| 70% |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; Molecular sieve; Cooling with ice; Inert atmosphere; |
1.2 General procedure for amide coupling/hydrolysis reaction.
General procedure: On an ice-water bath, to thesolution of acid (3 eq) in anhydrous DMF (7 mL), was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 3 equiv), hydrobenzotriazole (HOBt, 3 equiv), 4 Åmolecular sieves, and TEA (8.0 eq) with N2 protection. Fifteen minutes later, a solution of 6α-naltrexamine hydrochloride (12, 1.0 eq) in DMF (5 mL) was added dropwise. The resultedmixture was allowed to warm up to ambient temperature gradually. Upon completion of thereaction, the mixture was then filtered through celite. The filtrate was concentrated to removeDMF. Methanol (10 mL), and K2CO3 (3 eq) were then added to the residue and stirred at ambient temperature overnight. The mixture was then filtered through celite again. The filtrate wasconcentrated to remove methanol. The residue was partitioned between CH2Cl2 (50 mL) and brine (50 mL). The organic layer was separated and dried over anhydrous MgSO4, concentratedunder reduced pressure. The residue was then purified by column chromatography, eluting withCH2Cl2/MeOH (1% NH3·H2O) to afford the corresponding compound as free base. Uponconfirmation by 1H NMR and 13C NMR, the free base was then transformed into hydrochloridesalt by dissolving in MeOH (0.1 mL) and DCM (2 mL), adding HCl methanol solution (1.25 M,4 eq) with an ice-water bath, and stirred for 5 min. Diethyl ether (10 mL) was then added. Twohours later, the precipitate was collected by filtration, dried in vacuum to give the targetcompound as hydrochloride salt, which was used in the HPLC, LC-MS, and elemental analysis.1.3 Experimental procedures1.3.1 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[2-(isoquinolin-3-yl)acetamido)morphinan (1). The title compound was prepared following the general procedure1.2 in 70% yield. Hydrochloride salt: 1H NMR (400 MHz, DMSO-d6) 9.67 (s, 1H), 9.31 (brs,1H, exchangeable), 8.84 (brs, 1H, exchangeable), 8.37 (d, J = 8.56 Hz, 1H), 8.33 (d, J = 8.04 Hz,1H), 8.178.15 (m, 2H), 8.04 (t, J = 7.58 Hz, 1H), 7.87 (t, J = 7.46 Hz, 1H), 6.75 (d, J = 8.12 Hz,1H), 6.58 (d, J = 8.16 Hz, 1H), 6.29 (brs, 1H), 4.64 (d, J = 3.88 Hz, 1H), 4.45 (m, 1H), 4.06 (s,2H), 3.90 (d, J = 6.64 Hz, 1H), 3.34 (d, J = 19.96 Hz, 1H), 3.26 (m, 1H), 3.092.97 (m, 2H),2.94 (m, 1H), 2.70 (m, 1H), 2.43 (m, 1H), 1.87 (m, 1H), 1.62 (m, 1H), 1.501.35 (m, 2H),1.080.95 (m, 2H), 0.67 (m, 1H), 0.61 (m, 1H), 0.47 (m, 1H), 0.39 (m, 1H); 13C NMR (100 MHz,DMSO-d6) δ 169.19, 148.48, 147.37, 141.37, 140.74, 140.50, 138.04, 131.87, 131.35, 130.11,128.49, 127.87, 126.71, 123.43, 121.08, 119.65, 89.12, 71.00, 63.70, 59.21, 47.52, 47.17, 47.11,40.01, 31.67, 30.62, 25.02, 21.02, 6.86, 6.24, 3.42. MS m/z found 512.2699 (M + H)+. IR (Diamond, cm-1) νmax 3232.8, 1651.9, 1615.6, 1236.4, 1117.6, 765.6, 747.5. mp 203 °C dec. |
| 70% |
Stage #1: 2-(isoquinolin-3-yl)acetic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide for 0.25h; Cooling with ice; Molecular sieve; Inert atmosphere;
