Method for recovering irbesartan intermediate from irbesartan mother liquor
The process of recovering high-purity intermediate compounds from irbesartan mother liquor has solved the problem of unrecovered intermediates in the mother liquor, achieving material cost savings and reduced environmental pressure, and creating significant economic benefits.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- 珠海润都制药股份有限公司
- Filing Date
- 2025-12-31
- Publication Date
- 2026-05-12
AI Technical Summary
In existing technologies, the intermediates remaining in the mother liquor after irbesartan synthesis cannot be effectively recovered, leading to material waste and increased environmental treatment pressure.
High-purity intermediate compounds are recovered from irbesartan mother liquor through a specific processing procedure, including washing, separation, vacuum concentration and crystallization steps, and treatment with alkali and appropriate solvents to obtain high-purity intermediate compounds.
It enables efficient recycling of intermediates, reduces material costs and environmental treatment expenses, improves economic efficiency, and reduces environmental pressure.
Smart Images
Figure CN122010845A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical synthesis, and more specifically to a method for recovering irbesartan intermediates from irbesartan mother liquor. Background Technology
[0002] Irbesartan is a commonly used antihypertensive drug developed by Sanofi and approved for marketing in Europe and the United States in the 1990s. Its mechanism of action is similar to other sartan drugs; it is an angiotensin II receptor inhibitor. Compared to other drugs in the same class, it has better receptor selectivity, more precise action, and stable antihypertensive effects and target organ protection.
[0003] The chemical structure of irbesartan is 2-butyl-3-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1,3-diazaspiro[4.4]non-1-en-4-one, which can be divided into two parts: the butylspirocyclic ring and the biphenyltetrazole ring. 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-nitrile It is an important synthetic intermediate. Irbesartan can be obtained by performing a tetrazolium cyclization reaction on this intermediate.
[0004]
[0005] Studies have revealed that a considerable concentration of 4'-((4-oxo-2-propyl-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1'-biphenyl]-2-nitrile remains in the mother liquor obtained after the aforementioned tetrazolium cyclization reaction. Direct treatment as hazardous waste would result in significant waste, high hazardous waste treatment costs, and increased environmental pressure. Therefore, developing a method to recover the intermediates from the mother liquor would not only save material costs but also reduce the pressure on environmental treatment systems, demonstrating practical value. Summary of the Invention
[0006] This invention provides a method for recovering the 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. By treating the irbesartan mother liquor generated during irbesartan synthesis under suitable conditions, a high-purity intermediate is recovered and can be reused in irbesartan production.
[0007] The irbesartan mother liquor referred to in this plan comes from the following process:
[0008] The compound of formula (1) is cyclized in toluene with 1.8-2.2 equivalents of sodium azide and 1.8-2.2 equivalents of triethylamine and heated to 85℃-110℃. After the reaction is completed, the reaction solution is cooled and quenched with 1-2 equivalents of sodium azide and 10%-20% hydrochloric acid. The reaction solution is then extracted with 10%-35% sodium hydroxide or potassium hydroxide aqueous solution. The organic phase solution obtained by separation is the irbesartan mother liquor. The volume ratio of the sodium hydroxide or potassium hydroxide aqueous solution to the toluene solution is 1:10-1:5.
[0009] It should be noted that this solution is not only applicable to treating the mother liquor produced in the above process, but can also be used to treat solutions with any similar components.
[0010] The irbesartan mother liquor obtained by the above process mainly contains: Compound (1) 4'-((4-oxo-2-propyl-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1'-biphenyl]-2-nitrile , It also contains the compound of formula (2), 4'-((4-oxo-2-propyl-1,3-diazaspiro[4.4]non-1-en-1-yl)methyl)-[1,1'-biphenyl]-2-nitrile. , Compound (3) N-{[4-(2-cyanophenyl)phenyl]methyl}-1-(pentanoylamino)cyclopentanamide , And the compound irbesartan of formula (4) One or more of the following, wherein compound (1) is an intermediate remaining in the mother liquor, compounds (2) and (3) are reaction impurities, and compound (4) is irbesartan remaining in the mother liquor.
