Structure of 3382-18-1
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CAS No. : | 3382-18-1 |
Formula : | C11H13NO2 |
M.W : | 191.23 |
SMILES Code : | COC1=CC2=C(C=C1OC)CCN=C2 |
MDL No. : | MFCD00266748 |
InChI Key : | NSLJVQUDZCZJLK-UHFFFAOYSA-N |
Pubchem ID : | 30058 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302+H312+H332-H315-H319-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
* 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 |
---|---|---|
36% | for 5 h; Reflux | (2-Acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (800 mg, 2.55 mmol, 1.00 equiv) was added to a solution of 6,7-dimethoxy- 3,4-dihydroisoquinoline (100 mg, 2.62 mmol, 1.00 equiv) and ethanol (10 mL). The resulting solution was heated at reflux for about 5 hours, and then water (20 mL) was added. Following standard extractive workup with dichloromethane (3 x 50 mL), the crude residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (1:4)) to afford the title compound as a white solid (300 mg, yield = 36percent). 1Η NMR (300 MHz, CDCl3), δ 6.63 (s, IH), 6.55 (s, IH), 3.89 (s, 3H), 3.83 (s, 3H), 3.55 (s, IH), 3.22-3.28 (m, IH), 2.94-3.14 (m, 4H), 2.31-2.65 (m, 4H), 1.73-1.81 (t, IH , J = 11.4), 1.33-1.39 (m, IH), 0.996-1.067 (t, IH, J = 10.5), 0.79-0.85 (m, 6H) LC-MS : m/z = 318(MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 2: Process for the preparation of 6, 7-dimethoxy-3, 4-dihydroisoquinolineA solution of N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine (250gm) obtained from step 1 in toluene (500ml) and polyphosphoric acid (50gm) was heated at 110C for 5 hours. The resulting reaction mixture was cooled to 50C, quenched with water (500ml) and pH of the resulting solution was adjusted to about 8.3 with aqueous solution of sodium hydroxide [sodium hydroxide (690gm) + water (690ml)]. The resulting reaction mass was extracted by ethyl acetate (2 1250ml), dried over anhydrous sodium sulfate (50gm) and concentrated under reduced pressure to get 6, 7-dimethoxy-3, 4-dihydroisoquinoline (190gm).Yield: 215gmPurity: 99.67% (By HPLC) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | General procedure: The ligand (1.2 equiv) was dissolved in dry THF or toluene (10 mL for 0.96 mmol) under argonatmosphere. The solution was cooled to -72 C and n-BuLi (1.6 M solution in hexanes, 1.2 equiv) wasadded and reaction mixture was stirred for 20 min. Then the solution of amide 5c or oxazolidine 16 (1equiv) in an appropriate solvent (7 mL for 0.8 mmol) was added dropwise and the reaction mixture wasstirred at -72 C for next 25 min. Next a solution of 6,7-dimethoxy-3,4-dihydroisoquinoline 4a (1 equiv)in an appropriate solvent (7 mL for 0.8 mmol) was added. The reaction progress was controlled on TLC.The reaction mixture was quenched at -72 C with 5% HCl. When the reaction mixture reached roomtemperature, the phases were separated and the organic one was extracted with 5% HCl (3 x 2 mL). Theorganic phase was dried over Na2SO4 and the solvent evaporated to give 2,3-dimethoxy-8-oxoberberine3a. An analytical sample was crystallized from Et2O affording white crystals of 3a, mp 169-172 C. Thespectral characteristics of our sample corresponded to those of the literature data for (S)-(-)-3a.12[α]D -243.4 (c 0.475, CHCl3) was measured for a sample of (S)-3a with 57% ee obtained in reactionperformed with oxazolidine 16 and imine 4a in the presence of (-)-sparteine 6, HPLC[hexane/propan-2-ol = 4:1, (R)-3a: tR = 28.6 (minor), (S)-3a: tR = 32.8 min (major)] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether; at 20℃;Inert atmosphere; | General procedure: The 6,7-dimethoxy-3,4-dihydroisoquinoline (1.91 g, 10.0 mmol) was dissolved in dry diethyl ether (30 ml) and ethyl bromoacetate, benzyl bromide or the corresponding α-bromoacetophenone (15 mmol) was added. The reaction mixture was stirred overnight at room temperature under an argon atmosphere. The yellow precipitate was filtered off, washed with diethyl ether and dried in vacuo to give the products as a yellow powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether; at 20℃;Inert atmosphere; | General procedure: The 6,7-dimethoxy-3,4-dihydroisoquinoline (1.91 g, 10.0 mmol) was dissolved in dry diethyl ether (30 ml) and ethyl bromoacetate, benzyl bromide or the corresponding α-bromoacetophenone (15 mmol) was added. The reaction mixture was stirred overnight at room temperature under an argon atmosphere. The yellow precipitate was filtered off, washed with diethyl ether and dried in vacuo to give the products as a yellow powder. |
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 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 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 |
---|---|---|
In diethyl ether; at 20℃;Inert atmosphere; | General procedure: The 6,7-dimethoxy-3,4-dihydroisoquinoline (1.91 g, 10.0 mmol) was dissolved in dry diethyl ether (30 ml) and ethyl bromoacetate, benzyl bromide or the corresponding α-bromoacetophenone (15 mmol) was added. The reaction mixture was stirred overnight at room temperature under an argon atmosphere. The yellow precipitate was filtered off, washed with diethyl ether and dried in vacuo to give the products as a yellow powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With ammonium acetate; acetic acid; In tert-butyl methyl ether;Heating / reflux; | Example 9:; [00184] Into a 1 -neck round-bottom flask were added l-([l,2,4]triazolo[l,5-a]pyridin-6-yl)- 2-(6-methylpyridin-2-yl)ethane-l,2-dione (0.49 g, 0.0018 mol), 6,7-dimethoxy-3,4-dihydro- isoquinoline (0.42 g, 0.0022 mol), ammonium acetate (0.6 g, 0.007 mol) and 2-methoxy-2- methylpropane (9 mL, 0.07 mol). To the resulting suspension was added acetic acid (1.5 mL, 0.026 mol). The resulting mixture was refluxed overnight. LCMS showed product and no diketone peak. The solvent was rotovaped and 50 mL CH2Cl2 and 50 mL saturated Na2CO3 aqueous solution and 20 mL water were added. After extracted with CH2Cl2, the organic layer was combined and dried over Na2SO4. The organic solution was then filtered and rotovaped to driness. The residue was chromatographed (30-60% Acetone/Hexane) to give the title compound (0.3 g, 37%).1H-NMR (400 MHz, CDCl3), (J = Hz), δ 8.89 (s, IH), 8.41 (s, IH), 7.79 (d, IH, J = 8.8), 7.73 (s, IH), 7.71(d, IH, J = 8.0), 7.64 (dd, IH, J = 9.2, 4.0), 7.55 (t, IH, J = 7.6), 6.96 (d, IH, J = 7.6), 6.77 (s, IH), 4.07(t, 2H, J=8.0), 4.02 (s, 3H), 3.94 (s, 3H), 3.11 (t, 2H, J=8.0), 2.32 (s, 3H).MS (ES+) m/z 438.72 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | Example 11:; [001861 A mixture of l-(5-fluoro-6-methyl-pyridm-2-yl)-2-[l,2,4]triazolo[l,5-a]pyridin-6- yl-ethane-l,2-dione (0.552 g, 0.00194 mol), 3,4-dihydro-isoquinoline (0.3 g, 0.002 mol) , ammonium acetate (0.627 g, 0.008 mol) and acetic acid (1.57 mL, 0.0276 mol) in 7 mL of 2- methoxy-2-methylpropane