analytically pure sample of substrates 1. |
With potassium phosphate; copper(l) iodide; In ethylene glycol; isopropyl alcohol; at 20 - 90℃; for 24h;Inert atmosphere; | General procedure: Copper(I) iodide (200 mg, 1.0 mmol) and potassium phosphate (4.25 g, 20.0 mmol) were placedinto a 50 mL three-neck flask. The flask was evacuated and back-filled with argon. 2-Propanol(10.0 mL), ethylene glycol (1.11 mL), 1,2,3,4-tetrahydroisoquinoline (2.0 mL, 15 mmol) andiodobenzene (1.12 mL, 10.0 mmol) were added successively by syringe at room temperature. Thereaction mixture was heated at 90 C for 24 h and then allowed to cool to room temperature. Diethyl ether (20 mL) and water (20 mL) were then added to the reaction mixture. The organiclayer was extracted with diethyl ether (2 × 20 mL). The combined organic phases were washedwith brine and dried over sodium sulfate. The solvent was removed and the residue was purified bycolumn chromatography on silica gel using hexane/ethyl acetate (20:1) as an eluent. | |
With potassium phosphate; copper(l) iodide; ethylene glycol; In isopropyl alcohol; for 72h;Reflux; | General procedure: To a stirred suspension of CuI (213 mg, 1.12 mmol) and K3PO4 (4.25 g, 21.3 mmol) in i-PrOH (10 mL) were added ethyleneglycol (1.10 mL, 21.3 mmol), 6 (16.0 mmol), and 7 (10.0 mmol) at room temperature. The reaction mixture was heated at reflux for 72 h. After cooling to room temperature, the reaction mixture was poured into 25% NH3 aqueous solution, and the resulting mixture was extracted with EtOAc three times. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexanes/EtOAc = 95/5) to afford product 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; | General procedure: To a stirred solution of 1,2,3,4-THIQ (1.0 equiv.) in CH2Cl2 (10.0 mL/mmol), triethylamine(1.2 equivalent) was added and then cooled to 0 C. Acyl chloride (1.2 equivalent), sulfonyl chloride(1.2 equivalent), or diethylcarbamoyl chloride (1.2 equivalent) was added slowly at 0 C. The resultingreaction mixture was stirred at room temperature for 2 h under an argon atmosphere and thenpoured onto water (10.0 mL/mmol) and the organic layer was separated. The aqueous layer wasextracted two times with CH2Cl2 (10.0 mL/mmol), and the combined organic layer was washed withbrine (5.0 mL/mmol), dried over sodium sulfate, filtered, and concentrated under reduced pressure.Purification of the crude residue by flash column chromatography on silica gel, using the appropriatemixture of eluents, provided the corresponding N-protected 1,2,3,4-tetrahydroisoquinoline. Spectral data(1H- and 13C-NMR) of compounds (5a, 5c, 5d, 5e, 5g, 5h, 5k, 5l, 5m, 5n, 5o, 5q, 5r) which were reportedpreviously were compared and found in agreement with literature data. Furthermore, references wererepresented in supporting information. The characterization of novel compounds is given. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine; In dichloromethane; at 20℃; for 6h; | General procedure: 3-Bromopropionitrile (0.43 mL, 5.18 mmol) and triethylamine (1.4 mL, 10.4 mmol) were added to a solution of either <strong>[1745-07-9]6,7-dimethoxytetrahydroisoquinoline</strong> or 1-cyclohexylpiperazine (5.2 mmol) in CH2Cl2. The solution was stirred at room temperature for 6 h and then the reaction mixture was washed with H2O and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography using CH2Cl2/MeOH (95:5) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In acetonitrile;Reflux; | General procedure: 3-Bromo-1-propanol (0.22 mL, 2.5 mmol) and K2CO3 (0.41 g, 3.0 mmol) were added to a solution of either <strong>[1745-07-9]6,7-dimethoxytetrahydroisoquinoline</strong> or 1-cyclohexylpiperazine (3.0 mmol) in CH3CN (20 mL). The reaction mixture was stirred under reflux overnight. Then the solvent was removed under reduced pressure and, H2O was added to the crude residue. The aqueous mixture was extracted with CH2Cl2 (3 × 10 mL) and the organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford a crude residue which was purified by column chromatography with CH2Cl2/MeOH (95:5) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | General procedure: A mixture of the appropriate amine (1 equiv) or its hydrochloride salt and anhydrous K2CO3 (1-1.2 equiv) in dry solvent (MeCN, DCM or toluene) was stirred at room temperature for 30 min. A solution of 3-bromo-dihydrofuran-2(3H)-one (1 equiv) in dry solvent (MeCN, DCM) was then added dropwise over 15 min and stirring continued for 5-48 h at ambient temperature. The mixture was then filtered and the filtrate was evaporated to obtain a crude oily residue which was purified by recrystallization from 2-propanol (i-PrOH) or EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium iodide; In N,N-dimethyl-formamide; at 0 - 20℃; for 168h;Inert atmosphere; | General procedure: Compound 2 (10.0 mmol) was