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Method for preparing antiviral drug oseltamivir phosphate intermediate tert-butylamine derivative I

A technology for antiviral drugs and tert-butylamine, which is applied in the field of preparing antiviral drug Tamiflu intermediate tert-butylamine derivatives to achieve the effects of avoiding curing and increasing by-products

Active Publication Date: 2020-05-15
TIANJIN PHARMA GROUP XINZHENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The object of the present invention is to solve the existing problems of the intermediate tert-butylamine derivatives for the preparation of the neuraminidase inhibitor Tamiflu, and provide a method for preparing tert-butylamine derivatives By controlling the preparation temperature of the complex, the addition method of tert-butylamine and the time of the ring-opening reaction, the curing phenomenon and the increase of by-products in the reaction can be effectively controlled.

Method used

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  • Method for preparing antiviral drug oseltamivir phosphate intermediate tert-butylamine derivative I
  • Method for preparing antiviral drug oseltamivir phosphate intermediate tert-butylamine derivative I
  • Method for preparing antiviral drug oseltamivir phosphate intermediate tert-butylamine derivative I

Examples

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Effect test

reference example 1

[0057] Reference Example 1: (3R, 4S, 5R)-5-(tert-butylamino)-4-hydroxyl-3-(pent-3-yloxy)cyclohex-1-ene-1-carboxylic acid ethyl ester ( 1) (conventional method for preparing compound 1 disclosed in the patent CN100545145C)

[0058] 20.22g of magnesium chloride (212.33mmol, 0.9eq), 25.88g of tert-butylamine (353.88mmol, 1.5eq) and 120ml of toluene were added and stirred for 6 hours, during which time the system solidified severely. A solution of 60.00 g of compound B (235.92 mmol) and 150 ml of toluene was added into the system at 25° C., the temperature was raised to 50° C., and the reaction was carried out for 8 hours. An additional 20.71 g of tert-butylamine (283.10 mmol, 1.2 equivalents) was added to continue the reaction for 12 hours.

[0059]Stop heating, lower the temperature to 20-25°C, slowly add 210ml of 10% citric acid dropwise, separate the liquids, and concentrate the organic phase to dryness at 45°C under reduced pressure. Brown oil compound 1 was obtained: 69.30...

reference example 2

[0063] Reference Example 2: (1R, 5R, 6R)-7-(tert-butyl)-5-(pent-3-yloxy)-7-azabicyclo[4.1.0]hept-3-ene-3- Ethyl carboxylate (2)

[0064] Add 65.00g of compound 1 (198.50mmol) and 240ml of toluene, cool down to 0-5°C, replace with nitrogen, slowly add 24.33g of methanesulfonyl chloride (212.40mmol, 1.07 equivalents) dropwise, control the temperature at 5-10°C and stir for 1 hour, then cool down 40.77g of triethylamine (402.95mmol, 2.03 equivalents) was slowly added dropwise at 0-5°C, stirring was continued for 0.5 hours, and the temperature was raised to 70°C for 3 hours.

[0065] Post-treatment: lower the temperature to 10-15°C, and add dropwise an aqueous solution of potassium carbonate (27.71g of potassium carbonate dissolved in 98ml of water). The liquid was separated, and the organic phase was concentrated to dryness under reduced pressure at 45° C. to obtain 61.20 g of brown oil compound 2 with a yield of 99.70%.

reference example 3

[0066] Reference Example 3: (3R, 4R, 5S)-4-(tert-butylamino)-5-(diallylamino)-3-(pent-3-yloxy)cyclohex-1-ene-1 - Ethyl carboxylate (3)

[0067] Add 55.00g of compound 2 (177.74mmol), 23.30g of diallylamine (239.95mmol, 1.35eq) and 34.86g of benzenesulfonic acid (220.40mmol, 1.24eq), raise the temperature to 120°C, and react for 5.5h.

[0068] Cool down, add 82.5ml of toluene, continue to cool down to 5-10°C, slowly add NaOH solution prepared by 8.96g of sodium hydroxide and 110ml of water, complete the addition, and separate the liquids. The organic phase was adjusted to pH=7-8 with 1N hydrochloric acid, separated, and the organic phase was concentrated to dryness at 40°C under reduced pressure to obtain 61.30 g of brown oil compound 3, yield: 84.82%.

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Abstract

The invention discloses a method for preparing a tert-butylamine derivative, and relates to the field of drug synthesis. The method comprises the following steps: 1, preparing a magnesium-amine compound, namely, adding magnesium halide and tert-butylamine A into an aprotic solvent, and carrying out a mixing stirring reaction for 0.5-1.5 h at a temperature of 0-15 DEG C to prepare a mixed solutionA; 2, adding a compound B into the mixed solution A prepared in the step 1, and carrying out a stirring reaction for more than 8 hours to prepare a mixed solution B; and 3, supplementing tert-butylamine D into the mixed solution B prepared in the step 2, and carrying out a stirring reaction for 24-48h at a temperature of 50-70 DEG C to prepare a tert-butylamine derivative I. By controlling the preparation temperature of the compound, the addition mode of tert-butylamine and the time of the ring-opening reaction, the curing phenomenon in the reaction and the increase of by-products can be effectively controlled.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing an antiviral drug Tamiflu intermediate tert-butylamine derivative. Background technique [0002] Compound A is Oseltamivir Phosphate (Oseltamlvir Phosphate), trade name Tamiflu, chemical name (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethylpropoxy)- L-cyclohexene-1-carboxylic acid ethyl ester phosphate is a kind of viral neuraminidase inhibitor, which can act on all links of influenza virus infection, hinder the replication of influenza virus strains, and is used clinically for treatment Influenza types A and B. [0003] [0004] Compound I hereinafter is known to be useful as an intermediate for the preparation of neuraminidase inhibitor compound A. Patent CN100545145C discloses a scheme A for preparing compound I, including adding excess tert-butylamine and magnesium chloride to compound B. It has been found through research that in the preparation method o...

Claims

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Application Information

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IPC IPC(8): C07C227/08C07C229/48C07C231/12C07C233/52
CPCC07C227/08C07D203/02C07D203/26C07C231/02C07C231/12C07C2601/16C07C229/48C07C233/52Y02P20/55
Inventor 周红建李俊霞
Owner TIANJIN PHARMA GROUP XINZHENG
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