was refhαxed for 15 hours. Additional (0.3 g, 0.001 mol) diketone was added and the reaction mixture refluxed for 2 hours. After cooling to room temperature, the mixture was partitioned between CH2Cl2 and a saturated aqueous solution OfNa2CO3. The organic phases were dried over MgSO4, filtered and concentrated under vacuum. The resulting crude material that was purified by reverse phase preparative HPLC. Fractions containing the product by LC-MS were combined, concentrated and partitioned between CH2CI2 and a saturated aqueous solution OfNa2CO3. The organic phase was dried over MgSO4, filtered and concentrated under vacuum and triturated with Et2O to afford the title compound as a white solid (0.130 g, 17%).1H-NMR (300 MHz, CDCl3): 8.91 (s, IH), 8.44 (m, IH), 8.25 (m, broad, IH), 7.92 (m, broad, IH), 7.83 (dd, IH, J = 9 Hz, 2.8 Hz), 7.67-7.64 (m, IH), 7.44-7.27 (m, 4H), 4.12 (t, 2H, J = 6.5 Hz), 3.2 (t, 2H, J= 6.5Hz), 2.27 (d, 3H, J= 2.5 Hz). MS (ES+) m/z 396 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Step 1C: Tetrabenazine; To a round bottom flask was added 6,7-dimethoxy-3,4-dihydroisoquinoline (13 g, 67.8 mmol), 3 -dimethylaminomethyl-5 -methyl-hexan-2-one methiodide Ib (26 g, 81.4 mmol) and EtOH (130 mL). The suspension was heated to 80 0C overnight. The reaction mixture was allowed to cool to room temperature and H2O (200 mL) was added forming a precipitate. The EtOH was removed in vacuo and CH2Cl2 (400 mL) was EPO <DP n="15"/>added. A 10% NaOH solution was added to the mixture until basic. The aqueous layer was then extracted 3X with CH2Cl2 (250 mL). The organic layers were combined, dried over MgSO4 and concentrated. The crude reaction mixture was purified via flash column chromatography (0.5:9.5 Acetone:CH2Cl2) and further recrystallized from EtOAc and Hexanes to give 16.1 g (51 mmol) of a racemic mix of (3S,1 IbS) and (3R, 1 lbR)-3-isobutyl-9, 10-dimethoxy-1 ,3,4,6,7, 1 lb-hexahydro-pyrido[2, 1 - a]isoquinolin-2-one Ic (tetrabenazine, TBZ) in a 75% yield. The enantiomers of tetrabenazine were separated by SFC utilizing a Chiralpak AD-H column with 15% CAN/MeOH plus 0.5% DMEA at 2.5 mL/min at 100 bar and 35 0C to yield 4.3 g of (3R,l lbR)-tetrabenazine lc.l and 4.3 g of (3S,l lbS)-tetrabenazine lc.2. (3R,l lbR)-tetrabenazine lc.l: MS calcd: (317); Found 318.7 (M + H). (3S,l lbS)-tetrabenazine lc.2: MS calcd: (317); Found 318.7 (M + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Example 1 Preparation of Protected Diester 2 The dihydroisoquinoline 1 (1.0 eq.) and Boc anhydride (1.5 eq.) were dissolved in CH2Cl2 at room temperature to provide a 1.5 M solution with respect to the dihydroisoquinoline. The mixture was allowed to stir for 30 min. Following the allotted time, the reaction mixture was cooled to 0 C. and then diisopropylmalonate (1.5 eq.) followed by a pre-chilled solution of the Pd catalyst (0.008 eq.) in dichloromethane were added successively to the reaction mixture to provide a final reaction concentration of 0.84 M with respect to the starting dihydroisoquinoline. The reaction mixture was allowed to continue stirring at 2.5 C. for 15 h. Following this time EtOAc and brine were added to the reaction mixture. The aqueous layer was extracted with three portions of EtOAc and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the crude product. The crude material was dissolved in a minimal amount of dichloromethane and purified by flash