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Synthesis method of oseltamivir intermediate

A technology of oseltamivir and a synthesis method, which is applied in the field of synthesis of oseltamivir intermediates, can solve the problems of low reaction yield, strong corrosiveness, low yield and the like, and achieves lowering reaction temperature, improving yield, The effect of simplifying post-processing steps

Pending Publication Date: 2022-05-13
中润药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For example, the related technical report adopts the method of nucleophilic substitution of azide to synthesize the compound. As we all know, the azide compound is a first-class explosive dangerous article, which is not suitable for large-scale industrial production; there is also a synthetic route reported in the related technical report using a strong acid method. This compound has strong corrosiveness and low yield; another related technical report uses sulfonic acid as the main catalyst to prepare the compound, preferably using 10-camphorsulfonic acid, the same reaction yield is low, and contains solid brown oil, which needs to be passed through Column chromatography, difficult to purify

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  • Synthesis method of oseltamivir intermediate
  • Synthesis method of oseltamivir intermediate
  • Synthesis method of oseltamivir intermediate

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[0041] The present invention provides a method for synthesizing an oseltamivir intermediate, using Lewis acid catalysis to synthesize compound 2 from compound 1, and then preparing compound 2 into different salts for the next step of reaction to prepare oseltamivir. More specifically, metal halides are added to the organic solvent, then diallylamine is added to react to form a complex, and then mixed with compound 1 or its solution and heated to react, the reaction temperature is controlled between 20 and 70°C; The salt of Compound 2 was obtained by acid washing, drying, distillation, dissolution, salt refining and drying.

[0042] Synthetic routes include:

[0043]

Embodiment 1

[0046] Put 10kg of compound 1 and 50L of toluene into a 100L reaction kettle, 1.6kg of zinc chloride oil seal, blow nitrogen protection, and control the temperature at 20°C. After stirring for 1 hour, add 20 kg of diallylamine, raise the temperature to 50° C., and stir for 10 hours when the temperature reaches the beginning. After the reaction, keep the temperature below 20°C, add 20L of toluene and stir for 30 minutes, add 5% citric acid aqueous solution, stir and wash, and wash with 20L of saturated saline. Dry 2kg of anhydrous sodium sulfate for 1 hour, distill and concentrate under reduced pressure until no liquid flows out, add 20L of absolute ethanol and 5L of ethyl acetate, slowly add 3kg of 30% hydrogen chloride ethanol solution dropwise under stirring, and raise the temperature to 70±5°C. Stir for 1 hour from the time of arrival, cool down to 0° C. and keep stirring for 2 hours, centrifuge, wash the filter cake with 10 kg of ethyl acetate, and dry in a solid vacuum ov...

Embodiment 2

[0048] Put 20kg of compound 1 and 70L of DMSO into a 100L reactor, seal with 2.0kg of magnesium chloride oil, blow nitrogen protection, and control the temperature at 0°C. After stirring for 1 hour, add 20 kg of diallylamine, raise the temperature to 70° C., and stir for 6 hours when the temperature reaches the beginning. After the reaction, keep the temperature below 20°C, add 20 LDMSO and stir for 30 minutes, add 10% citric acid aqueous solution, stir and wash, and wash with 20 L of saturated saline. Dry 2kg of anhydrous sodium sulfate for 3 hours, distill and concentrate under reduced pressure until no liquid flows out, add 15L of absolute ethanol and 10L of ethyl acetate, slowly add 9kg of 30% maleic acid ethanol solution dropwise under stirring, heat up to 70±5°C, Stir for 1 hour from the time the temperature reaches, lower the temperature to 5°C and keep stirring for 2 hours, centrifuge, wash the filter cake with 10 kg of ethyl acetate, and dry in a solid vacuum oven at ...

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Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a synthesis method of an oseltamivir intermediate. The synthesis method comprises the following steps: reacting metal halide with diallylamine to generate a complex; the preparation method comprises the following steps: reacting a complex with ethyl (1R, 5R, 6R)-7-(tert-butyl)-5-(pent-3-oxyl)-7-azabicyclo [4.1. 0] hept-3-ene-3-carboxylate, and salifying the obtained product after the reaction is ended, thereby obtaining the salt of the compound ethyl (3R, 4R, 5S)-4-(tert-butylamine)-5-(dienamino)-3-(pent-3-oxyl) cyclohex-1-ene-1-carboxylate, namely, the compound ethyl (3R, 4R, 5S)-4-(tert-butylamine)-5-(dienamino)-3-(pent-3-oxyl) cyclohex-1-ene-1-carboxylate. The metal halide is adopted for catalysis, the target product forms a salt form, the quality and stability of the product can be remarkably improved, the post-treatment step is simplified, the high-purity product can be obtained without the purification step of silica gel column chromatography, the yield of the product is improved, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, in particular to a synthesis method of an oseltamivir intermediate. Background technique [0002] Influenza is a disease that seriously affects the normal life of human beings, and it is also one of the most infectious diseases in the world. Influenza virus is one of the pathogens that cause human influenza. Influenza virus neuraminidase is an important component of influenza virus, which can prevent virus aggregation and assist the release of progeny virions from infected cells, thus inhibiting the function of neuraminidase That is, it can prevent the release of the virus and play a role in controlling influenza. It is an important target of anti-influenza virus drugs. Its inhibitor oseltamivir phosphate (trade name: Tamiflu) is a representative drug that has been listed and is mainly used for Treatment of uncomplicated influenza A and B. [0003] compound It is one of the impor...

Claims

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Application Information

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IPC IPC(8): C07C229/48C07C227/18
CPCC07C227/18C07B2200/07C07C2601/16C07C229/48
Inventor 魏林华邓成斌肖甜谭治明
Owner 中润药业有限公司