dissolved in dry dimethylformamide under dry nitrogen atmosphere and potassium iodide (5.00 mmol) was added into it. The solution was cooled down to 0 C and the secondary amine (HNRR′, see Scheme 1 and 21.00 mmol,) was added into the solution. The reaction mixture was stirred for 7 days at room temperature, then it was poured into a mixture of ice, saturated sodium hydrogencarbonate solution (200 ml) and diethyl ether (50 ml) after which the phases were separated and the aqueous mixture was extracted with diethyl ether (4 × 60 ml). The ether solution was washed with brine (50 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography in order to yield the products 3-8 as colourless oils (eluents, yields and spectroscopic parameters are given below). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium carbonate; In N,N-dimethyl-formamide;Reflux; | General procedure: Compounds 11a-e and 12a-d were prepared alkilating <strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong> (1.2 mmol) in the presence of intermediates 9a-e or 10a-d (1 mmol) in DMF (20 mL) and in presence of Na2CO3 (2 mmol). The mixture was refluxed overnight. The DMF was evaporated and the residue was partitioned between H2O (20 mL) and CHCl3 (20 mL). The organic phase was separated and the aqueous phase was extracted with CHCl3 (3 × 50 mL) and the collected solutions were dried over Na2SO4 and evaporated. The residue was purified on silica gel column chromatography in specific condition below reported for each compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | General procedure: A solution of carboxylic acid 3a,b (1 mmol) and CDI (1.1 mmol) in dry THF was stirred at room temperature overnight. A solution of <strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong> (1 mmol) in THF was added at the mixture and the solution was stirred at room temperature for 6 h. The solvent was evaporated and the residue was dissolved in H2O (50 mL). The aqueous phase was extracted with AcOEt (3 × 50 mL). The collected organic solution was dried over Na2SO4 and evaporated. The residue was purified on silica gel column chromatography in specific condition below reported for each compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | General procedure: A solution of carboxylic acid 3a,b (1 mmol) and CDI (1.1 mmol) in dry THF was stirred at room temperature overnight. A solution of <strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong> (1 mmol) in THF was added at the mixture and the solution was stirred at room temperature for 6 h. The solvent was evaporated and the residue was dissolved in H2O (50 mL). The aqueous phase was extracted with AcOEt (3 × 50 mL). The collected organic solution was dried over Na2SO4 and evaporated. The residue was purified on silica gel column chromatography in specific condition below reported for each compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium carbonate; In N,N-dimethyl-formamide; at 80℃; for 30h; | (3-(tosylmethyl)-5-methyl-2-methylenehexyl)trimethylsilane (Formula 4; 72.0 mg, 0.195 mmol) and Na2CO3 (41.4 mg, 0.391 mmol) were added to DMF (2 mL). Then, <strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong> (Formula 3; 75.4 mg, 0.391 mmol) was added thereto, and the mixture was heated up to 80 C. and stirred for 30 hr. Distilled water was put into the reaction solution to complete the reaction, and then the temperature was increased to normal temperature. An organic layer was extracted, the organic layer collected was washed with distilled water and a brine solution, and the remaining solvent was distilled under reduced pressure. Anhydrous magnesium sulfate was used to dry the organic layer, filtration under reduced pressure and evaporation under reduced pressure were performed, and then column chromatography was used to obtain 53.3 mg (yield 75%) of the title compound. 1H NMR (400 MHz, CDCl3) d 0.59 (s, 9H), 0.87 (d, J=5.6 Hz, 3H), 0.89 (d, J=5.6 Hz, 3H), 1.24-1.34 (m, 2H), 1.37-1.43 (ddd, J=9.2, 8.8, 3.6 Hz, 1H), 1.51 (d, J=4 Hz, 2H), 1.59-1.70 (m, 1H), 2.31-2.35 (m, 1H), 2.37 (dd, J=7.2, 7.6 Hz, 1H), 2.42-2.47 (m, 1H), 2.57-2.63 (m, 1H), 2.70-2.75 (dd, J=6.5, 7.0 Hz, 1H), 2.76-2.80 (m, 2H), 3.52 (s, 2H), 3.86 (s, 6H), 4.68 (s, 1H), 4.71 (s, 1H), 6.53 (s, 3H), 6.56 (s, 3H); 13C NMR (100 MHz, CDCl3) d 0.00, 23.06, 24.46, 25.05, 26.13, 29.51, 42.36, 43.46, 51.79, 56.71, 57.04, 63.78, 109.05, 110.27, 112.16, 127.31, 127.91, 147.91, 148.15, 150.46; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; acetonitrile; at 60℃; for 5h;Inert atmosphere; | Preparation of 4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrido[3,2-d]pyrimidine 0.20 g of 6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3H-pyrido[3,2-d]pyrimidin-4-one and 0.22 g of <strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong> are suspended in 10 ml of acetonitrile and 1 ml of dimethylformamide in a flask. 