Process for the preparation of quaternary n-alkyl morphinan alkaloid salts
A technology for alkoxymorphinan and alkaloid, which is applied in the field of separation and method of alkoxymorphinan containing 3-alkoxymorphinan, and can solve problems such as pain relief and blocking
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Embodiment 1
[0088] N-cyclopropylmethyl-noroxymorphone methyl bromide in 1-methyl-2-pyrrolidone: synthesis of methyl bromide
[0089] A 3-neck 500-mL flask was equipped with an addition funnel, thermocouple, condenser, and mechanical stirrer. 100 mL of 1-methyl-2-pyrrolidone was added to the flask under blown dry nitrogen, and heated to 55°C. A powder funnel was used instead of the additional funnel, 100 gm of naltrexone anhydrous base was added under stirring, the funnel was "rinsed" with 25 mL of 1-methyl-2-pyrrolidone, and the temperature was adjusted to 55-58°C. Reinstall the additional funnel in the 3-neck flask. Separately, cool 25 mL of anhydrous 1-methyl-2-pyrrolidone in a graduated cylinder. The methyl bromide gas was condensed in an ice bath in a thin lecture bottle and 25 mL of the methyl bromide in liquid form was measured out into another cold graduated cylinder. The cold methyl bromide liquid and 1-methyl-2-pyrrolidone were combined and mixed. The methyl bromide solution ...
Embodiment 2
[0092] From N-alkylation: a method for product purification of N-cyclopropylmethyl-noroxymorphone methyl bromide
[0093] First remove the unwanted of phenolic (O-alkyl) by-products. The solution was heated to 50-65 °C with an additional 500 mL of methanol. The solution was cooled at 20-25°C for 60-90 minutes. The sodium salt crystallized under stirring and was recovered by vacuum filtration. Dry at 60°C under nitrogen, and weigh 53-55 g of the sodium salt.
[0094] The product was regenerated by adjusting the pH of the sodium salt solution in methanol / water (100 mL, ratio 5:7.5) to 0.5-1 with 25 g of 45% hydrobromic acid. Filter the solution, add 150mL methanol, adjust the temperature to 50-55°C, and finally cool to ice bath temperature. The white precipitated product was recovered by vacuum filtration and rinsed with 75 mL of methanol. After drying to 75°C, the pure product weighed about 45 g. The product was tested by HPLC and was 99.5% pure relative to analytical st...
Embodiment 3
[0097] N-cyclopropylmethyl-noroxymorphone methyl bromide in N,N-dimethylformamide (DMF): synthesis of methyl bromide
[0098] Naltrexone base (40.0 g) was dissolved in N,N-dimethylformamide (DMF) (50 mL Mallinckrodt, AR) with gentle heating and purged with dry house nitrogen. Methyl bromide (5 mL, Aldrich) cooled to ice bath temperature was measured into a cold (ca. 5° C.) 10 mL graduated cylinder and quickly added to the reaction flask. With the bubbler left in place, the glass flask was heated at 65°C for 10 hours. After a brief reflux, the crude product was recovered from DMF by precipitation with acetone (75 mL, Mallinckrodt AR). A white solid was isolated by vacuum filtration and rinsed with acetone (Mallinckrodt AR). The crude product (22.7 g) was dissolved in methanol (Mallinckrodt AR) / deionized water (110 mL, 80 / 20), charcoal treated (0.5 g, DARCO KB-B, Ba#M-1014) and allowed to crystallize. The salt product (17.2 g) was again recrystallized from methanol / deionized ...
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