Search

CN-122010845-A - Method for recovering irbesartan intermediate from irbesartan mother liquor

CN122010845ACN 122010845 ACN122010845 ACN 122010845ACN-122010845-A

Abstract

The invention discloses a method for recovering irbesartan intermediate 4'- ((4-oxo-2-propyl-1, 3-diazaspiro [4.4] non-1-en-3-yl) methyl) - [1,1' -biphenyl ] -2-nitrile from irbesartan mother liquor. According to the invention, after the mother solution is washed by alkali liquor, crystallization is carried out in ethyl acetate or ethanol at low temperature, and the irbesartan intermediate is recovered from the irbesartan mother solution, so that the obtained product has high purity, can be directly recovered for synthesis of irbesartan, and reduces the production cost and the environmental protection pressure.

Inventors

  • CHEN XINDI
  • XIAO WEIFENG
  • LIU JIE
  • CHEN XINMIN
  • ZHANG RUYI
  • HAN SHI

Assignees

  • 珠海润都制药股份有限公司
  • 润都制药(荆门)有限公司

Dates

Publication Date
20260512
Application Date
20251231

Claims (4)

  1. 1. Recovery type (1) from irbesartan mother liquor A method of chemical compounds, characterized in that it is carried out according to the following process scheme: (1) Adding 0.1-0.5 times of alkali liquor into irbesartan mother liquor for washing, standing for layering, keeping an organic layer, concentrating under reduced pressure until the organic layer is dried to obtain a residue, adding a solvent a into the obtained residue according to the proportion of 0.4L-1L of the residue per kilogram, and stirring for dissolving to obtain a first solution, wherein the alkali liquor is sodium hydroxide aqueous solution or potassium hydroxide aqueous solution, and the pH=11-14; (2) Cooling the first solution to 5-10 ℃, preserving heat, crystallizing, filtering, taking a filter cake, washing with a solvent b at 5-10 ℃ to obtain a solid wet product 1; (3) Concentrating the second solution to 1/4-1/2 of the original volume, cooling to 5-10deg.C, maintaining the temperature for crystallization, filtering, collecting the filter cake to obtain solid wet product 2, mixing solid wet product 1 and solid wet product 2, and drying to obtain the final product of compound of formula (1); The Irbesartan mother liquor is from the following flow path of formula (1) The method comprises the steps of adding 1.8-2.2 equivalents of sodium azide and 1.8-2.2 equivalents of triethylamine into toluene solution, heating to 85-110 ℃ for reaction, cooling the reaction solution after the reaction is finished, adding 1-2 equivalents of sodium azide, quenching the reaction solution by hydrochloric acid with the mass concentration of 10-20%, extracting the reaction solution by sodium hydroxide or potassium hydroxide aqueous solution with the mass concentration of 10-35%, and separating to obtain an organic phase solution which is irbesartan mother solution, wherein the volume ratio of the sodium hydroxide or potassium hydroxide aqueous solution to the toluene solution is 1:10-1:5.
  2. 2. Recovery from irbesartan mother liquor according to claim 1 (1) The method of the compound is characterized in that the solvent a and the solvent b are one selected from ethanol and ethyl acetate.
  3. 3. Recovery from irbesartan mother liquor according to claim 1 (1) The method of the compound is characterized in that the volume ratio of the second solution to the first solution is 1:1-3:1.
  4. 4. Recovery from irbesartan mother liquor according to claim 1 (1) The method of the compound is characterized in that the irbesartan mother liquor is of the formula (1) The concentration of the compound is 0.005 kg/L-0.012 kg/L.