0.65 g of (benzo-triazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate, 255 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene are subsequently added, and the mixture is heated at 60 C. under nitrogen until the reaction has proceeded to completion (HPLC check, about 5 hours). A precipitate precipitates out of the reaction solution. This is filtered off, rinsed with water and dried, giving 0.17 g of 4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo[2,3-b]pyri-din-5-yl)pyrido[3,2-d]pyrimidine ("A7") as white solid (yield 50%, content 97%); MS-FAB (M+H+)=439; Rf (polar method): 1.68 min; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.87 (s, 1H), 9.10 (d, J=1.9, 1H), 8.75 (d, J=1.7, 1H), 8.55 (s, 1H), 8.49 (d, J=8.9, 1H), 8.19 (d, J=8.8.1H), 7.61-7.55 (m, 1H), 6.89 (s, 1H), 6.85 (s, 1H), 6.61 (dd, J=3.3, 1.8, 1H), 3.75 (d, J=6.8, 6H), 3.08 (s, 2H), 2.84-2.70 (m, 2H), 2.66 (dd, J=26.0, 24.3, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triethylamine; In dichloromethane; at 20℃; for 2h; | General procedure: To the solution of the appropriate amine (1 mmol) in 5ml of CH2Cl2, the corresponding aromatic sulfonyl chloride(1 mmol) was added, followed by the addition of one equivalent of TEA. The resulting mixture was stirred for 2 h at ambient temperature, monitored by TLC (n-hexane/ethyl acetate= 2:1). Next, 5 ml of water was poured into the reaction mixture and extracted by EtOAc (2x20mL). The collected organic phase was dried over anhydrous Na2SO4, filtered and evaporated to dryness. Crude products were purified by either flash chromatography (n-hexane/EtOAc) or recrystallization(EtOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With triethylamine; In dichloromethane; at 20℃; for 2h; | General procedure: To the solution of the appropriate amine (1 mmol) in 5ml of CH2Cl2, the corresponding aromatic sulfonyl chloride(1 mmol) was added, followed by the addition of one equivalent of TEA. The resulting mixture was stirred for 2 h at ambient temperature, monitored by TLC (n-hexane/ethyl acetate= 2:1). Next, 5 ml of water was poured into the reaction mixture and extracted by EtOAc (2x20mL). The collected organic phase was dried over anhydrous Na2SO4, filtered and evaporated to dryness. Crude products were purified by either flash chromatography (n-hexane/EtOAc) or recrystallization(EtOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In acetonitrile;Reflux; | To a solution of 24 (0.18 mmol, 0.066 g) in CH3CN (10 mL), <strong>[1745-07-9]6,7-dimethoxytetrahydroisoquinoline</strong> (0.09 mmol, 0.017 g) and K2CO3 (0.09 mmol, 0.013 g) were added. The resulting mixture was stirred under reflux overnight. After cooling down, the solvent was evaporated under reduced pressure and the residue was dissolved in H2O and extracted with CH2Cl2 (3×5mL). The collected organic layers were dried over Na2SO4 and the solvent was evaporated under reduced pressure to afford a crude residue as a yellow oil which was purified through column chromatography with CH2Cl2/MeOH (99:1) to afford the final compound as a white solid (yield 60%): 1H NMR δ=2.65-2.85 (m, 4H, NCH2CH2Ar), 3.25 (s, 2H, NCH2Ar), 3.60 (s, 2H, COCH2N), 3.78 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.70 (d, 2H, J=5.5Hz, CH2NHCO), 6.38 (s, 1H, aromatic), 6.60 (s, 1H, aromatic), 7.05-7.70 (m, 9H, aromatic), 7.45-7.60 (br s, 1H, NH); 13C NMR: 28.21; 38.09; 54.52; 57.09; 59.04; 59.12; 59.53; 113.41; 113.92; 115.35; 117.35; 120.05 (J2 C-F=23Hz); 122.80; 122.90; 124.04; 126.57; 126.69; 129.80 (J3 C-F=8.5Hz); 130.97; 131.67; 139.61; 140.46; 152.52; 153.35; 165.08 (J1 C-F=245Hz); 167.60. LC-MS (ESI+) m/z 496 [M+Na]+. Anal. (C28H29FN3O3·HCl·H2O) C, H, N. |
60% | With potassium carbonate; In acetonitrile;Reflux; | To a solution of 24 (0.18 mmol, 0.066 g) in CH3CN (10 mL), <strong>[1745-07-9]6,7-dimethoxytetrahydroisoquinoline</strong> (0.09 mmol, 0.017 g) and K2CO3(0.09 mmol, 0.013 g) were added. The resulting mixturewas stirredunder reflux overnight. After cooling down, the solvent was evaporatedunder reduced pressure and the residue was dissolved inH2O and extracted with CH2Cl2 (3x 5 mL). The collected organiclayers were dried over Na2SO4 and the solvent was evaporatedunder reduced pressure to afford a crude residue as a yellow oilwhich was purified through column chromatography with CH2Cl2/MeOH (99:1) to afford the final compound as a white solid (yield60%): 1H NMR δ= 2.65-2.85 (m, 4H, NCH2CH2Ar), 3.25 (s, 2H,NCH2Ar), 3.60 (s, 2H, COCH2N), 3.78 (s, 3H, OCH3), 3.82 (s, 3H,OCH3), 4.70 (d, 2H, J= 5.5 Hz, CH2NHCO), 6.38 (s, 1H, aromatic), 6.60(s, 1H, aromatic), 7.05-7.70 (m, 9H, aromatic), 7.45-7.60 (br s, 1H,NH); 13C NMR: 28.21; 38.09; 54.52; 57.09; 59.04; 59.12; 59.53;113.41; 113.92; 115.35; 117.35; 120.05 (J2 C-F= 23 Hz); 122.80;122.90; 124.04; 126.57; 126.69; 129.80 (J3 C-F= 8.5 Hz); 130.97;131.67; 139.61; 140.46; 152.52; 153.35; 165.08 (J1 C-F= 245 Hz);167.60. LC-MS (ESI+) m/z 496 [M+Na]+. Anal.