Preparation method of oseltamivir acetyl aziridine intermediate

A technology of viracetaziridine and intermediates, applied in the field of pharmaceutical chemical industry, can solve problems such as low yield, potential safety hazard, harsh reaction conditions, etc., and achieve the effects of abundant raw material sources, increased production capacity, and easy large-scale production

Inactive Publication Date: 2018-09-04
EAST CHINA UNIV OF SCI & TECH
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  • Abstract
  • Description
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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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  • Preparation method of oseltamivir acetyl aziridine intermediate
  • Preparation method of oseltamivir acetyl aziridine intermediate

Examples

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Effect test

Embodiment 1

[0024] Preparation of ethyl 3,4-allylaziridine-5-hydroxyshikimate, compound Ⅲ:

[0025] Get 66mL of water and 33mL of absolute ethanol and join in the 250mL one-necked flask, add allylamine (3.226g, 57.3mmol) wherein, then the 3,4-allyl aziridine-5 of gained in embodiment 4 -Ethyl hydroxyshikimate, that is, compound II (5.003g, 19.1mmol), was added to it, heated to 75°C and stirred, reacted for 5 hours, cooled down to room temperature, added 100mL ethyl acetate for extraction, and the aqueous layer was washed with 50mL acetic acid Ethyl was washed twice, the organic layers were combined and dried with anhydrous magnesium sulfate, the solid magnesium sulfate was filtered off, ethyl acetate and part of ethanol were distilled off under reduced pressure to obtain a light yellow liquid, compound III (3.947 g, 17.7 mmol), yield 93%. Purified by column chromatography for structure identification.

[0026] Compound III was detected by nuclear magnetic resonance apparatus, and the re...

Embodiment 2

[0029] 3-(1-ethylpropoxy)-4-allylamino-5-hydroxyethyl oxalate is the preparation of compound IV:

[0030] Compound III (6.004g, 26.9mmol) obtained in Example 1 was placed in a 250mL single-necked flask, and 30mL of 3-pentanol was first added to dissolve it, and boron trifluoride diethyl ether (5.735g, 40.4mmol) was added thereto at room temperature, and heated to React at 70°C for 3 hours. After TLC monitors that the raw materials disappear completely, cool the reaction solution to room temperature, add 100mL ethyl acetate and water to it, stir, and add potassium carbonate solid to adjust the pH to about 10, separate the liquid, and use ethyl acetate The aqueous layer was washed twice (2×50 mL), the ethyl acetate was combined and dried, and the ethyl acetate and 3-pentanol were evaporated to obtain compound IV (7.526 g, 24.2 mmol) as a yellow liquid with a yield of 90%. Purified by column chromatography for structure identification.

[0031] Compound Ⅳ was detected with a nuc...

Embodiment 3

[0034] 3-(1-Ethylpropoxy)-4-amino-5-hydroxyshikimate ethyl ester is the preparation of compound V:

[0035] Compound IV (5.003 g, 16.1 mmol) obtained in Example 2 was placed in a 250 mL one-necked flask, dissolved in 100 mL of ethanol, and 1,3-dimethylbarbituric acid (2.761 g, 17.7 mmol) was added at room temperature, Then palladium acetate (36mg, 0.16mmol) and triphenylphosphine (168mg, 0.64mmol) were added, protected with nitrogen, and heated to 35°C for 2 hours to complete the reaction. Then distill off ethanol at about 30°C, add 100mL ethyl acetate and 5%wt potassium carbonate aqueous solution to each of them, extract and separate the layers and wash the aqueous layer twice (2×50mL) with ethyl acetate, combine the ethyl acetate with anhydrous After drying over magnesium sulfate, the ethyl acetate was distilled off to obtain a yellow liquid, compound V (4.065 g, 15.0 mmol), with a yield of 93%. Purified by column chromatography for structure identification.

[0036] Compo...

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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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D203/26
CPCC07D203/26
Inventor 施小新何云刚聂良邓
Owner EAST CHINA UNIV OF SCI & TECH
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