Preparation method of oseltamivir acetyl aziridine intermediate

Abstract

The invention discloses a preparation method of an oseltamivir acetyl aziridine intermediate I (shown in a figure 1). The preparation method is characterized in that the oseltamivir acetyl aziridine intermediate I is prepared through six chemical synthesis steps (in figure 2) by taking a shikimic acid epoxy derivative II as a raw material, wherein the yield is 44 to 61 percent. The preparation method comprises the following six chemical synthesis steps: (1) carrying out ring opening in a 3-site of an epoxy compound II, and carrying out 'one-pot' three-step tandem reaction, thus forming 3,4-aziridine compound III; (2) selectively attacking the 3-site by 3-pentanol, and carrying out the ring opening, thus obtaining a compound IV; (3) removing an allyl group in a 4-site, thus obtaining a compound V; (4) carrying out amino acetylization in the 4-site, thus obtaining a compound VI; (5) carrying out hydroxyl methyl sulfonylation in a 5-site, thus obtaining a compound VII; (6) attacking 5-site by a 4-acetamino group, and carrying ring closing, thus obtaining the oseltamivir acetyl aziridine intermediate I.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical industry, and relates to a preparation method of medicine, in particular to a preparation method of an oseltamivir acetylaziridine intermediate. technical background [0002] The full chemical name of Oseltamivir phosphate is 4-acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester phosphate, which is An effective medicine for preventing and treating bird flu. For a long time, the outbreak of bird flu has brought serious disasters to mankind. In 1999, it was the oseltamivir phosphate (trade name: Tamiflu) jointly developed by Gilead Company and Swiss Roche (Roche) Company that was launched on the market, which brought the bird flu that ravaged human society under control. In order to prevent and treat influenza, oseltamivir phosphate It has also become a strategic reserve drug in many countries. [0003] Oseltamivir phosphate is a neuraminidase inhibi...

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Problems solved by technology

[0003] Oseltamivir phosphate is a neuraminidase inhibitor (see: Nature.1993,363,418; WO91 / 16320; J.Med.Chem.1998,41,2451; J.Am.Chem.Soc.1997,119,681 ), but so far, only Roche’s method, which has industrial value and can be produced, is not enough to deal with global problems from the perspective of the production capacity of oseltamivir phosphate alone (see: Angew.Chem.Int.Ed. 2006, 45, 7330)

A method jointly developed by Gilead and Roche discloses a method that uses naturally occurring shikimic acid and quinic acid as starting materials to introduce 1-ethylpropoxy functional groups through stereoselective reduction of ketals. , the introduction of nitrogen-containing functional groups with azide reagent, allylamine, or tert-butylamine, the stereoselective ring-opening reaction of aziridine and other steps have realized the industrial production of oseltamivir phosphate (see: Org.Process Res.Dev. 1999,3,266; Org.Process Res.Dev.2004,8,86; J.Am.Chem.Soc.1997,119, 681; J.Org.Chem.1998,63,4545; Angew.Chem.Int.Ed .2006,45,7330; US5763483 / 1998; WO99 / 55664; US5886213 / 1999; WO98 / 07685; EP1059283 / 2000), but there are many problems in its synthesis process: inflammable and explosive The chemical sodium azide, although its production can be carried out in an explosion-proof workshop, there are always potential safety hazards, and it is also easy to lead to a low yield in the production process; in the synthesis process of this method, strong corrosive trifluoromethanesulfonic acid is used (The price is also very expensive), the by-products produced by its corrosion not only bring difficulties to the purification and separation work, but also will inevitably cause additional losses of the product and affect the yield of the production process

However, the currently disclosed methods for synthesizing oseltamivir phosphate are still difficult to overcome the disadvantages of using dangerous flammable and explosive reagents, using expensive reagents, long synthetic routes, low yield, harsh reaction conditions, and unfriendly environment, resulting in difficulties in industrial production Oseltamivir Phosphate

At present, influenza is breaking out all over the world from time to time, and the demand for Tamiflu, which can effectively deal with influenza, is increasing unabated. Therefore, people in the industry expect relevant scientific and technological workers to study and improve to provide a safer, easier, and Inexpensive and efficient preparation method of oseltamivir phosphate to meet the needs of all human beings for the strategic reserve of avian influenza prevention and treatment drugs

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