Stage #2: alpha-Naltrexamine dihydrochloride at 20℃; Cooling with ice;
Stage #3: With potassium carbonate In methanol at 20℃; |
17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[2-(isoquinolin-3-yl)acetamido)morphinan (1)
General procedure: On an ice-water bath, to the solution of acid (3equiv, prepared in house, see Supplementary data for details) in anhydrous DMF (7mL), was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 3equiv), hydrobenzotriazole (HOBt, 3equiv), 4Å molecular sieves, and TEA (8.0equiv) under N2 protection. Fifteen minutes later, a solution of 6α-naltrexamine hydrochloride (19, 1.0equiv) in DMF (5mL) was added dropwise. The resulted mixture was allowed to warm up to ambient temperature gradually. Upon completion of the reaction, the mixture was then filtered through celite. The filtrate was concentrated to remove DMF. Methanol (10mL), and K2CO3 (3equiv) were then added to the residue and stirred at ambient temperature overnight. The mixture was then filtered through celite again. The filtrate was concentrated to remove methanol. The residue was partitioned between CH2Cl2 (50mL) and brine (50mL). The organic layer was separated and dried over anhydrous MgSO4, concentrated under reduced pressure. The residue was then purified by column chromatography, eluting with CH2Cl2/MeOH (1% NH3·H2O) to afford the corresponding compound as free base. Upon confirmation of the structure by 1H NMR and 13C NMR, the compound was then transformed into hydrochloride salt by dissolving the free base in MeOH (0.1mL) and DCM (2mL), adding HCl methanol solution (1.25M, 4equiv) under an ice-water bath, and stirred for 5min. Diethyl ether (10mL) was then added. Two hours later, the precipitate was collected by filtration, dried in vacuum to give the target compound as hydrochloride salt, which was then used in the HPLC, LC-MS, elemental analysis, and biological screenings. The title compound was prepared in 70% yield. Hydrochloride salt: 1H NMR (400MHz, DMSO-d6) δ 9.67 (s, 1H), 9.31 (br s, 1H, exchangeable), 8.84 (br s, 1H, exchangeable), 8.37 (d, J=8.56Hz, 1H), 8.33 (d, J=8.04Hz, 1H), 8.17-8.15 (m, 2H), 8.04 (t, J=7.58Hz, 1H), 7.87 (t, J=7.46Hz, 1H), 6.75 (d, J=8.12Hz, 1H), 6.58 (d, J=8.16Hz, 1H), 6.29 (br s, 1H), 4.64 (d, J=3.88Hz, 1H), 4.45 (m, 1H), 4.06 (s, 2H), 3.90 (d, J=6.64Hz, 1H), 3.34 (d, J=19.96Hz, 1H), 3.26 (m, 1H), 3.09-2.97 (m, 2H), 2.94 (m, 1H), 2.70 (m, 1H), 2.43 (m, 1H), 1.87 (m, 1H), 1.62 (m, 1H), 1.50-1.35 (m, 2H), 1.08-0.95 (m, 2H), 0.67 (m, 1H), 0.61 (m, 1H), 0.47 (m, 1H), 0.39 (m, 1H); 13C NMR (100MHz, DMSO-d6) δ 169.19, 148.48, 147.37, 141.37, 140.74, 140.50, 138.04, 131.87, 131.35, 130.11, 128.49, 127.87, 126.71, 123.43, 121.08, 119.65, 89.12, 71.00, 63.70, 59.21, 47.52, 47.17, 47.11, 40.01, 31.67, 30.62, 25.02, 21.02, 6.86, 6.24, 3.42. HRMS m/z found 512.2699, calculated 512.2544 (M+H)+. IR (Diamond, cm-1) νmax 3232.8, 1651.9, 1615.6, 1236.4, 1117.6, 765.6, 747.5. Mp 203°C dec. |
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