chromatography on SiO2 (15-30% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). The product 2 was a colorless solid that existed as a mixture of rotamers in solution at room temperature 94%: [α]26D-69.0 (c 0.21, CHCl3); 1H NMR (CDCl3) δ 0.81-1.02 (m, 6H), 1.06-1.17 (m, 6H), 1.23-1.38 (m, 9H), 2.51-2.63 (m, 1H), 2.64-2.77 (m, 1H), 3.20-3.29 (m, 0.6H), 3.32-3.41 (m, 0.4H), 3.51-3.58 (m, 1H), 3.62-3.70 (m, 6H), 3.70-3.76 (m, 0.4H), 3.91-4.01 (m, 0.6H), 4.65-4.82 (m, 1H), 4.83-4.98 (m, 1H), 5.71 (apparent d, J=5.7 Hz, 0.6H), 5.78 (apparent d, J=7.9 Hz, 0.4H), 6.42-6.49 (m, 1H), 6.77 (s, 0.6H), 6.81 (s, 0.4H); 13C NMR (CDCl3) δ 21.02, 21.09, 21.18, 21.32, 27.24, 27.95, 28.02, 37.60, 39.34, 52.11, 52.83, 55.48, 55.52, 59.28, 60.08, 68.58, 68.76, 68.82, 79.46, 80.03, 110.09, 110.73, 111.13, 126.11, 126.18, 126.37, 127.07, 146.81, 146.87, 147.93, 153.86, 154.30, 166.29, 166.78, 166.94, 167.06. | |
94% | Example 1Preparation of Protected Diester 2 The dihydroisoquinoline 1 (1.0 eq.) and Boc anhydride (1.5 eq.) were dissolved in CH2Cl2 at room temperature to provide a 1.5 M solution with respect to the dihydroisoquinoline. The mixture was allowed to stir for 30 min. Following the allotted time, the reaction mixture was cooled to 0 C. and then diisopropylmalonate (1.5 eq.) followed by a pre-chilled solution of the Pd catalyst (0.008 eq.) in dichloromethane were added successively to the reaction mixture to provide a final reaction concentration of 0.84 M with respect to the starting dihydroisoquinoline. The reaction mixture was allowed to continue stirring at 2.5 C. for 15 h. Following this time EtOAc and brine were added to the reaction mixture. The aqueous layer was extracted with three portions of EtOAc and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the crude product. The crude material was dissolved in a minimal amount of dichloromethane and purified by flash chromatography on SiO2 (15-30% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). The product 2 was a colorless solid that existed as a mixture of rotamers in solution at room temperature 94%: [α]26D -69.0 (c 0.21, CHCl3); 1H NMR (CDCl3) δ 0.81-1.02 (m, 6H), 1.06-1.17 (m, 6H), 1.23-1.38 (m, 9H), 2.51-2.63 (m, 1H), 2.64-2.77 (m, 1H), 3.20-3.29 (m, 0.6H), 3.32-3.41 (m, 0.4H), 3.51-3.58 (m, 1H), 3.62-3.70 (m, 6H), 3.70-3.76 (m, 0.4H), 3.91-4.01 (m, 0.6H), 4.65-4.82 (m, 1H), 4.83-4.98 (m, 1H), 5.71 (apparent d, J=5.7 Hz, 0.6H), 5.78 (apparent d, J=7.9 Hz, 0.4H), 6.42-6.49 (m, 1H), 6.77 (s, 0.6H), 6.81 (s, 0.4H); 13C NMR (CDCl3) δ 21.02, 21.09, 21.18, 21.32, 27.24, 27.95, 28.02, 37.60, 39.34, 52.11, 52.83, 55.48, 55.52, 59.28, 60.08, 68.58, 68.76, 68.82, 79.46, 80.03, 110.09, 110.73, 111.13, 126.11, 126.18, 126.37, 127.07, 146.81, 146.87, 147.93, 153.86, 154.30, 166.29, 166.78, 166.94, 167.06. | |
94% | The dihydroisoquinoline 1 (1.0 eq.) and Boc anhydride (1.5 eq.) were dissolved in CH2Cl2 at room temperature to provide a 1.5 M solution with respect to the dihydroisoquinoline. The mixture was allowed to stir for 30 min. Following the allotted time, the reaction mixture was cooled to 0 C. and then diisopropylmalonate (1.5 eq.) followed by a pre-chilled solution of the Pd catalyst (0.008 eq.) in dichloromethane were added successively to the reaction mixture to provide a final reaction concentration of 0.84 M with respect to the starting dihydroisoquinoline. The reaction mixture was allowed to continue stirring