脱氧熊果苷的合成研究
摘要
脱氧熊果苷(4-[(2-四氢吡喃)氧]苯酚)是一种新型、高效的酪氨酸酶抑制剂,可作为化妆品添加剂实现美白作用。与现有常用的酪氨酸酶抑制剂对苯二酚、熊果苷等相比,该物质具有更好的美白效果,不会对黑色素细胞造成永久性的伤害,且停用一段时间之后皮肤黑色素可恢复到正常含量。
本课题的研究内容,是在借鉴前人报道的脱氧熊果苷合成方法基础上,提出一条改进的合成脱氧熊果苷的路线,并对其工艺条件进行优化研究。改进的合成路线以对苯二酚和苄氯为起始原料,首先进行单酚羟基缩合得对苄氧基苯酚；接着,对苄氧基苯酚与3,4-二氢吡喃反应得到2-[(4-苄氧基)苯氧基]四氢吡喃；然后,2-[(4-苄氧基)苯氧基]四氢吡喃加氢脱去苄基得到4-[(2-四氢吡喃)氧]苯酚,同时研究了不同吸附剂的使用以控制对苯二酚含量。
反应过程中,考察了反应温度、催化剂用量、投料比等对收率的影响,得出比较适宜的反应条件。即对苯二酚在甲醇钠、甲醇体系中与氯化苄反应,温度控制在64.5℃,反应时间1.5h,收率可达到75%；另一酚羟基与3,4-二氢吡喃醚化的过程中以二氯甲烷作溶剂、吡啶对甲基苯磺酸盐作催化剂,反应温度30℃,反应时间5 h,收率80%；2-[(4-苄氧基)苯氧基]四氢吡喃以乙酸乙酯做溶剂、碳酸钠做吸附剂钯碳催化加氢脱去苄基得到4-[(2-四氢吡喃)氧]苯酚,反应温度30℃,反应时间24 h,产品脱氧熊果苷中对苯二酚含量低于100 ppm,收率79%。产品熔点测定结果与文献报道值一致,目标化合物的的纯度经液相色谱确定,其结构经核磁共振表征确定。最后,对该工艺进行了中试放大研究,并进行了成本核算,证明工艺可行。
综合研究结论可得出此合成路线收率高,原料廉价易得,反应温和,操作简便,具有较好的工业价值。
4-[(Tetrahydro-2H-pyran-2-yl)oxy]phenol (Deoxyarbutin) is a new and effective tyrosinase inhibitor which could be used as cosmetic additive to achieve skin lightening. Compared with the present popular tyrosinase inhibitors such as arbutin hydroquinone, white effect of deoxyarbutin is much better. And the damage caused by deoxyarbutin to melanophore is not permanent, therefore, the composition of melanophore could be recovered to a normal level after stopping using it for a period of time.
This study focuses on an improved synthetic route of 4-[(tetrahydro-2H-pyran-2-yl)oxy]phenol and its optimization conditions on the basis of the proposed route reported by precusors. The improved synthetic route was designed with the single phenolic hydroxyl condensation for the preparation of p-benzyloxyphenol starting from hydroquinone and benzyl chloride followed by the reaction with 3,4-dihydropyran to afford 2-[4-(benzyloxy) phenoxy] tetrahydropyran. Eventually,4-[(2-tetrahydropyran)oxy]phenol was prepared by hydrogenation to rid the benzyl off. And the use of different alkaline sorbents was also studied for the purpose of controlling the concentration of hydroquinone.
Appropriate reaction conditions were obtained by studying the influence of several factors on the yield in terms of reaction temperature, amount of catalyst and rate of charge. A 75% yield was obtained by the 1.5 hour reaction of hydroquinone with benzyl chloride at 64.5℃in the sodium hydroxide, methanol system. A 80% yield was obtained by the etherification of the other phenolic hydroxyl group with 3,4-dihydropyran at 30℃for 5 hours using dichloromethane as solvent and pyridine p-toluenesulfonate salt as a catalyst. And a 79% yield of 4-[(2-tetrahydropyran)oxy]phenol was obtained by hydrogenation of 2-[4-(benzyloxy)phenoxy]tetrahydropyran to rid of the benzyl at 30℃for 24 hours using ethyl acetate as solvent, palladium as catalyst and sodium carbonate as absorbent.The content of hydroquinone in the product was lower than 100 ppm. The melting point of the product obtained was found to be the conformity of those reported in literatures. The purity of the title compound was analized by HPLC, and its structure was confirmed by 1H-NMR. And also, pilot process and cost accounting were studied. The results proved that this process is feasible in production.
