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Oseltamivir phosphate preparation method

A technology of oseltamivir phosphate and trifluoroacetic acid, which is applied in the field of preparation of oseltamivir phosphate, can solve the problems that the heavy metals in the product are not easy to meet the standard, the recovery of precious catalysts is difficult, and the reuse cannot be performed, and the preparation method is simple and heavy. The effect of good performance, improved quality and yield

Active Publication Date: 2019-03-08
西安吉泰医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In summary, the problems existing in the existing synthetic oseltamivir phosphate process are: the use of toxic and explosive products, the operation process produces highly toxic and explosive products, pressure operation, difficult recovery of valuable catalysts, can not be reused, heavy metals in the product are not Easy to meet standards, high cost

Method used

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  • Oseltamivir phosphate preparation method
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  • Oseltamivir phosphate preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] 1. Add 541.5g (1.116mol, HPLC99.989%) of compound 2 into 700mL of trifluoroacetic acid, stir, heat up to 45-55°C, and keep it warm for 3 hours; cool the reaction solution to 20-30°C, add 250mL of toluene , the reaction solution was concentrated under reduced pressure in a hot water bath at 45-55°C until no liquid flowed out. Add 1000mL of toluene to the concentrate, cool down to 0-10°C, and add 300mL of cold water to maintain 0-10°C; control the temperature at 0-10°C, slowly Add 158.75g (3.969mol) of sodium hydroxide solution in water (500mL) dropwise, adjust the pH to about 12-13, let it stand for stratification, extract the water layer with 500mL of toluene, let it stand for separation, combine the organic layers and wash each time with 250mL of water Three times, stand still and separate layers; the organic layer is dried with 50g of anhydrous sodium sulfate, filtered, the combined filtrate is concentrated under reduced pressure in a hot water bath at 45-55°C until no...

Embodiment 2

[0027] In this example, the diethanolamine in Example 1 was replaced with equimolar ammonium formate, and the other steps were the same as in Example 1 to obtain 85.7 g of white solid oseltamivir phosphate crude product, with an HPLC purity of 99.854% and a single largest impurity of 0.083%; Add 85.7g of crude oseltamivir phosphate to 3428mL of ethanol aqueous solution with a volume concentration of 99.2%, raise the temperature to reflux to dissolve, lower the temperature to 65-70°C, add 4.3g of activated carbon, raise the temperature to reflux, stir for 30 minutes, filter, and the filtrate Cool down to 45-55°C, there is solid precipitation, continue to stir and cool down to below -10°C, stir for 2 hours, filter, and vacuum-dry the filter cake at 50-60°C to obtain 84.3g of oseltamivir phosphate as a white solid crystal form A , yield 94.85%, HPLC purity 99.913%, single largest impurity 0.054%.

Embodiment 3

[0029]The palladium charcoal recovered in step 2 of the above example 1 was re-reacted according to the method of step 2, and 86.5g of white solid oseltamivir phosphate crude product could be obtained, with an HPLC purity of 99.854% and a single largest impurity of 0.083%; 86.5g of oseltamivir phosphate Add the crude Tasvir to 3460mL ethanol aqueous solution with a volume concentration of 99.2%, heat up to reflux to dissolve, cool to 65-70°C, add 4.3g of activated carbon, heat up to reflux, stir for 30 minutes, filter, and cool the filtrate to 45-55°C , there is solid precipitation, continue to stir and cool down to below -10°C, stir for 2 hours, filter, and vacuum-dry the filter cake at 50-60°C to obtain 84.8g of oseltamivir phosphate in crystal form A, with a yield of 95.41%, HPLC purity 99.908%, single largest impurity 0.055%.

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Abstract

The invention discloses an oseltamivir phosphate preparation method which includes the steps: taking (3R, 4R, 5s)-4-n-acetyl (1, 1-dimethyl ethyl) amino-5-N, N-diallyl amino-3-(1-ethyl propoxy)-1-cyclohexene-1-ethyl carboxylate hydrochloride acquired by non-azide reaction as a starting raw material; removing tertiary butyl and diallyl; enabling the raw material and phosphoric acid to form salt toobtain crude oseltamivir phosphate; refining the crude oseltamivir phosphate by an ethanol water solvent to obtain high-purity oseltamivir phosphate with a crystal form A. The method does not adopt sodium azide, azide and sodium hydride and is safe and environmentally friendly. The purity of the starting raw material is 99.9% or more, the purity of an intermediate and a crude product is 99.5% or more, the purity of the oseltamivir phosphate is 99.9%, the quality and the yield of the oseltamivir phosphate are improved, cost is reduced, and the preparation method is simple, good in repeatabilityand suitable for mass production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of oseltamivir phosphate. Background technique [0002] Oseltamivir phosphate, English name Oseltamivir phosphate, chemical substance registration number CAS RN is 196618-13-0, is a neuraminidase inhibitor jointly developed by Gilead Company of the United States and Roche Company of Switzerland, and the trade name is Da Philippine is an effective drug for preventing and treating bird flu. Oseltamivir phosphate was launched in Switzerland and the United States in 1999, and in my country in October 2001. Its indications are mainly for the treatment of influenza A and B in adults and children aged 1 and over; Influenza A and B prophylaxis in adults and adolescents 13 years and older. [0003] Influenza, also known as influenza, is an acute respiratory infectious disease caused by influenza virus, which seriously affects human health. 20%...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/52C07C231/12C07C231/24
CPCC07C231/12C07C231/24C07C233/52
Inventor 陆海东白静波王亦群宋彦妮
Owner 西安吉泰医药有限公司
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