Gastrodin chemical synthesis method suitable for industrialization

Abstract

The invention discloses a gastrodin chemical synthesis method. The method comprises the steps as follows: under Lewis acid catalysis, D-glucose reacts with acetic oxide, pentacetyl-D-glucose is obtained and not subjected to separation and purification; the pentacetyl-D-glucose and the p-cresol are catalyzed by Lewis acid and subjected to a glycosylation reaction directly in an organic solvent, so that 4-methylphenyl 2,3,4,6-O-tetracetyl-b-D-glucopyranoside is generated; then the 4-methylphenyl-2,3,4,6-O-tetracetyl-b-D-glucopyranoside reacts with 1,3-dibromo-5,5-dimethylhydantoin under the action of an initiator or in solar radiation, so that 4-bromomethyl-2,3,4,6-0-tetracetyl-b-D-glucopyranoside is obtained; then under the alkalescence condition, 4-bromomethyl-2,3,4,6-0-tetracetyl-b-D-glucopyranoside is hydrolyzed selectively, so that 4- Hydroxymethyl phenyl-2,3,4,6-O-tetracetyl-b-D-glucopyranoside is obtained; and finally an acetyl protecting group is removed from a methyl alcohol-sodium methoxide system, so that the gastrodin is obtained. Compared with a conventional method, the gastrodin chemical synthesis method has the advantages as follows: raw materials are easy to obtain, the cost is low, reaction products in all steps can be prepared through recrystallization, the process is simple, the reaction period is short, the yield is high, and the method is more suitable for preparing the gastrodin in large scale.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical industry, in particular to a method for chemically synthesizing gastrodin. Background technique [0002] Gastrodin, whose chemical name is 4-hydroxymethylphenyl-β-D-glucopyranoside, is the main active ingredient of the orchid plant Gastrodia elata, which has sedative, anticonvulsant, anti-inflammatory and immune-enhancing effects. It is widely used in the adjuvant treatment of vertigo, headache (neurasthenia and neurasthenia syndrome, vascular headache, tension headache, brain trauma syndrome, migraine, etc.) and epilepsy. [0003] At present, gastrodin raw materials for clinical application mainly come from plant extraction and chemical synthesis. Since the content of gastrodin in Gastrodia elata is extremely low (about 0.1%), there are problems such as high extraction cost, heavy workload, and resource limitation in obtaining gastrodin by plant extraction. To develop a method for large-sc...

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Problems solved by technology

At present, there are few literature reports on the biosynthesis of gastrodin, mainly focusing on cell culture and microbial transformation [Cai Jie, Jia Yi, Hua Yanan, Li Nan, Establishment of biosynthetic gastrodin transformation system in ginseng hairy roots, Plant Resources and Environmental Science, 2005, 14 (2), 29-31; Gong Jiashun, Ma Weipeng, Pu Junxue, Xu Shuguan, Zheng Shuangqing, Xiao Chunjie, Baihua Datura suspension culture cells transform p-hydroxybenzaldehyde to gastrodin, Acta Pharmaceutica Sinica, 2006 , 41(10), 963-966; Zhu Hongli, Song Jirong, Huang Jianxin, Zhang Jia, Ma Zhenyu, Yang Mingyan, Synthesis of Gastrodin by Microbial Transformation, Acta Pharmaceutica Sinica, 2006, 41(11), 1074-1077], but all biological The methods of synthesizing gastrodin are all in the stage of laboratory exploration, and it will take time to realize large-scale industrial production

[0005] The chemical synthesis of gastrodin began in the 1980s. In 1980, Zhou Jun and others completed the chemical synthesis of gastrodin for the first time [Zhou Jun, Yang Yanbin, Yang Chongren, Chemical Research on Gastrodin II, Acta Chemical Journal, 1980, 32 (2), 162-166], this synthetic route uses a large amount of toxic red phosphorus and bromine, which has serious waste treatment problems, which is not conducive to production safety and environmental safety, and the total yield is low (24%), and the production cost is high , but this synthetic route is still adopted by the main manufacturers of synthetic gastrodin raw materials in my country

In 1984, Pang Qijie and others reported an improved method for the synthesis of gastrodin [Pang Qijie, Zhong Yuguo, Improvement of the synthesis method of gastrodin, Pharmaceutical Industry, 1984, (3), 3-4], which still uses red phosphorus and bromine , just change the potassium borohydride reduction step to Raney nickel catalytic hydrogenation, although the improvement of this synthesis method has increased the total yield (31%), but the practical application is of little significance, and it also faces the problem of introducing heavy metals

In 2004, Dai Xiaochang and others reported the chemical synthesis process of gastrodin and its similar phenolic glycosides [Dai Xiaochang, Peng Xiao, Wu Songfu, Yang Wansong, Mao Yu, The chemical synthesis process of gastrodin and its similar phenolic glycosides, Journal of Yunnan University for Nationalities (Natural Science Edition), 2004, 3 (2), 83-85], this process only uses phosphorus tribromide to replace the red phosphorus and bromine used in the above two synthetic methods, and there is no substantial change in addition, Also facing the problems of environmental pollution, low yield and high cost

As mentioned earlier, the preparation of tetraacetylbromoglucose needs to use red phosphorus and bromine or phosphorus tribromide, thereby causing serious harm and pollution to producers and the environment; and tetraacetylbromoglucose itself is unstable and inconvenient Production storage and use, resulting in low yields (35-46.5%) of subsequent glycosylation reactions under alkaline and phase-transfer catalysis conditions, and the need to decompose the resulting glycosylation product 4-formylphenyl-2,3 ,The formyl group in 4,6-O-tetraacetyl-β-D-glucopyranoside is reduced to a hydroxymethyl group. In the reduction process, potassium borohydride or Raney nickel is used to catalyze hydrogenation. The price of potassium borohydride Therefore, the production cost is high, and Raney nickel catalytic hydrogenation reduction also faces the problem of introducing heavy metals into the product

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