at 2.5 C. for 15 h. Following this time EtOAc and brine were added to the reaction mixture. The aqueous layer was extracted with three portions of EtOAc and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the crude product. The crude material was dissolved in a minimal amount of dichloromethane and purified by flash chromatography on SiO2 (15-30% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). The product 2 was a colorless solid that existed as a mixture of rotamers in solution at room temperature 94%: [α]26D -69.0 (c 0.21, CHCl3); 1H NMR (CDCl3) δ 0.81-1.02 (m, 6H), 1.06-1.17 (m, 6H), 1.23-1.38 (m, 9H), 2.51-2.63 (m, 1H), 2.64-2.77 (m, 1H), 3.20-3.29 (m, 0.6H), 3.32-3.41 (m, 0.4H), 3.51-3.58 (m, 1H), 3.62-3.70 (m, 6H), 3.70-3.76 (m, 0.4H), 3.91-4.01 (m, 0.6H), 4.65-4.82 (m, 1H), 4.83-4.98 (m, 1H), 5.71 (apparent d, J=5.7 Hz, 0.6H), 5.78 (apparent d, J=7.9 Hz, 0.4H), 6.42-6.49 (m, 1H), 6.77 (s, 0.6H), 6.81 (s, 0.4H); 13C NMR (CDCl3) δ 21.02, 21.09, 21.18, 21.32, 27.24, 27.95, 28.02, 37.60, 39.34, 52.11, 52.83, 55.48, 55.52, 59.28, 60.08, 68.58, 68.76, 68.82, 79.46, 80.03, 110.09, 110.73, 111.13, 126.11, 126.18, 126.37, 127.07, 146.81, 146.87, 147.93, 153.86, 154.30, 166.29, 166.78, 166.94, 167.06. |
94% | The dihydroisoquinoline 1 (1.0 eq.) and Boc anhydride (1.5 eq.) were dissolved in CH2Cl2 at room temperature to provide a 1.5 M solution with respect to the dihydroisoquinoline. The mixture was allowed to stir for 30 min. Following the allotted time, the reaction mixture was cooled to 0 C. and then diisopropylmalonate (1.5 eq.) followed by a pre-chilled solution of the Pd catalyst (0.008 eq.) in dichloromethane were added successively to the reaction mixture to provide a final reaction concentration of 0.84 M with respect to the starting dihydroisoquinoline. The reaction mixture was allowed to continue stirring at 2.5 C. for 15 h. Following this time EtOAc and brine were added to the reaction mixture. The aqueous layer was extracted with three portions of EtOAc and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the crude product. The crude material was dissolved in a minimal amount of dichloromethane and purified by flash chromatography on SiO2 (15-30% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). The product 2 was a colorless solid that existed as a mixture of rotamers in solution at room temperature 94%: [α]26D -69.0 (c 0.21, CHCl3); 1H NMR (CDCl3) δ 0.81-1.02 (m, 6H), 1.06-1.17 (m, 6H), 1.23-1.38 (m, 9H), 2.51-2.63 (m, 1H), 2.64-2.77 (m, 1H), 3.20-3.29 (m, 0.6H), 3.32-3.41 (m, 0.4H), 3.51-3.58 (m, 1H), 3.62-3.70 (m, 6H), 3.70-3.76 (m, 0.4H), 3.91-4.01 (m, 0.6H), 4.65-4.82 (m, 1H), 4.83-4.98 (m, 1H), 5.71 (apparent d, J=5.7 Hz, 0.6H), 5.78 (apparent d, J=7.9 Hz, 0.4H), 6.42-6.49 (m, 1H), 6.77 (s, 0.6H), 6.81 (s, 0.4H); 13C NMR (CDCl3) δ 21.02, 21.09, 21.18, 21.32, 27.24, 27.95, 28.02, 37.60, 39.34, 52.11, 52.83, 55.48, 55.52, 59.28, 60.08, 68.58, 68.76, 68.82, 79.46, 80.03, 110.09, 110.73, 111.13, 126.11, 126.18, 126.37, 127.07, 146.81, 146.87, 147.93, 153.86, 154.30, 166.29, 166.78, 166.94, 167.06. