Preparation method of droxidopa

Abstract

The invention provides a preparation method of droxidopa. The preparation method comprises the following steps: taking 3,4-dihydroxy benzaldehyde as a raw material, performing hydroxyl protection through benzyl chloride to obtain 3,4-dibenzyloxybenzaldehyde, enabling 3,4-dibenzyloxybenzaldehyde and glycine to generate asymmetric condensation reaction under the catalysis of L-threonine aldolase / pyridoxal phosphate, obtaining an L-threo and erythro-3-(3,4-dibenzyloxyphenyl) serine acetate intermediate state through acetic acid salt formation, obtaining intermediate L-threo-3-(3,4-dibenzyloxyphenyl) serine after the intermediate state is heated with water and backflows, and finally removing protected benzyl through Pd / C to prepare the droxidopa. The preparation method provided by the invention has the benefits that the reaction steps are shortened, the process is simplified, meanwhile, the whole total reaction yield is obviously improved, and the raw material cost can be more greatly reduced.

Description

technical field [0001] The invention relates to a preparation method of droxidopa, which belongs to the technical field of pharmaceutical synthesis. Background technique [0002] Droxidopa, English name Droxidopa, chemical name L-threo-3-(3,4-dihydroxyphenyl)serine, its structural formula is as follows: [0003] [0004] Droxidopa is a synthetic amino acid that restores abnormally reduced norepinephrine concentrations in the brain to normal levels and is used in the treatment of primary autonomic weakness (Parkinson's disease, multiple system atrophy, and pure autonomic weakness ), dopamine β hydroxylase deficiency, non-diabetic autonomic neuropathy, and other patients with symptomatic neurogenic orthostatic hypotension (NOH). Droxidopa is the first and only drug approved by the US Food and Drug Administration (FDA) for the treatment of NOH, and it is also the first new treatment option for the symptomatic treatment of NOH in the past two decades. [0005] There have be...

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Problems solved by technology

[0013] This route still uses piperonal, a class of piperonal, as a starting material, and commercial purchase is relatively difficult

In addition, the route steps are not reduced, and there are even more steps for preparing the intermediate N-methoxycarbonylphthalimide. The target configuration compound is still obtained by chiral resolution, and the resolution yield is low. , which directly leads to the low overall yield of the whole process, and the disadvantage of high preparation cost has not been improved. Even if the preparation scale of this process is relatively large, it is still not conducive to industrial scale-up production

[0014] Through literature search, it can be known that there are other literatures describing the synthesis of droxidopa, but these routes all have the disadvantages of long reaction steps, high cost of raw materials, and difficult availability of raw materials.

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