7alpha-methyl fused ring morphine derivative as well as preparation method and application thereof
A technology of fused ring and morphine, applied in the field of 7α-methyl fused ring morphine derivatives and its preparation
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Embodiment 1
[0031] N-cyclopropylmethyl-7α-methyl-7β-hydroxymethyl-6α,14α-endo-ethylene-tetrahydronorthebaine
[0032]
[0033] Reaction route:
[0034]
[0035] Reaction conditions: (a) DIAD / acetonitrile, reflux, 4h; pyridine hydrochloride, methanol, room temperature, 2 days; (b) cyclopropanoyl chloride, triethylamine, dichloromethane, room temperature, 12h; (c) formaldehyde acrolein, lithium tetrafluoroborate, room temperature, 28h; (d) hydrogen, palladium carbon, ethanol, room temperature, 8h; (e) lithium aluminum hydride, tetrahydrofuran, room temperature, 2h.
[0036] Reaction steps:
[0037] a) Add thebaine (1g, 3.2mmol, 1eq) into a 50mL three-neck flask, then add anhydrous acetonitrile (10mL) to dissolve it, replace it with argon three times, and slowly drop it into the above solution using a dropping funnel Diisopropyl azodicarboxylate (0.68mL, 3.5mmol, 1.1eq) was added, and after the dropwise addition, the mixture was refluxed for 4h and cooled to room temperature. The solv...
Embodiment 2
[0043] N-Cyclopropylmethyl-7α-methyl-7β-aldehyde-6α,14α-endo-ethylene-tetrahydronorthebaine
[0044]
[0045] synthetic route:
[0046]
[0047] Reaction conditions: (f) oxalyl chloride, dimethyl sulfoxide, dichloromethane, triethylamine, -78°C to room temperature, 2h.
[0048] Reaction steps:
[0049] f) Add oxalyl chloride (0.06mL, 0.74mmol, 1.25eq) and anhydrous dichloromethane (3mL) into an eggplant-shaped flask, cool to -78°C, add anhydrous dimethyl sulfoxide (0.11mL, 1.53 mmol, 2.6eq) was dissolved in anhydrous dichloromethane (2mL), stirred for 5min; to the above mixture was added a solution of compound 6 (250mg, 0.59mmol, 1eq) dissolved in anhydrous dichloromethane (1mL), Stir for 20min; then add triethylamine (0.41mL, 2.94mmol, 5eq), remove the -78°C dry ice-acetone bath, and react at room temperature for 2h. The reaction solution was washed successively with saturated ammonium chloride solution (5mL x 3) and saturated sodium bicarbonate solution (5mL x 3), t...
Embodiment 3
[0051] (20R)-N-Cyclopropylmethyl-7α-methyl-7β-(1-phenyl-hydroxymethyl)-6α,14α-endo-ethylene-tetrahydronorthebaine
[0052]
[0053] synthetic route:
[0054]
[0055] Reaction conditions: (g) halides, n-butyllithium, tetrahydrofuran, -78°C, 0.25h.
[0056] Reaction steps:
[0057] g) Add bromobenzene (188mg, 1.2mmol, 10eq) and anhydrous tetrahydrofuran (2.5mL) into a Schlenk tube, cool to -78°C, replace argon three times, and add dropwise to the above reaction solution under the protection of argon Add n-butyllithium (2.4M in n-hexane, 0.5mL, 1.2mmol, 10eq), stir for 10min, then slowly inject compound 7 (50mg, 0.12mmol, 1eq) into anhydrous tetrahydrofuran solution (1mL), keep Reaction at -78°C for 0.25h. Remove the dry ice-acetone bath, quench with saturated ammonium chloride solution, add ethyl acetate (10mL x 3) and water (10mL) for extraction, combine the organic phases, wash with saturated brine (15mL), and add anhydrous sodium sulfate After drying and filtering,...
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