Description

Method for recovering irbesartan intermediate from irbesartan mother liquor Technical Field The invention relates to the field of drug synthesis, in particular to a method for recovering an irbesartan intermediate from an irbesartan mother solution. Background Irbesartan (Irbesartan) is a commonly used antihypertensive drug developed by the company sirofine and marketed in the european collection in the 90 s of the 20 th century. The mechanism of action of the compound is similar to that of other sartan drugs, and the compound is an angiotensin II receptor inhibitor, has better receptor selectivity and more accurate action compared with similar drugs, and has stable blood pressure reducing effect and target organ protecting function. Irbesartan has the chemical structure of 2-butyl-3- { [2' - (1H-tetrazol-5-yl) biphenyl-4-yl ] methyl } -1, 3-diazaspiro [4.4] non-1-en-4-one, and can be divided into two parts, namely butyl spiro and biphenyl tetrazole. In the synthesis of irbesartan, 4'- ((4-oxo-2-propyl-1, 3-diazaspiro [4.4] non-1-en-3-yl) methyl) - [1,1' -biphenyl ] -2-carbonitrileIs an important synthetic intermediate, and the irbesartan finished product can be obtained after the intermediate is subjected to tetrazole cyclization reaction. It has been found that 4'- ((4-oxo-2-propyl-1, 3-diazaspiro [4.4] non-1-en-3-yl) methyl) - [1,1' -biphenyl ] -2-carbonitrile remains in a considerable concentration in the mother liquor obtained by the treatment after the end of the tetrazole cyclization reaction, and if the mother liquor is directly used as hazardous waste treatment, a great amount of waste is caused, and high hazardous waste treatment cost and environmental protection treatment pressure are generated. Therefore, if a method is developed to recycle the intermediate in the mother liquor, not only the material cost can be saved, but also the pressure of an environment-friendly treatment system can be reduced, and the method has practical value. Disclosure of Invention The invention provides a method for recovering irbesartan intermediate 4'- ((4-oxo-2-propyl-1, 3-diazaspiro [4.4] non-1-en-3-yl) methyl) - [1,1' -biphenyl ] -2-nitrile from irbesartan mother liquor. The irbesartan mother liquor generated in the irbesartan synthesis process is treated by proper conditions, and the intermediate with high purity is recovered and obtained, so that the irbesartan can be repeatedly used for the production of irbesartan. The irbesartan mother liquor referred to in this scheme comes from the following process: And (3) heating 1.8-2.2 equivalents of sodium azide and 1.8-2.2 equivalents of triethylamine to 85-110 ℃ in toluene for cyclization reaction, cooling the reaction liquid after monitoring the reaction, adding 1-2 equivalents of sodium azide into 10-20% hydrochloric acid quenching reaction liquid, extracting the reaction liquid by using 10-35% sodium hydroxide or potassium hydroxide aqueous solution, and separating to obtain an organic phase solution which is irbesartan mother solution, wherein the volume ratio of the sodium hydroxide or potassium hydroxide aqueous solution to the toluene solution is 1:10-1:5. It should be noted that the present solution is not only applicable to the treatment of mother liquor produced by the above process, but may be used to treat solutions of any similar composition. The irbesartan mother liquor obtained according to the above process mainly contains: the compound 4'- ((4-oxo-2-propyl-1, 3-diazaspiro [4.4] non-1-en-3-yl) methyl) - [1,1' -biphenyl ] -2-carbonitrile of formula (1) , And contains the compound 4'- ((4-oxo-2-propyl-1, 3-diazaspiro [4.4] non-1-en-1-yl) methyl) - [1,1' -biphenyl ] -2-carbonitrile of formula (2) , The compound of formula (3) N- { [4- (2-cyanophenyl) phenyl ] methyl } -1- (pentanoylamino) cyclopentacarboxamide , Irbesartan, a compound of formula (4) Wherein the compound of formula (1) is an intermediate remaining in the mother liquor, the compounds of formula (2) and formula (3) are reaction impurities, and the compound of formula (4) is irbesartan remaining in the mother liquor. The method for recovering the compound of the formula (1) from the irbesartan mother liquor comprises the steps of washing the irbesartan mother liquor with water or alkali liquor, separating an organic layer, concentrating under reduced pressure to remove most of solvent to obtain oily residues, dissolving the residues, cooling for crystallization, filtering to obtain a solid to obtain the compound of the formula (1), concentrating the filtrate under reduced pressure, cooling for crystallization, filtering to obtain the solid to obtain the compound of the formula (1), and combining two parts of the compound solids of the formula (1) to obtain the product. More specifically, the scheme operates according to the following process flow: (1) Adding an irbesartan mother solution into an alkali liquor for washing, standing for layering, keeping an organic layer, concentrating under