Synthesis method of 8-amino-1-{[2-(trimethylsilyl) ethyoxyl] methoxy} octane-3-ketone

Abstract

The invention relates to a synthesis method of 8-amino-1-{[2-(trimethylsilyl) ethyoxyl] methoxy} octane-3-ketone, and belongs to the technical field of chemical synthesis of medicines. The method comprises the following steps: protecting diphenylmethylamine by N-Boc, reacting with sodium hydride to obtain a sodium salt intermediate, and carrying out substitution reaction on the sodium salt intermediate and 1, 5-dibromopentane to obtain an intermediate-1; preparing a zinc bromide intermediate from the intermediate-1, enabling the zinc bromide intermediate to react with 3-{[2-(trimethylsilyl) ethyoxyl] methoxy} methyl propionate to generate an intermediate-2, and carrying out catalytic hydrogenation deprotection reaction on the intermediate-2 to obtain the lipoic acid intermediate, namely 8-amino-1-{[2-(trimethylsilyl) ethyoxyl] methoxy} octane-3-ketone. The method has the advantages of mild process conditions, easily available raw materials and high purity of each intermediate, is beneficial to quality control and improvement of raw material medicine production, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one. Background technique [0002] α-lipoic acid is a vitamin-like compound that can eliminate free radicals that accelerate aging and cause disease. It is both water-soluble and fat-soluble. Universal antioxidant drug. α-lipoic acid has a certain effect on the treatment of many diseases such as liver disease, diabetes, HIV virus, tumor, nervous system degeneration, radiation injury, arsenic, mercury, cadmium and other heavy metal poisoning, for example, it can assist in the treatment of type II diabetes and improve Pancreatic islets function in glucose metabolism, protect nerve cells, prevent cataracts, prevent muscle damage and so on. [0003] As shown in the following chemical structural formula, in the molecular structure of α-lipoic acid, there is a chiral carb...

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Problems solved by technology

Although people have developed a racemization method for S-lipoic acid, the conversion of S-lipoic acid into cyclic lipoic acid is relatively harsh on actual production conditions, corrosive to equipment, and the yield is low, resulting in expensive production costs; The second is to use 6,8-dihydroxyoctanoic acid methyl ester or 6-hydroxy-8-chlorooctanoic acid methyl ester as the starting material to make mesylate, and then stereoselectively form R-lipoic acid. The process of this method is more complicated , especially not easy to obtain pure product; the third is to hydrolyze racemic 6,8-dichlorooctanoic acid ethyl ester into (±) dichlorooctanoic acid, and then use a resolving agent to split, rethio and cyclization, the method is basically Can save costs, but because about 50% of S-(-)-6,8-dichlorooctanoic acid is still unused, the cost is higher

[0007] The preparation methods of R-lipoic acid in the prior art, including the three methods mentioned above, all have high cost, low yield and large raw material consumption, which cannot meet the requirements of industrialized scale-up production, and because of high waste discharge Disadvantages of not meeting the requirements of green production

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