(C28H29FN3O3.HCl.H2O) C, H, N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | General procedure: To a solution of one of the appropriate acids among 7, 12, and 14 (0.67mmol) in dry THF (10mL), 1,1'-carbonyldiimidazole (0.87mmol, 0.14g) was added. The resulting mixture was stirred under argon for 2h, and then a solution of one of the appropriate amines (0.87mmol) in THF (10mL) was added to it in a dropwise manner. Then few drops of DMF were added to the reaction mixture which was left overnight under stirring at room temperature. Water (10mL) was then added and the mixture was extracted with Et2O (3×10mL). The collected organic layers were dried over Na2SO4 and the solvent was evaporated under reduced pressure to afford the final amide compounds as oils which were purified by column chromatography with CH2Cl2/AcOEt (95:5) as eluent. | |
With N,N-dimethyl-formamide; In tetrahydrofuran; at 20℃;Inert atmosphere; | General procedure: To a solution of one of the appropriate acids among 7, 12, and 14 (0.67mmol) in dry THF (10mL), 1,1'-carbonyldiimidazole (0.87mmol, 0.14g) was added. The resulting mixture was stirred under argon for 2 h, and then a solution of one of the appropriate amines (0.87mmol) in THF (10mL) was added to it in a dropwise manner. Then few drops of DMF were added to the reaction mixture which was left overnight under stirring at room temperature. Water (10mL) was then added and the mixture was extracted with Et2O (3×10mL). The collected organic layers were dried over Na2SO4 and the solvent was evaporated under reduced pressure to afford the final amide compounds as oils which were purified by column chromatography with CH2Cl2/AcOEt (95:5) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | The compound was synthetized starting from a mixture of the appropriate carboxylic acid (1 mmol) and 1,1’-carbonyldiimidazole (1.1 mmol) in dry THF. The mixture was stirred at room temperature overnight. A solution of 6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline (1 mmol) in dry THF was dropped into the reaction complex. The mixture was stirred at room temperature for 4h. 15 mL of H20 was added to the reaction mixture, the aqueous phase was re-extracted with AcOEt (3 x 50 mL), and the combined solution was dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography for to obtain a yellow solid. Eluted with CHCI3. Yield 36%. 1H NMR (CDCI3) O 2.63 (m, 1H), 2.83 (m, 1H), 3.64 (m, 2H), 3.91 -4.22 (m, 11H), 4.53 (5, 1H), 4.73 (5, 1H), 6.55 (5, 1 H), 6.62 (5, 1H), 6.95 (d, 2H, J = 8Hz), 7.25-7.30 (m, 2H), 7.48-7.53 (m, 4H). ESI+/MS m/z: 418 [M + H]ESI/MS/MS m/z: 194 (100), 165 (54). Anal. C, H, N [C26H27N04]. mp144-146 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.8% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 3h; | General procedure: A mixture of 5-substituted phenyl-2-furancarboxylic acid 2 (100mmol) and 1,2,3,4-tetrahydroisoquinoline (105mmol) or <strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong> (105mmol) dissolved in anhydrous dichloromethane, their coupling reaction was then performed in the presence of EDCI (120mmol) and HOBt (120mmol) to provide the different title compounds 4 (4a-4o) or 5 (5a-5o), respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 110℃;Inert atmosphere; | General procedure: Pd2(dba)3 (0.02 mmol, 20.6 mg), BINAP (0.05 mmol, 28.6 mg) and NaO-t-Bu (1.1 mmol, 100.5mg) were added into a 25 mL well dried bottom flasks with two necks then evacuated and backfilled three times with Argon. After that, injection 3.0 mL of toluene to bottom. The reactionwas refluxing at 110 for 15 min and then added 1,2,3,4-tetrahydroisoquinoline(2.2 mmol,0.6 mL) or <strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong>(2.2 mmol, 849 mg), and an arylbromide (1.1 mmol,2 equiv) after cool to room temperature. The mixture was stirred at 110 overnight. When the reaction completed, it was quenched with water and extracted with ethylacetate. Then purification the crude by column chromatography using petroleum / ethyl acetate to afford pure product of 1p-w, 1x. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium carbonate; In N,N-dimethyl-formamide;Reflux; | 3b (1 mmol) was alkylated with 6,7-dimethoxy-1 2,3,4-tetrahydroisoquinoline (1.2 mmol) in DMF (20 mL) using Na2CO3 as a base (2 mmol). The mixture was refluxed overnight. DMF was evaporated and the residue was partitioned between H20 (20 mL) and CHCI3 (20 mL). The organic phase was separated, the aqueous phase was extracted with CHCI3 (3 x 50 mL) and the collected organic fractions were dried overNa2504 and evaporated. The residue was purified on silica gel column chromatography (CH2CI2/EtOAc 1:1 v/v) yielding 74 % 4-((6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)- yl)methyl)-2-(4-fluorophenyl)oxazole (4b) as a brown oil. Hydrochloride salt was recrystallized from MeOH/Et20. Mp: 232-235 C. ESI/MS m/z: 369 [M+H], 391 [M+Na]. ESI/MS/MS m/z: 352 (16), 230 (50), 176 (98), 121 (100). 