This proposed synthetic process is much of industrial value because of the high yield, easily available and cheap materials, the moderate reaction conditions and the convenient operation.
本课题的研究内容,是在借鉴前人报道的脱氧熊果苷合成方法基础上,提出一条改进的合成脱氧熊果苷的路线,并对其工艺条件进行优化研究。改进的合成路线以对苯二酚和苄氯为起始原料,首先进行单酚羟基缩合得对苄氧基苯酚；接着,对苄氧基苯酚与3,4-二氢吡喃反应得到2-[(4-苄氧基)苯氧基]四氢吡喃；然后,2-[(4-苄氧基)苯氧基]四氢吡喃加氢脱去苄基得到4-[(2-四氢吡喃)氧]苯酚,同时研究了不同吸附剂的使用以控制对苯二酚含量。
反应过程中,考察了反应温度、催化剂用量、投料比等对收率的影响,得出比较适宜的反应条件。即对苯二酚在甲醇钠、甲醇体系中与氯化苄反应,温度控制在64.5℃,反应时间1.5h,收率可达到75%；另一酚羟基与3,4-二氢吡喃醚化的过程中以二氯甲烷作溶剂、吡啶对甲基苯磺酸盐作催化剂,反应温度30℃,反应时间5 h,收率80%；2-[(4-苄氧基)苯氧基]四氢吡喃以乙酸乙酯做溶剂、碳酸钠做吸附剂钯碳催化加氢脱去苄基得到4-[(2-四氢吡喃)氧]苯酚,反应温度30℃,反应时间24 h,产品脱氧熊果苷中对苯二酚含量低于100 ppm,收率79%。产品熔点测定结果与文献报道值一致,目标化合物的的纯度经液相色谱确定,其结构经核磁共振表征确定。最后,对该工艺进行了中试放大研究,并进行了成本核算,证明工艺可行。
综合研究结论可得出此合成路线收率高,原料廉价易得,反应温和,操作简便,具有较好的工业价值。
4-[(Tetrahydro-2H-pyran-2-yl)oxy]phenol (Deoxyarbutin) is a new and effective tyrosinase inhibitor which could be used as cosmetic additive to achieve skin lightening. Compared with the present popular tyrosinase inhibitors such as arbutin hydroquinone, white effect of deoxyarbutin is much better. And the damage caused by deoxyarbutin to melanophore is not permanent, therefore, the composition of melanophore could be recovered to a normal level after stopping using it for a period of time.
This study focuses on an improved synthetic route of 4-[(tetrahydro-2H-pyran-2-yl)oxy]phenol and its optimization conditions on the basis of the proposed route reported by precusors. The improved synthetic route was designed with the single phenolic hydroxyl condensation for the preparation of p-benzyloxyphenol starting from hydroquinone and benzyl chloride followed by the reaction with 3,4-dihydropyran to afford 2-[4-(benzyloxy) phenoxy] tetrahydropyran. Eventually,4-[(2-tetrahydropyran)oxy]phenol was prepared by hydrogenation to rid the benzyl off. And the use of different alkaline sorbents was also studied for the purpose of controlling the concentration of hydroquinone.
Appropriate reaction conditions were obtained by studying the influence of several factors on the yield in terms of reaction temperature, amount of catalyst and rate of charge. A 75% yield was obtained by the 1.5 hour reaction of hydroquinone with benzyl chloride at 64.5℃in the sodium hydroxide, methanol system. A 80% yield was obtained by the etherification of the other phenolic hydroxyl group with 3,4-dihydropyran at 30℃for 5 hours using dichloromethane as solvent and pyridine p-toluenesulfonate salt as a catalyst. And a 79% yield of 4-[(2-tetrahydropyran)oxy]phenol was obtained by hydrogenation of 2-[4-(benzyloxy)phenoxy]tetrahydropyran to rid of the benzyl at 30℃for 24 hours using ethyl acetate as solvent, palladium as catalyst and sodium carbonate as absorbent.The content of hydroquinone in the product was lower than 100 ppm. The melting point of the product obtained was found to be the conformity of those reported in literatures. The purity of the title compound was analized by HPLC, and its structure was confirmed by 1H-NMR. And also, pilot process and cost accounting were studied. The results proved that this process is feasible in production.
This proposed synthetic process is much of industrial value because of the high yield, easily available and cheap materials, the moderate reaction conditions and the convenient operation.
引文
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