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 0.5h; | The dihydroisoquinoline 1 (1.0 eq.) and Boc anhydride (1.5 eq.) were dissolved in CH2Cl2 at room temperature to provide a 1.5 M solution with respect to the dihydroisoquinoline. The mixture was allowed to stir for 30 min. Following the allotted time, the reaction mixture was cooled to 0 C. and then diisopropylmalonate (1.5 eq.) followed by a pre-chilled solution of the Pd catalyst (0.008 eq.) in dichloromethane were added successively to the reaction mixture to provide a final reaction concentration of 0.84 M with respect to the starting dihydroisoquinoline. The reaction mixture was allowed to continue stirring at 2.5 C. for 15 h. Following this time EtOAc and brine were added to the reaction mixture. The aqueous layer was extracted with three portions of EtOAc and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the crude product. The crude material was dissolved in a minimal amount of dichloromethane and purified by flash chromatography on SiO2 (15-30% EtOAc-hexanes, elution was observed at 285 nm and 228 nm). The product 2 was a colorless solid that existed as a mixture of rotamers in solution at room temperature 94%: [α]26D -69.0 (c 0.21, CHCl3); 1H NMR (CDCl3) δ 0.81-1.02 (m, 6H), 1.06-1.17 (m, 6H), 1.23-1.38 (m, 9H), 2.51-2.63 (m, 1H), 2.64-2.77 (m, 1H), 3.20-3.29 (m, 0.6H), 3.32-3.41 (m, 0.4H), 3.51-3.58 (m, 1H), 3.62-3.70 (m, 6H), 3.70-3.76 (m, 0.4H), 3.91-4.01 (m, 0.6H), 4.65-4.82 (m, 1H), 4.83-4.98 (m, 1H), 5.71 (apparent d, J=5.7 Hz, 0.6H), 5.78 (apparent d, J=7.9 Hz, 0.4H), 6.42-6.49 (m, 1H), 6.77 (s, 0.6H), 6.81 (s, 0.4H); 13C NMR (CDCl3) δ 21.02, 21.09, 21.18, 21.32, 27.24, 27.95, 28.02, 37.60, 39.34, 52.11, 52.83, 55.48, 55.52, 59.28, 60.08, 68.58, 68.76, 68.82, 79.46, 80.03, 110.09, 110.73, 111.13, 126.11, 126.18, 126.37, 127.07, 146.81, 146.87, 147.93, 153.86, 154.30, 166.29, 166.78, 166.94, 167.06. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | In ethanol; for 5h;Reflux; | (2-Acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (800 mg, 2.55 mmol, 1.00 equiv) was added to a solution of 6,7-dimethoxy- 3,4-dihydroisoquinoline (100 mg, 2.62 mmol, 1.00 equiv) and ethanol (10 mL). The resulting solution was heated at reflux for about 5 hours, and then water (20 mL) was added. Following standard extractive workup with dichloromethane (3 x 50 mL), the crude residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (1:4)) to afford the title compound as a white solid (300 mg, yield = 36%). 1Η NMR (300 MHz, CDCl3), δ 6.63 (s, IH), 6.55 (s, IH), 3.89 (s, 3H), 3.83 (s, 3H), 3.55 (s, IH), 3.22-3.28 (m, IH), 2.94-3.14 (m, 4H), 2.31-2.65 (m, 4H), 1.73-1.81 (t, IH , J = 11.4), 1.33-1.39 (m, IH), 0.996-1.067 (t, IH, J = 10.5), 0.79-0.85 (m, 6H) LC-MS : m/z = 318(MH)+. |
Stage C: Preparation of substantial pure crystalline form A of Tetrabenazine; 3-((Dimethylamino) methyl)-5-methylhexan-2-one methiodide (80gm) was added to the solution of 6, 7-dimethoxy-3, 4-dihydroisoquinoline (40gm) in isopropanol (288ml) at 25C and the resulting reaction mass was heated at 40-45C for 15 hours. The resulting insoluble material was filtered, washed with isopropanol (80ml) and filtrate was concentrated under reduced pressure up to the 150ml reaction volume. The reaction solution was diluted with methylene dichloride (1200ml) and water (1000ml) and pH was adjusted to 8.5 with sodium hydroxide solution [10%, 100ml]. The organic layer was separated, washed with water (3 x 1000ml) and concentrated under reduced pressure to obtain residue. The residue was dissolved in methanol (300ml) at 50C, and resulting solution was treated with an activated carbon (20gm) at 50-60C for 30minutes and then it was filtered and filtrate was further stirred at 20-25C for 2 