1H NMR (CDCI3) O:2.94 (5, 4H, CH2NCH2), 3.75-3.79 (m, 4H, NCH2CH2), 3.82 (5, 3H, CH3), 3.88 (5, 3H,CH3), 6.50 (s, 1H), 6.58 (s, 1H), 7.11-7.17 (m, 2H), 7.67 (s, 1H), 8.03 (dd, 2H, J= 5.5,8.8 Hz). Purity of final compound was established by combustion analysis of thecorresponding hydrochloride salt, confirming a purity 95 %. (C,N,I-1)C21 H21 FN2O3HCI(H20)o.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | [0040] The carboxylic acid previously described (11) (1 meq) is placed to react in anhydrous THF (20 mL) with carbonyldiimidazole(1.1 meq) and the mixture is stirred up at room temperature for five hours. 6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline(2) (1 meq) is added and it is left to react overnight. It is concentrated, is recovered with waterand extracted with CHCl3 (3 x 20 mL). The compound is purified on chromatography column (CHCl3).Yellow solid. Yield55% ESI+/MS m/z: 441 [M+ Na]+, ESI+/MS/MS m/z: 441 (100). 1 H-NMR (δ): 2.90 (m, 2H, NCH2CH2 isoquinoline), 3.78(s, 6H, OCHs), 4.15 (m, 2H, NCH2CH2 isoquinoline), 4:56 (s, 2H, NCH2 isoquinoline) 7.57-8.35 (m, 10H, aromatics). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | [0034] 5-bromo-pyridin-2-carboxylic acid (1)(1meq) is placed to react in anhydrous THF (10mL) with carbonyldiimidazole(1.1 meq) and the mixture is stirred at room temperature for five hours. <strong>[1745-07-9]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline</strong>(2) (1 meq) is added and it is left to react overnight. The solvent is concentrated, is recovered with water and extractedwith CHCl3 (3 x 20 mL). The compound is purified on chromatography column (CH2Cl2/MeOH 98/2). White solid. Yield64% ESI +/MS m/z: 399 [M +Na]+, ESI +/MS/MS m/z: 399 (100), 227 (60). 1H-NMR (δ):2.85(m,2H,NCH2CH2 isoquinoline),3.29 (m, 2H, NCH2CH2 isoquinoline), 4.22 (s, 2H, NCH2 isoquinoline), 3.78 (s, 6H, OCH3), 6.40-9.09 (m, 5 H, aromatics). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate; In acetonitrile; at 90℃; | General procedure: General procedure for the synthesis of 4a-4f Tetrahydroisoquinoline derivatives A (0.50 g, 3.75 mmol), E (1.09 g, 3.75 mmol) and K2CO3 (1.55g, 11.262 mmol) were dissolved in to acetonitrile (20 mL) in a 50 mL RB flask. The mixture was refluxed overnight at 90C. After the reaction was completed, CH3CN was evaporated off to obtain a solid mass which was poured into water (50 mL) and extracted with CH2Cl2 (225 mL). The combined organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to obtain the pure product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In acetonitrile; at 90℃; | General procedure for the synthesis of 4a-4f Tetrahydroisoquinoline derivatives A (0.50 g, 3.75 mmol), E (1.09 g, 3.75 mmol) and K2CO3 (1.55g, 11.262 mmol) were dissolved in to acetonitrile (20 mL) in a 50 mL RB flask. The mixture was refluxed overnight at 90C. After the reaction was completed, CH3CN was evaporated off to obtain a solid mass which was poured into water (50 mL) and extracted with CH2Cl2 (225 mL). The combined organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to obtain the pure product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.1% | With sodium tris(acetoxy)borohydride; In ethyl acetate; at 20 - 30℃;Inert atmosphere; | In a 25 ml round-bottom flask compound is added in 16A (254 mg, 1 . 32mmol), compound 16B (336 mg, 1 . 20mmol), ethyl acetate (2 ml), stirring, add three acetoxy nabh (304 mg, 1 . 44mmol). Stir at room temperature overnight, TLC detection raw material the reaction is complete. Saturated sodium bicarbonate aqueous solution for quenching the reaction, then using ethyl acetate extraction, combined with the organic layer, dry anhydrous sodium sulfate, concentrated after the silica gel column chromatography, with petroleum ether: ethyl acetate (5:1) as eluant, get white solid product 16 (231 mg, yield: 42.1%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.5% | With sodium tris(acetoxy)borohydride; In ethyl acetate; at 20 - 30℃;Inert atmosphere; | In a 25 ml round-bottom flask compound is added in 17A (254 mg, 1 . 32mmol), compound 17B (372 mg, 1 . 20mmol), ethyl acetate (2 ml), stirring, add three acetoxy nabh (304 mg, 1 . 44mmol). Stir at room temperature overnight, TLC detection raw material the reaction is complete. Saturated sodium bicarbonate aqueous solution for quenching the reaction, then using ethyl acetate extraction, combined with the organic layer, dry anhydrous sodium sulfate, concentrated after the silica gel column chromatography, with petroleum ether: ethyl acetate (5:1) as eluant, get white solid product 17 (225 mg, yield: 38.