[0011] The method for recovering formula (1) from irbesartan mother liquor is as follows: wash the irbesartan mother liquor containing the aforementioned irbesartan with water or alkaline solution, separate the organic layer, concentrate under reduced pressure to remove most of the solvent, and obtain an oily residue. Then dissolve the residue, cool it to crystallize, filter it to obtain the solid to obtain the compound of formula (1); take the filtrate, concentrate it under reduced pressure, cool it to crystallize, filter it to obtain the solid to obtain the compound of formula (1), and combine the two solids of formula (1) to obtain the product.
[0012] More specifically, this solution operates according to the following process: (1) Wash the irbesartan mother liquor with alkaline solution, let it stand to separate into layers, retain the organic layer and concentrate it under reduced pressure to dryness to obtain the residue. Add solvent a to the obtained residue at a ratio of 0.4L-1L per kilogram of residue, stir to dissolve, and obtain the first solution. (2) Cool the first solution to 5℃-10℃, keep it warm to crystallize, filter, take the filter cake and wash it with solvent b at 5℃-10℃ to obtain wet product 1 of compound (1), combine solvent b used to wash the filter cake and the filtrate to obtain the second solution; (3) Take the second solution and concentrate it to 1 / 4-1 / 2 of the original volume, cool it to 5-10℃, keep it warm to precipitate crystals, filter it, and take the filter cake to obtain wet product 2 of compound (1); combine wet product 1 and wet product 2 of compound (1), and dry them to obtain the finished product of compound (1).
[0013] Furthermore, solvent a and solvent b are both selected from ethanol and ethyl acetate.
[0014] Further, the volume of the alkaline solution mentioned in step (1) is 1 / 10 to 1 / 2 of the volume of the irbesartan mother liquor, and the pH is 11 to 14; Furthermore, the volume ratio of the second solution to the first solution is 1:1 to 3:1; Furthermore, the concentration of formula (1) in the irbesartan mother liquor is 0.005-0.012 kg / L.
[0015] As an example, a process for producing irbesartan mother liquor is described below to explain the origin of the typical irbesartan mother liquor described in this scheme. However, this scheme is not only applicable to mother liquors produced by the process described below, but can be used to treat solutions of various different compounds whose main components are compounds of formulas (1) to (4).
[0016] Compound of formula (1) It is dissolved in toluene at a concentration of approximately 0.4 kg / L to 0.5 kg / L. Then, approximately 2 equivalents of triethylamine hydrochloride and approximately 2 equivalents of sodium azide are added, and the mixture is heated to 105 °C for reaction. After the reaction is complete, the reaction solution is cooled, the reaction is quenched with 15% hydrochloric acid, and the organic layer is extracted with 10% potassium hydroxide. The organic layer is separated to obtain irbesartan mother liquor. The irbesartan mother liquor obtained at this time contains compounds of formulas (1) to (4), and the concentration of formula (1) in the irbesartan mother liquor is 0.005-0.012 kg / L.
[0017] Beneficial effects: Recovering synthetic intermediates from the mother liquor generated during the production process yields high-purity intermediates that can be directly reused without refining. This saves material costs, reduces the burden on the environmental treatment system, and improves economic efficiency. Based on actual production conditions, directly treating the unrecovered irbesartan mother liquor wastewater incurs high environmental costs. Treating the wastewater generated from the recovery of irbesartan intermediates reduces environmental costs by 87%, to only 13% of the original cost. Furthermore, the recovered irbesartan intermediates can be directly reused in irbesartan production. Depending on the production scale, the recovered irbesartan intermediates can generate millions in economic benefits annually. Attached Figure Description
[0018] Figure 1 HPLC chromatogram of the product prepared according to Example 3 Figure 2 HPLC chromatogram of the product prepared according to Comparative Example 1 Detailed Implementation
[0019] The present invention will be further illustrated below by way of embodiments, providing a clear and complete description of the technical solutions in the specification. It should be understood that the following embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Example 1
[0020] Irbesartan stock solution: Take compound (1) 4'-((4-oxo-2-propyl-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1'-biphenyl]-2-nitrile 566 kg of irbesartan was dissolved in 1280 L of toluene. Then, 405 kg of triethylamine hydrochloride and 190 kg of sodium azide were added, and the mixture was heated to 105 °C to proceed with the reaction. After the reaction was complete, the reaction solution was cooled, quenched with 15% hydrochloric acid, and the organic layer was extracted with 300 L of 10% sodium hydroxide aqueous solution. The organic layer was separated to obtain the irbesartan mother liquor. Example 2
[0021] Take approximately 800 L of the irbesartan stock solution obtained according to the method described in Example 1.