hours. The resulting solids were filtered, washed with methanol (150ml), dried at 50-55C for 8 hours. The resulting solids were milled, sifted through 40 mesh sieve and micronized.Yield: 65gmPurity: 99.96% (By HPLC) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine; In tetrahydrofuran; for 8h;Reflux; | To a solution of hydrazonyl halide i (5 mmol) and 6,7-dimethoxy-3,4-dihydroisoquinoline iii (5 mmo) in tetrahydrofuran (THF) (40 ml) was added triethylamine (TEA) (1.4 ml, 10 mmol) at room temperature. The reaction mixture was refluxed for 8 h. The mixture was then poured on water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate and then filtered. The solvent was evaporated under reduced pressure. The solid product was collected and crystallized from ethanol. Yield: (70%) as an orange solid (from ethanol); m.p 130-132 C. IR (KBr, cm-1): 1660 (CO); 1H NMR (300 MHz, DMSO-d6): δ, ppm: 2.5 (s, 3H, CH3), 2.7 (m, 2H, CH2), 3.6 (s, 3H, OMe), 3.7 (s, 3H, OMe), 4.0 (m, 2H, CH2), 6.5 (s, 1H, H10b), 6.6 (s, 1H, H7), 6.7 (s, 1H, H10) 6.9-7.4 (m, 5H, Ph-H) MS (EI): m/z = 351 (M+). Anal. Calcd. for C20H21N3O3 (351.41): C, 68.36; H, 6.02; N, 11.96. Found: C, 68.56; H, 6.14; N, 11.88. |
70% | With triethylamine; In tetrahydrofuran; for 8h;Reflux; | To a solution of hydrazonyl halide, i (5 mmol) and 6,7-dimethoxy-3,4-dihydroisoquinoline ii (5 mmol) in tetrahydrofuran (THF) (40 ml) were added triethylamine (TEA) (1.4 ml, 10 mmol) at room temperature. The reaction mixture was refluxed for 8 h. The mixture was then poured on water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, and then filtered. The solvent was evaporated under reduced pressure. The solid product was collected and crystallized from ethanol. Yield: (70%) as an orange solid (from ethanol); m.p 130-132 C. IR (KBr, cm-1): 1660 (CO); 1H NMR (300 MHz, DMSO-d6): δ, ppm: 2.5 (s, 3 H, CH3), 2.7 (m, 2 H, CH2), 3.6 (s, 3 H, OMe), 3.7 (s, 3 H, OMe), 4.0 (m, 2 H, CH2), 6.5 (s, 1 H, H10b), 6.6 (s, 1 H, H7), 6.7 (s, 1 H, H10), 6.9-7.4 (m, 5 H, Ph-H) MS (EI): m/z = 351 (M+). Anal. Calcd. for C20H21N3O3 (351.41): C, 68.36; H, 6.02; N, 11.96. Found: C, 68.56; H, 6.14; N, 11.88. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With triethylamine; In 1,4-dioxane; at 100℃; for 1.5h;Microwave irradiation; | General procedure: The mixture of the appropriate aminonaphtholhydrochloride (0.44mmol), 6,7-dimethoxy-3,4-dihydroisoquinoline (2a, 0.4mmol) or 3,4-dihydroisoquinoline (2b, 0.4mmol) and Et3N (60mg, 0.6mmol) in 1,4-dioxane (5mL) was placed in a 10mL reaction vial and heated in a CEM LabMate microwave reactor under the microwave conditions given depicted in Tables 1 and 2. The solvent was then evaporated off and the crude product was crystallized with cold EtOH (8-12mL), filtered off and recrystallized from EtOH (11-15mL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In neat (no solvent); at 80 - 100℃; for 6.5h;Microwave irradiation; | General procedure: In a 10 mL pressurized reaction vial, 0.5 mmolindole (1) or indole-2-carboxylic acid (6), 0.5mmol cyclic imine (2, 4, 9or 12) and Et3N (for theamount used see Table 1) were placed. Thereaction mixture was heated in an oil bath or in a CEM Discover SP MW reactor.The reaction conditions are listed in Tables 1 and 2 and the work-up procedurein the text |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine; In 1,4-dioxane; at 80℃; for 1h;Microwave irradiation; | General