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Preparation method of oseltamivir phosphate

A technology of oseltamivir phosphate and phosphoric acid, applied in the field of preparation of oseltamivir phosphate, can solve the problems such as the synthesis method of oseltamivir phosphate needs to be optimized and the purity of oseltamivir phosphate is low, and achieve high quality and purity , the effect of improving yield

Pending Publication Date: 2021-08-27
弘健制药(上海)有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] For the related technologies mentioned above, with the aggravation of the influenza epidemic in recent years, the demand for oseltamivir phosphate is increasing day by day. Although there are multiple ways to synthesize oseltamivir phosphate, the purity of oseltamivir phosphate obtained is low , the synthesis method of oseltamivir phosphate needs to be optimized

Method used

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  • Preparation method of oseltamivir phosphate
  • Preparation method of oseltamivir phosphate
  • Preparation method of oseltamivir phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: a kind of preparation method of oseltamivir phosphate comprises the following steps:

[0042] S1, add 93g of trifluoroacetic acid and 45g of hydrochloride into the reaction flask, heat up to 48°C, react for 1h, concentrate under reduced pressure to recover trifluoroacetic acid, add 45g of toluene, cool down to 0°C, add 75g of distilled water, add 30% hydrogen Sodium oxide solution to adjust the pH to 12-13, add 172g of toluene, stand to separate layers, extract the organic phase with 40g of toluene, wash with 25% sodium chloride solution, separate the organic phase, dehydrate with anhydrous magnesium sulfate for 2h, and depressurize Concentrate, add 13g of ethyl acetate, stir at 38°C for 10min, add 129g of heptane, cool down to 25°C for crystallization, filter with suction, and dry in vacuum for 6h to obtain an intermediate product;

[0043] The structural formula of hydrochloride is:

[0044]

[0045] The structural formula of the intermediate product...

Embodiment 2

[0050] Embodiment 2: A kind of preparation method of oseltamivir phosphate, the difference with embodiment 1 is, in the preparation method of oseltamivir phosphate, the step of S1 is: mix 93g trifluoroacetic acid and 45g hydrochloride Add it into the reaction flask, heat up to 48°C, react for 1h, concentrate under reduced pressure to recover trifluoroacetic acid, add 45g of toluene, cool down to 0°C, add 75g of distilled water, add 30% sodium hydroxide solution to adjust the pH to 12-13, add 172g Toluene, standing for stratification, using 40g toluene to extract the organic phase for 3 times, combining the organic phase after extraction, washing with 25% sodium chloride solution, separating the organic phase, dehydrating with anhydrous magnesium sulfate for 2h, concentrating under reduced pressure, adding 13g of ethyl acetate was stirred at 38°C for 10min, 129g of heptane was added, the temperature was lowered to 25°C for crystallization, suction filtration, and vacuum drying f...

Embodiment 3

[0053] Embodiment 3: A preparation method of oseltamivir phosphate, the difference from Example 1 is that in S2 of the preparation method of oseltamivir phosphate, at a temperature of 45°C, first 50% of the filtrate Drop into phosphoric acid / ethanol solution, stir and react for 0.8h, then add dropwise the remaining filtrate, stir and react for 0.4h.

[0054] After analysis, the final product is the target product oseltamivir phosphate refined product, with a purity of 99.8%.

[0055] 1 H NMR (D 2 O, 400MHz) δ: 0.87 (t, J = 7.2Hz, 3H, CH 3 ), 0.91(t, J=7.2Hz, 3H, CH 3 ), 1.31(t, J=7.2Hz, 3H, CH 3 ), 1.47~1.52 (m, 1H, CH 2 ),1.56~1.62(m,3H,CH 2 ),2.11(s,3H,COCH 3 )2.51~2.58(m, 1H, CH), 2.99(dd, J=17.2Hz, J=5.6Hz, 1H, cyclohexene-H), 3.56~3.65(m, 2H, cyclohexene 6-H) , 4.08(dd, J=11.6Hz, J=9.2Hz, 1H, cyclohexene-H), 4.25~4.31(m, 2H, CH2), 4.35(d, J=8.8Hz, 1H, cyclohexene- H), 4.80 (bs, HOD), 6.88 (s, 1H, cyclohexene 2-ene-H).

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Abstract

The invention relates to the technical field of drug synthesis, and particularly discloses a preparation method of oseltamivir phosphate, which comprises the following steps: heating trifluoroacetic acid and hydrochloride to react, diluting and concentrating, adjusting pH, layering, extracting, washing, dehydrating, concentrating, crystallizing and drying to obtain an intermediate product; preparing an intermediate product / ethanol solution, stirring and mixing 1, 3-dimethyl barbituric acid, triphenylphosphine, palladium acetate and absolute ethyl alcohol to obtain a mixture, dropwise adding the mixture into the intermediate product / ethanol solution, decolorizing, carrying out suction filtration, dropwise adding the filtrate into a phosphoric acid / ethanol solution, stirring, adding absolute ethyl alcohol, standing, carrying out suction filtration, washing and drying to obtain an oseltamivir phosphate crude product; and heating and stirring the oseltamivir phosphate crude product, absolute ethyl alcohol and distilled water, decolorizing, carrying out suction filtration, adding absolute ethyl alcohol into the filtrate, cooling and crystallizing, carrying out suction filtration, washing, and drying to obtain the oseltamivir phosphate refined product. The oseltamivir phosphate prepared by the preparation method disclosed by the invention is relatively high in purity and relatively good in yield.

Description

technical field [0001] The application relates to the technical field of drug synthesis, more specifically, it relates to a preparation method of oseltamivir phosphate. Background technique [0002] Oseltamivir phosphate, also known as "Tamiflu", is a new antiviral drug, its chemical name is (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethyl Propoxy)-1-cyclohexene-1-carboxylate ethyl ester, usually phosphate (1:1) for medicinal purposes, its active metabolite is a strong and effective selective avian influenza virus neuraminidase inhibitor , clinically mainly used for the treatment of influenza. Tamiflu is the first orally effective inhibitor of influenza virus neuraminidase. It has inhibitory effects on influenza A and B. At the same time, it has extremely low toxicity to humans and animals, and rarely produces drug resistance. It is considered It is currently the most specific anti-influenza drug developed. [0003] Oseltamivir phosphate can be synthesized from chiral raw mate...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C231/24C07C233/52
CPCC07C231/12C07C231/24C07C2601/16C07C233/52
Inventor 朱江畅兰显跃蔡浩旗柏挺周秋火华吉涛
Owner 弘健制药(上海)有限公司
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