Dimemorfan [(C)-3-methyl-N-methylmorphinan, DF], widely used as an antitussive drug without narcotic effects, is an analogue of dextromethorphan [(C)-3-methoxyN-methylmorphinan, DM]. However, it is not metabolized to dextrophan, which causes phencyclidine (PCP)-like adverse effects. Since its introduction in 1975 in Japan, the efficacy and safety of dimemorfan have been well established. Recently dimemorfan has been recognized as a neuro-protective agent. Its psychotropic effects were investigated for the clinical treatment of brain diseases such as Alzheimer’s and Parkinson’s. Dimemorfan was discovered through extensive screening of morphine derivatives synthesized at the Central Research Laboratories of Yamanouchi Pharmaceutical Co., Ltd. The patented route (Scheme 1) starts by addition of p-tolymagnesium chloride to Nmethyl-5,6,7,8-tetrahydroisoquinolinium bromide. Reduction of the resulting product with sodium borohydride, followed by resolution with L-(C)-tartaric acid and treatment with phosphoric acid to afford the target compound. However, the overall yield was only 15% and the procedure required 70 h to cyclize the requisite ring system using phosphoric acid. A few other improved methods followed nearly the same reaction sequence using different chiral resolving agents such as L-(C)-mandelic acid but postponed the methylation to the final step. All these modifications gave low yields (11–23%) and/or were time consuming (40–80 h). Herein we report an efficient synthesis of dimemorfan from dextromethorphan. Our strategy for the preparation of dimemorfan focused on the commercially available dextromethorphan as the starting material (Scheme 2). Initially we intended to convert dextromethorphan to dimemorfan directly via coupling reaction, but this method failed due to the instability of the O-demethylated intermediate of dextromethorphan. As an alternative, dextromethophan was selectively N-demethylated and protected as its carbamate, which was O-demethylated and activated as the phenolic triflate. Subsequent coupling followed by deprotection and reduction led to dimemorfan phosphate.

中文翻译：

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从右美沙芬高效合成地美沙芬

Dimemorfan [(C)-3-methyl-N-methylmorphinan, DF] 广泛用作镇咳药，无麻醉作用，是右美沙芬 [(C)-3-甲氧基N-甲基吗啡喃，DM] 的类似物。然而，它不会代谢为右旋糖酐，这会导致苯环利定 (PCP) 样的不良反应。自 1975 年在日本推出以来，dimemorfan 的疗效和安全性已得到很好的确立。最近，dimemorfan 被认为是一种神经保护剂。它的精神作用被研究用于临床治疗脑部疾病，如阿尔茨海默氏症和帕金森氏症。Dimemorfan 是通过对山之内制药株式会社中央研究实验室合成的吗啡衍生物的广泛筛选而发现的。 专利路线（方案 1）开始于向 Nmethyl-5,6,7 添加对甲苯基氯化镁，8-四氢异喹啉溴化物。用硼氢化钠还原所得产物，然后用 L-(C)-酒石酸拆分，用磷酸处理，得到目标化合物。然而，总产率仅为 15%，该过程需要 70 小时才能使用磷酸环化所需的环系。其他一些改进的方法遵循几乎相同的反应顺序，使用不同的手性拆分剂，如 L-(C)-扁桃酸，但将甲基化推迟到最后一步。所有这些修改都产生了低产量（11-23%）和/或耗时（40-80 小时）。在本文中，我们报告了一种从右美沙芬有效合成 dimemorfan 的方法。我们制备 dimemorfan 的策略集中在市售的右美沙芬作为起始材料（方案 2）。最初我们打算通过偶联反应将右美沙芬直接转化为二甲吗喃，但由于右美沙芬的 O-去甲基化中间体的不稳定性，该方法失败了。作为替代方案，右美沙芬被选择性地 N-去甲基化并保护为其氨基甲酸酯，其被 O-去甲基化并作为酚类三氟甲磺酸酯活化。随后的偶联随后去保护和还原导致磷酸二甲吗喃。