procedure: The mixture of the appropriate aminonaphtholhydrochloride (0.44mmol), 6,7-dimethoxy-3,4-dihydroisoquinoline (2a, 0.4mmol) or 3,4-dihydroisoquinoline (2b, 0.4mmol) and Et3N (60mg, 0.6mmol) in 1,4-dioxane (5mL) was placed in a 10mL reaction vial and heated in a CEM LabMate microwave reactor under the microwave conditions given depicted in Tables 1 and 2. The solvent was then evaporated off and the crude product was crystallized with cold EtOH (8-12mL), filtered off and recrystallized from EtOH (11-15mL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine; In 1,4-dioxane; at 100℃; for 1.5h;Microwave irradiation; | General procedure: The mixture of the appropriate aminonaphtholhydrochloride (0.44mmol), 6,7-dimethoxy-3,4-dihydroisoquinoline (2a, 0.4mmol) or 3,4-dihydroisoquinoline (2b, 0.4mmol) and Et3N (60mg, 0.6mmol) in 1,4-dioxane (5mL) was placed in a 10mL reaction vial and heated in a CEM LabMate microwave reactor under the microwave conditions given depicted in Tables 1 and 2. The solvent was then evaporated off and the crude product was crystallized with cold EtOH (8-12mL), filtered off and recrystallized from EtOH (11-15mL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine; In 1,4-dioxane; at 100℃; for 1.5h;Microwave irradiation; | General procedure: The mixture of the appropriate aminonaphtholhydrochloride (0.44mmol), 6,7-dimethoxy-3,4-dihydroisoquinoline (2a, 0.4mmol) or 3,4-dihydroisoquinoline (2b, 0.4mmol) and Et3N (60mg, 0.6mmol) in 1,4-dioxane (5mL) was placed in a 10mL reaction vial and heated in a CEM LabMate microwave reactor under the microwave conditions given depicted in Tables 1 and 2. The solvent was then evaporated off and the crude product was crystallized with cold EtOH (8-12mL), filtered off and recrystallized from EtOH (11-15mL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With potassium phosphate; In acetonitrile; at 70℃;Molecular sieve; | General procedure: A mixture of 3,4-dihydro-isoquinoline imine 1 (0.2 mmol), arylacyl bromides 2 (0.24 mmol), K3PO4 (0.24 mmol), 4A molecular sieves (powder, 50 mg) and MeCN (0.5 mL) was stirred at 70C for 1.5-3h. Upon the consumption of imine 1 (monitored by TLC), the reaction was cooled to room temperature, filtered, concentrated and purified by a silica gel flash chromatography (PE/EtOAc) to afford compound 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With mercury dichloride; zinc; In N,N,N,N,N,N-hexamethylphosphoric triamide; toluene; for 3h;Reflux; | General procedure: A solution of methyl 1-bromocycloalkanecarboxylate1 (0.022 mol) and 6,7-dimethoxy-3,4-dihydroisoquinoline2 (0.02 mol) in anhydrous toluene (10 ml) was added dropwisewith stirring to a boiling mixture of zinc chips (2 g), a catalytic amount of mercury dichloride, anhydrous toluene (20 ml), and HMPA(2 ml). The mixture was refluxed for 3 h, cooled, decanted, and hydrolyzed with 5% acetic acid. The organic layer was separated, and the aqueous one was twice extracted with toluene. The organic phase was dried with anhydrous sodium sulfate, the solvents were distilled off, and the products were twice recrystallized from ethyl acetate. For characteristics of compounds 4a-c and 6, see Online Supplementary Materials. |
Tags: 3382-18-1 synthesis path| 3382-18-1 SDS| 3382-18-1 COA| 3382-18-1 purity| 3382-18-1 application| 3382-18-1 NMR| 3382-18-1 COA| 3382-18-1 structure
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