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.5% | With sodium tris(acetoxy)borohydride; In ethyl acetate; at 20 - 30℃;Inert atmosphere; | In a 25 ml round-bottom flask compound is added in 18A (254 mg, 1 . 32mmol), compound 18B (367 mg, 1 . 20mmol), ethyl acetate (2 ml), stirring, add three acetoxy nabh (304 mg, 1 . 44mmol). Stir at room temperature overnight, TLC detection raw material the reaction is complete. Saturated sodium bicarbonate aqueous solution for quenching the reaction, then using ethyl acetate extraction, combined with the organic layer, dry anhydrous sodium sulfate, concentrated after the silica gel column chromatography, with petroleum ether: ethyl acetate (5:1) as eluant, get white solid product 18 (264 mg, yield: 45.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.6% | With sodium tris(acetoxy)borohydride; In ethyl acetate; at 20 - 30℃;Inert atmosphere; | In a 25 ml round-bottom flask compound is added in 19A (254 mg, 1 . 32mmol), compound 19B (372 mg, 1 . 20mmol), ethyl acetate (2 ml), stirring, add three acetoxy nabh (304 mg, 1 . 44mmol). Stir at room temperature overnight, TLC detection raw material the reaction is complete. Saturated sodium bicarbonate aqueous solution for quenching the reaction, then using ethyl acetate extraction, combined with the organic layer, dry anhydrous sodium sulfate, concentrated after the silica gel column chromatography, with petroleum ether: ethyl acetate (5:1) as eluant, get white solid product 19 (231 mg, yield: 39.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.3% | With sodium tris(acetoxy)borohydride; In ethyl acetate; at 20 - 30℃;Inert atmosphere; | In a 25 ml round-bottom flask compound is added in 21A (212 mg, 1 . 1mmol), compound 21B (214 mg, 1 . 0mmol), ethyl acetate (2 ml), stirring, add three acetoxy nabh (254 mg, 1 . 2mmol). Stir at room temperature overnight, TLC detection raw material the reaction is complete. Saturated sodium bicarbonate aqueous solution for quenching the reaction, then using ethyl acetate extraction, combined with the organic layer, dry anhydrous sodium sulfate, concentrated after the silica gel column chromatography, with petroleum ether: ethyl acetate (5:1) as eluant, get white solid product 21 (158 mg, yield: 40.3%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.7% | With sodium tris(acetoxy)borohydride; In ethyl acetate; at 20 - 30℃;Inert atmosphere; | In a 25 ml round-bottom flask compound is added in 22A (212 mg, 1 . 1mmol), compound 22B (350 mg, 1 . 0mmol), ethyl acetate (2 ml), stirring, add three acetoxy nabh (254 mg, 1 . 2mmol). Stir at room temperature overnight, TLC detection raw material the reaction is complete. Saturated sodium bicarbonate aqueous solution for quenching the reaction, then using ethyl acetate extraction, combined with the organic layer, dry anhydrous sodium sulfate, concentrated after the silica gel column chromatography, with petroleum ether: ethyl acetate (4:1) as eluant, get white solid product 22 (187 mg, yield: 35.7%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.1% | With sodium tris(acetoxy)borohydride; In ethyl acetate; at 20 - 30℃;Inert atmosphere; | In a 25 ml round-bottom flask compound is added in 32A (322 mg, 1 . 67mmol), compound 32B (300 mg, 1 . 52mmol), ethyl acetate (2 ml), stirring, add three acetoxy nabh (386 mg, 1 . 83mmol). Stir at room temperature overnight, TLC detection raw material the reaction is complete. Saturated sodium bicarbonate aqueous solution for quenching the reaction, then using ethyl acetate extraction, combined with the organic layer, dry anhydrous sodium sulfate, concentrated after the silica gel column chromatography, with petroleum ether: ethyl acetate (5:1) as eluant, get white solid product 32 (286 mg, yield: 50.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.5% | With sodium tris(acetoxy)borohydride; In ethyl acetate; at 20 - 30℃;Inert atmosphere; | In a 25 ml round-bottom flask compound is added in 76C (400 mg, 1 . 61mmol), compound D (341 mg, 1 . 77mmol), ethyl acetate (2 ml), stirring, add three acetoxy nabh (409 mg, 1 . 93mmol). Stir at room temperature overnight, TLC detection raw material the reaction is complete. Saturated sodium bicarbonate aqueous solution for quenching the reaction, then using ethyl acetate extraction, combined with the organic layer, dry anhydrous sodium sulfate, concentrated after the silica gel column chromatography, with petroleum ether: ethyl acetate (4:1) as eluant, get white solid product compound 76 (312 mg, yield: 45.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.6% | With triethylamine; In dichloromethane; at 20 - 30℃; for 0.5h;Inert atmosphere; | The 70A (773 mg, 4 . 0mmol) by adding 100 ml round bottom flask, and using dichloromethane (20 ml) to dissolve, first under stirring by adding triethylamine (669μl, 4 . 