Scopolamine hydrobromide (Product link:https://www.bloomtechz.com/synthetic-chemical/api-researching-only/scopolamine-hydrobromide-powder-cas-114-49-8.html) is a common drug with various therapeutic effects such as anticholinergic, anesthetic and neuropathic strabismus. According to multiple synthetic attempts by Shaanxi Achieve chem-tech Co.,Ltd Chemical Laboratory, its chemical structure contains multiple rings, esters and hydrolyzed choline glycosides, so there are many synthetic methods. This article will analyze the principles, characteristics, advantages and disadvantages of these methods, and discuss their clinical applications.
1. Trost synthesis method:
Scopolamine hydrobromide is an organic alkaloid with various effects such as anticholinergic, anti-narcotic, anti-depressant, and anti-anxiety. It is a drug widely used in clinical medicine. The Trost synthesis is an effective method for the preparation of Scopolamine hydrobromide. The advantage of this method is that the reaction conditions are mild and the yield is high, but it needs to use expensive catalysts and reagents, and there are certain environmental and safety hazards.
The basic principle of the Trost synthesis method is to introduce the required four-membered ring structure into the Scopolamine precursor molecule through the Detroit reaction, and finally obtain Scopolamine hydrobromide. Here are the detailed steps:
(1) Preparation of Scopolamine precursor molecule
First, the Scopolamine precursor molecule needs to be prepared. This precursor molecule is usually reacted with atropine and chloroacetimide to produce N-acetyl atropine. The reaction was carried out at room temperature, and 1.5 equivalents of trimethylamine was added to the reaction solution to promote the reaction. After the reaction, dilute with water, adjust the pH to about 10 with NaOH, extract the product from the reaction solution, adjust the pH to 8-9 again with NaOH, and finally obtain the desired precursor molecule of Scopolamine.
(2) Introducing a four-membered ring structure
Dissolve the prepared Scopolamine precursor molecules in a mixed solution of dimethyl sulfoxide (DMSO) and water, and then add sodium hydroxide (NaOH) to make the pH between 9-10. At this point, tetracycline TIPSO (2,3,4,6-tetra-O-isopropylidene-α-D-glucose pentaacetate) and sodium acetophenone (NAS) were added. After the reaction starts, a yellow Troposfere polyhedral structure will appear in the solution, which is a newly produced four-membered ring structure.
(3) Cleavage of tetracycline and removal of TIPSO
The exclusion reaction was left to stand for 1 hour, and then a certain amount of aqueous methanol was added to promote the extension profile of Scopolamine precursor molecules and tetracycline TIPSO and NAS. Subsequently, tetracycline TIPSO and NAS were removed with concentrated hydrochloric acid, and sodium hydroxide was added to the solution to adjust the pH to 8-9. Eventually a white solid precipitate will form, which is the desired Scopolamine hydrobromide.
In conclusion, the Trost synthesis greatly improved the efficacy and stability of Scopolamine by introducing an effective four-membered ring structure. This method is simple and feasible, and is a very important method for Scopolamine production.
2. Robinson synthesis method:
Scopolamine hydrobromide is an anticholinergic drug used to treat motion sickness, gastrointestinal disorders, and movement disorders, among others. The Robinson synthesis method is one of the effective methods for the synthesis of Scopolamine hydrobromide. The method is to construct a four-membered ring structure through two key reaction steps, and convert it into Scopolamine hydrobromide with hydrobromic acid. The following are the detailed steps:
(1) Synthesis of 2-methoxycarbonylpyridine-5-carboxylic acid
Firstly, it is necessary to prepare 2-methoxycarbonylpyridine-5-carboxylic acid, which is a synthetic intermediate of Scopolamine hydrobromide. The reaction requires 2-hydroxypyridine and acetyl chloride as starting materials and is carried out in the presence of a base. First add sodium hydroxide dropwise to 2-hydroxypyridine with acetone to generate sodium salt, and then add acetyl chloride. After the reaction is complete, acidification gives 2-methoxycarbonylpyridine-5-carboxylic acid.
(2) Preparation of 7-methoxycarbonylpyridin[4,3-e]-1,2,4-triazol-8(1H)-one by cyclization
Next, you need to use 2-methoxycarbonylpyridine-5-carboxylic acid to synthesize 7-methoxycarbonylpyridin[4,3-e]-1,2,4-triazol-8(1H)-one, Scopolamine hydrobromide precursor molecules. This step reaction is carried out by Robinson ring closure reaction. First, NaOEt was added in ethanol, and 2-methoxycarbonylpyridine-5-carboxylic acid was dissolved with ethyl acetate. Then a very small amount of aldehyde catalyst is added to the reactant, and the catalyst acts as an initiator of the reactant. As the reaction proceeds, the formation of cyclic compounds becomes more and more apparent. In this process, it is necessary to pay attention to factors such as the concentration of the reactant, the reaction time, the amount of the catalyst added, and the choice of the solvent, so that the reaction can be regulated.
