Process for producing miglitol key intermediate

Abstract

The invention relates to a preparation method of a drug used for diabetes, namely Miglitol intermediate N-hydroxyethyl glucosamine. The preparation method is characterized in that glucose and ethanolamine are used as initial raw materials; with solvent, active nickel catalyst and amine compounds are used as catalysts for the catalytic hydrogenation; the reaction pressure and the temperature are controlled for the reaction; when the reaction is finished, N-hydroxyethyl glucosamine white crystals are obtained after post-processing and refining; the yield is larger than 90 percent, and the purity is larger than or equal to 98.5 percent (HPLC detection). The preparation method solves the problems of the prior art of high cost, harsh reaction conditions and complex preparing process caused by the adoption of dear metals (catalysts such as platinum, palladium-charcoal, etc.) with high catalytic activity for the catalytic hydrogenation.

Description

technical field [0001] The invention relates to a method for synthesizing a diabetes drug, in particular to a method for synthesizing an important intermediate of the diabetes drug miglitol. Background technique [0002] Migliitol is a new type of hypoglycemic drug researched and developed by the German Bayer Pharmaceutical Company in the early 1980s, and is a new small intestinal α-glucosidase inhibitor. Chemical name: [2S,3R,4R,5S]-1-(2-hydroxyethyl)-2-(hydroxymethyl)-3,4,5,-trihydroxypiperidine. The molecular structure is as follows: [0003] [0004] At present, there are two main types of synthetic processes involving miglitol: (1) chemical synthesis is usually to first obtain 1-deoxynojirimycin, then modify it and introduce different substituents to obtain various derivatives, and then Reaction with ethylene oxide to prepare miglitol (2) The method of combining chemical synthesis and biocatalysis uses glucose as the starting material, and ethanolamine is used to p...

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Problems solved by technology

[0008] EP0477160 is a kind of synthetic method of N-(butyl)-glucamine, and this patent adopts 4% Pd-C as catalyst, uses glucose and butylamine as raw material, hydrogenation obtains N-(butyl) in autoclave )-glucosamine, this patent mentions N-hydroxyethylglucamine, but does not mention the synthetic method of N-hydroxyethylglucamine, and prepares its method by EP0477160 preparation N-(butyl)-glucosamine Homologue N-hydroxyethylglucosamine, unable to obtain the target product

[0009] CN200310108319.8 provides a synthetic method of N-(2-hydroxyethyl)-glucosamine, using glucose and ethanolamine as raw materials, and using 5% Pd-CaCO 3 -1~5% Pb catalyzer carries out hydrogenation reduction reaction, promptly does skeleton with calcium carbonate, adds 1~5% lead and makes the 5% palladium catalyst of palladium part poisoning, the shortcoming of this method is: (1) this reaction is due to The participation of ethanolamine is about 12 strongly alkaline pH value, and the common feature of precious metal palladium or platinum is that catalytic activity is big, and reaction condition requirement is lower, is applicable to neutral or acidic reaction condition (Wen Ren "drug synthesis reaction" second Page 336 of edition ②) acidity and alkalinity make its activity reduce; (2) add 1~5% lead as poisoning agent and make part palladium poisoning, only improve the selectivity of hydrogenation reaction under certain conditions, but make catalyst activity reduce, reaction speed change Slow, unfavorable for hydrogenation reaction (the third paragraph of page 367 of Wen Ren's "drug synthesis reaction" second edition); The essence of this method is to use precious metal palladium as a catalyst, and the catalytic efficiency of partial palladium poisoning does not fully bring into play the precious metal palladium. The test shows that this reaction can only be improved at high pressure (greater than 6MPa) and higher temperature (greater than 60°C). According to the conditional reaction conditions provided by CN200310108319.8, the time is as long as 30-48 hours, and the yield is only 73%. %, the purity is not high, and the heavy metal limit of the product is difficult to meet the Pharmacopoeia standard

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