8mmol), then adding bromine second grade acid ethyl ester (442μl, 4 . 0mmol), reaction at room temperature 30 min. After stopping the reaction, concentration after the silica gel column chromatography separation (petroleum ether: ethyl acetate = 2:1) to obtain compound 70B (800 mg, yield 71.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium carbonate; In acetonitrile; at 90℃; for 6h; | General procedure: Compound 8 (70.6 mg, 0.24 mmol) and 5,6-dimethoxyisoindoline(68.5 mg, 0.38 mmol) were dissolved in CH3CN (30 mL), followed by addition of K2CO3 (138.8 mg, 1.00 mmol). The mixture was heated under reflux and stirred at 90 C for 6 h. After cooling and filtration, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate/triethyamine) = 10:10:1, v/v/v) to afford 13(56.8 mg, 59%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With potassium carbonate; In acetonitrile; at 90℃; for 6h; | General procedure: Compound 8 (70.6 mg, 0.24 mmol) and 5,6-dimethoxyisoindoline(68.5 mg, 0.38 mmol) were dissolved in CH3CN (30 mL), followed by addition of K2CO3 (138.8 mg, 1.00 mmol). The mixture was heated under reflux and stirred at 90 C for 6 h. After cooling and filtration, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate/triethyamine) = 10:10:1, v/v/v) to afford 13(56.8 mg, 59%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium carbonate; In acetonitrile; at 90℃; for 6h; | General procedure: Compound 8 (70.6 mg, 0.24 mmol) and 5,6-dimethoxyisoindoline(68.5 mg, 0.38 mmol) were dissolved in CH3CN (30 mL), followed by addition of K2CO3 (138.8 mg, 1.00 mmol). The mixture was heated under reflux and stirred at 90 C for 6 h. After cooling and filtration, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate/triethyamine) = 10:10:1, v/v/v) to afford 13(56.8 mg, 59%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate; In acetonitrile; at 90℃; for 6h; | General procedure: Compound 8 (70.6 mg, 0.24 mmol) and 5,6-dimethoxyisoindoline(68.5 mg, 0.38 mmol) were dissolved in CH3CN (30 mL), followed by addition of K2CO3 (138.8 mg, 1.00 mmol). The mixture was heated under reflux and stirred at 90 C for 6 h. After cooling and filtration, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate/triethyamine) = 10:10:1, v/v/v) to afford 13(56.8 mg, 59%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate; In acetonitrile; at 90℃; for 6h; | General procedure: Compound 8 (70.6 mg, 0.24 mmol) and 5,6-dimethoxyisoindoline(68.5 mg, 0.38 mmol) were dissolved in CH3CN (30 mL), followed by addition of K2CO3 (138.8 mg, 1.00 mmol). The mixture was heated under reflux and stirred at 90 C for 6 h. After cooling and filtration, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate/triethyamine) = 10:10:1, v/v/v) to afford 13(56.8 mg, 59%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine; In dichloromethane; at 20℃; | General procedure: To a solution of 2 (0.36 g, 1.98 mmol) in DCM (DCM, 10 mL) was added 3f (0.36 g, 1.96 mmol) and triethylamine (0.21 g, 2.08 mmol), the mixture was stirred at room temperature for 3-4 hours. After concentration under reduced pressure, the residue was purified by silica gel chromatography (PE/EA=1/1, v/v) to afford the title compound (0.53 g, 78%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | General procedure: 10429] Procedure was analogous to general procedure G. A flame-dried, 25-mE Radley tube, equipped with a Teflon- coated stir bar and a rubber septum, was charged with 3,5-di-tert-butylphenol (206.3 mg, 1.0 mmol, 1.0 equiv.). The reaction vessel was then purged with a steady stream of N2 for 2 mm prior to the addition of dry and degassed CH2C12 (8.0 mE). A separate, flame-dried test tube (1 6x 125- mE) was charged with [Cu(CH3CN)4](PF5) (29.8 mg, 0.08 mmol, 0.08 equiv.), N,N?-di-tert-butylethelenediamine (25.8 mg, 32.3 IL, 0.15 mmol, 0.15 equiv.), and CH2C12 (2.0 mE) to afford a homogeneous, pink solution. This solution was then added to the Radley tube via syringe to afford a final volume of 10.0 mE and a concentration of 0.1 M with respect to the phenol. The rubber septum was then rapidly removed and replaced with a Radley cap, which was connected to a tank of 02 and pressurized to 1 atm. Under a constant 02 pressure (1 atm), the reaction was vented 3 times for 10 s to eliminate N2. The reaction mixture was then stirred at room temperature for 4 h, depressurized by opening to the atmosphere, and argon gas was bubbled through the reaction mixture for 2 minutes to eliminate 02. Then, amine (2.0 mmol, 2.0 equiv.) was added to the reaction mixture via a syringe and the reaction mixture was stirred for 12 h at 500 C. Then, the reaction mixture was cooled to 00 C., followed by the addition of NaI3H4 (95.0 mg g, 2.0 mmol, 2.0 equiv.) and MeOR (3 mE). The reaction mixture was warmed to room temperature and stirred for 2 h. Afterwards, the reaction mixture