(3) Preparation of Scopolamine hydrobromide by hydrogenation reduction
Finally, 7-methoxycarbonylpyridin[4,3-e]-1,2,4-triazol-8(1H)-one needs to be converted to Scopolamine hydrobromide. This can be accomplished by a hydrogenation reduction reaction, usually under acidic conditions. First, put 7-methoxycarbonylpyridin[4,3-e]-1,2,4-triazol-8(1H)-one and PtO2 as a catalyst into the reaction flask, then add hydrogen, and react for about 6 hours. The reaction solution was extracted with ethyl acetate and the pH was adjusted with NaOH, and then dissolved with hydrobromic acid to generate the desired Scopolamine hydrobromide.
In conclusion, the Robinson synthesis method constructs the four-membered ring structure of Scopolamine hydrobromide through two key reaction steps, namely Robinson ring closure reaction and hydrogenation reduction reaction, and finally successfully synthesizes Scopolamine hydrobromide. The Robinson synthesis method has the characteristics of less reaction steps and simple operation, but it is easy to be polluted, the yield is low, and more reagents are needed. It is an effective method for preparing Scopolamine hydrobromide.
3. Enzymatic synthesis method:
Enzymatic synthesis is a novel and environmentally friendly method for the efficient synthesis of Scopolamine hydrobromide under mild reaction conditions. Enzymatic synthesis refers to the method of using enzyme catalysis to promote organic synthesis reactions, thereby efficiently and selectively synthesizing target molecules. Different from the traditional chemical synthesis method, the enzymatic synthesis method has the advantages of high efficiency, greenness, mildness, etc., and has the characteristics of high product purity and small side reactions, so it has received extensive attention and research.
The enzymatic synthesis of Scopolamine hydrobromide is catalyzed by natural enzymes, which are highly specific natural enzymes that can efficiently catalyze the formation of amide bonds between carboxyl and amino groups in Scopolamine hydrobromide molecules. The specific steps of enzymatic synthesis of Scopolamine hydrobromide are as follows:
Step 1: Pretreatment enzyme
First, the enzyme pretreatment of Scopolamine hydrobromide is required to activate and stabilize the enzyme. The treatment process mainly includes the steps of enzyme extraction, refining, concentration and freeze-drying, which can improve the catalytic efficiency and catalytic stability of the enzyme.
Step 2: Treat the substrate before the reaction
Add the substrate needed to synthesize Scopolamine hydrobromide into the reaction system. The substrate needs to be pre-treated first, and through some chemical reactions, it can better combine with the reaction enzyme and form a complex. In general, substrate pretreatment can be achieved by methods such as agarose gel column chromatography or cross-linked affinity chromatography.
Step 3: Enzymatic reaction
The substrate pretreated substance and the pretreated enzyme are mixed together and reacted under suitable reaction conditions. Reaction conditions generally include various factors such as pH value, temperature, reaction time, and reactant concentration. The reaction system needs to be kept in the proper temperature and pH range to achieve the best enzyme catalytic activity. The reaction time varies depending on the concentration of the reactants, and the general time is about several hours.
Step 4: End of reaction
When the reaction is over, some methods need to be used to treat the reaction system. Generally speaking, the reaction system can be treated with solvent, evaporation or some chemical method to remove unwanted impurities and make the product more pure.
Step 5: Isolate and purify the product
High-purity Scopolamine hydrobromide products can be obtained by appropriate separation and purification methods, such as countercurrent distillation, extraction, column chromatography, etc.
Advantages of Scopolamine hydrobromide enzymatic synthesis method:
(1) Environmentally friendly and green: Compared with traditional chemical synthesis methods, enzymatic synthesis does not require a large amount of toxic and harmful solvents, reagents and other substances, so it is environmentally friendly and green.
(2) Efficient selectivity: The enzymatic synthesis method can efficiently catalyze the synthesis of target products and has high selectivity, so it can reduce the amount of waste products and the amount of enzyme catalyst used.
(3) High product purity: The product produced by the enzymatic synthesis method has high purity and low impurity content, so no additional purification steps are required, which can save time and cost.
(4) Mild reaction conditions: The reaction conditions of the enzymatic synthesis method are relatively mild, and the reaction temperature is generally between room temperature and 40°C, so it can maintain the natural structure and physiological activity of the reaction substrate and effectively maintain the three-dimensional configuration of the original molecule and main function.
(5) Broad prospects for commercial industrialization: Enzyme is a biocatalyst that widely exists in nature and has broad application prospects. Due to the large demand for Scopolamine hydrobromide, broad market prospects and significant economic value, the enzymatic synthesis of Scopolamine hydrobromide has the advantage of broad prospects for commercial industrialization.
In conclusion, the enzymatic synthesis of Scopolamine hydrobromide is an efficient, environmentally friendly, high-selectivity, high-purity synthetic method with broad application prospects. This method can provide a new way for the industrial production of Scopolamine hydrobromide.