was quenched by the addition of NaHSO4 (20 mE, 10% by weight aqueous solution), phases were separated, and the aqueous phase was extracted with CH2C12 (3x20 mE). The combined organic fractions were then dried over Mg504, filtered and concentrated in vacuo to afford a residue which was analyzed directly by ?H-NMR. The crude reaction mixture was then purified using a l3iotage IsoleraTM One (15% EtOAc in hexanes) to afford the N,O-fused acetal product in 78% (213.3 mg, 0.78 mmol) was isolated yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | at 20℃; for 18h; | General procedure: This was obtained from 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (100.6 mg) and MA6-019 (100 mg) using the general method 1 (Scheme 1) (reaction was carried out at room temperature, reaction time ~18 h). Aqueous NaHCO3 (5 mL) was added to the reaction mixture, and extracted with EtOAc (2 x 5 mL), dried (Na2SO4), evaporated to obtain the crude product, which was triturated with EtOAc/hexanes to provide the pure compound MA7-051 as an off white solid (107 mg, 75%). HPLC: >96% [tR = 7.7 min, 5-95% gradient MeOH, water (with 0.1% TFA), 20 min]. 1H NMR (400 MHz, DMSO) delta 10.64 (s, 1H), 6.65 (s, 1H), 6.60 (s, 1H), 3.83-3.72 (m, 2H), 3.69 (s, 3H), 3.68 (s, 3H), 3.58 (d, J = 8.0, 1H), 2.95-2.89 (m, 1H), 2.86-2.80 (m, 1H), 2.65-2.75 (m, 2H), 2.65-2.52 (m, 2H), 2.20-2.08 (m, 1H), 1.95-1.85 (m, 1H). HRMS (ESI+): m/z calcd for C16H21N2O4 (M+H)+ 305.1495, found 305.1489, m/z calcd for C16H20N2O4Na (M+Na)+ 327.1315, found 327.1315. HPLC-MS: HPLC-MS (ESI+): m/z 305.2 [100%, (M+H)+], 631.3 [10%, (2M+Na)+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; | General procedure: To a stirred solution of 1,2,3,4-THIQ (1.0 equiv.) in CH2Cl2 (10.0 mL/mmol), triethylamine(1.2 equivalent) was added and then cooled to 0 C. Acyl chloride (1.2 equivalent), sulfonyl chloride(1.2 equivalent), or diethylcarbamoyl chloride (1.2 equivalent) was added slowly at 0 C. The resultingreaction mixture was stirred at room temperature for 2 h under an argon atmosphere and thenpoured onto water (10.0 mL/mmol) and the organic layer was separated. The aqueous layer wasextracted two times with CH2Cl2 (10.0 mL/mmol), and the combined organic layer was washed withbrine (5.0 mL/mmol), dried over sodium sulfate, filtered, and concentrated under reduced pressure.Purification of the crude residue by flash column chromatography on silica gel, using the appropriatemixture of eluents, provided the corresponding N-protected 1,2,3,4-tetrahydroisoquinoline. Spectral data(1H- and 13C-NMR) of compounds (5a, 5c, 5d, 5e, 5g, 5h, 5k, 5l, 5m, 5n, 5o, 5q, 5r) which were reportedpreviously were compared and found in agreement with literature data. Furthermore, references wererepresented in supporting information. The characterization of novel compounds is given. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.1% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; for 2.5h; | A 12 L three-neck flask is charged with compound 2(475 g, 2.065 mol), compound 1 (474.8 g, 2.065 mol), K2CO3 (314 g, 2.273 mol), KI (68.6 g, 0.413 moL) and DMF (2.5 L) and the resulting mixture is heated to 70 C. and stirred for 2.5 hours. After LC-MS showed that the reaction was complete, the mixture is cooled to 50 C. and methanol (620 mL) is added. Then the mixture was cooled to 30 C. and water (4.75 L) was added. The resulting suspension was cooled to 10 C. and for 1 hour. The solid is filtered, washed with water (2×2.5 L) and air dried for 2 days to afford the compound 3 (630 g, 89.1%) as a yellow solid. (0310) |
With potassium carbonate; In acetonitrile;Reflux; | General procedure: The 1,2,3,4-tetrahydroisoquinoline derivative (1 eq), 1-(bromomethyl)-4-nitrobenzene (1 eq) or 1-(2-bromoethyl)-4-nitrobenzene (1 eq) and K2CO3 (3 eq) were refluxed in MeCN overnight. The reaction mixture was cooled to rt, filtered and the filtrate concentrated under reduced pressure. The residual solid was taken up in DCM and washed with H2O twice. The organic layer was dried over MgSO4, the solvent removed under reduced pressure and the residue purified by flash column chromatography. |
Tags: 1745-07-9 synthesis path| 1745-07-9 SDS| 1745-07-9 COA| 1745-07-9 purity| 1745-07-9 application| 1745-07-9 NMR| 1745-07-9 COA| 1745-07-9 structure
[ 2328-12-3 ]
6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride
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6-Methoxy-1,2,3,4-tetrahydroisoquinoline
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6-Methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride
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[ 2328-12-3 ]
6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride
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6-Methoxy-1,2,3,4-tetrahydroisoquinoline
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