[0022] At room temperature, 140 L of 1% sodium hydroxide solution was added to the mother liquor of irbesartan for washing, followed by separation, and the toluene layer was retained. The obtained toluene layer solution was then concentrated to dryness under reduced pressure to obtain approximately 5 kg of oily residue. 2.5 L of ethanol was added to the residue and stirred to dissolve it.
[0023] After dissolution, the temperature was lowered to 5°C and kept warm for 3 hours to allow crystals to precipitate. The mixture was then filtered, and the filter cake was washed with about 1.5 L of cold ethanol to obtain wet product 1 of compound (1). The filtrate was distilled under reduced pressure to a volume of approximately 1.25 L, cooled to 5 °C, kept warm for 3 h to allow crystals to precipitate, and then filtered to obtain wet product 2 of compound (1).
[0024] Wet sample 1 and wet sample 2 of compound (1) were mixed and dried to obtain approximately 1.5 kg of compound (1) with a purity of 98.8% and a total impurity content of approximately 0.35%. Example 3
[0025] Take approximately 800 L of the irbesartan stock solution obtained according to the method described in Example 1.
[0026] At room temperature, 140 L of 1% sodium hydroxide solution was added to the mother liquor of irbesartan for washing, followed by separation, and the toluene layer was retained. The obtained toluene layer solution was then concentrated to dryness under reduced pressure to obtain approximately 5 kg of oily residue. 2.5 L of ethyl acetate was added to the residue and stirred to dissolve.
[0027] After dissolution, the temperature was lowered to 5°C and kept warm for 3 hours to allow crystals to precipitate. The mixture was then filtered, and the filter cake was washed with about 1.5 L of cold ethyl acetate to obtain wet product 1 of compound (1). The filtrate was distilled under reduced pressure to a volume of about 1.5L, cooled to 5℃, kept warm for 3 hours to allow crystals to precipitate, and then filtered to obtain wet product 2 of compound (1).
[0028] Wet sample 1 and wet sample 2 of compound (1) were mixed and dried to obtain approximately 2.3 kg of compound (1) with a purity of 99.6% and a total impurity content of approximately 0.14% (e.g., ...). Figure 1 As shown, the retention time of the peak of compound (1) is about 32.05 min, and the retention time of the overlapping peak of compound (2) and compound (3) is about 17.0 min. Comparative Example 1
[0029] Take approximately 800 L of the irbesartan stock solution obtained according to the method described in Example 1.
[0030] At room temperature, 140 L of aqueous solution was added to the mother liquor of irbesartan for washing, followed by separation, and the toluene layer was retained. The obtained toluene layer solution was then concentrated to dryness under reduced pressure to obtain approximately 5 kg of oily residue. 2.5 L of ethyl acetate was added to the residue and stirred to dissolve.
[0031] After dissolution, the temperature was lowered to 5°C and kept warm for 3 hours to allow crystals to precipitate. The mixture was then filtered, and the filter cake was washed with about 1.5 L of cold ethyl acetate to obtain wet product 1 of compound (1). The filtrate was distilled under reduced pressure to a volume of about 1.5L, cooled to 5℃, kept warm for 3 hours to allow crystals to precipitate, and then filtered to obtain wet product 2 of compound (1).
[0032] Wet sample 1 and wet sample 2 of compound (1) were mixed and dried to obtain approximately 1.9 kg of compound (1) with a purity of 95.9% and a total impurity content of approximately 3.6% (e.g., ...). Figure 2As shown, the retention time of the peak of compound (1) is about 32.64 min, and the retention time of the overlapping peak of compound (2) and compound (3) is about 18.30 min. Comparative Example 2
[0033] Take approximately 800 L of the irbesartan stock solution obtained according to the method described in Example 1.
[0034] At room temperature, 140 L of 0.1% sodium hydroxide solution was added to the mother liquor of irbesartan for washing, followed by separation, and the toluene layer was retained. The obtained toluene layer solution was then concentrated to dryness under reduced pressure to obtain approximately 5 kg of oily residue. 2.5 L of methanol was added to the residue and stirred to dissolve it.
[0035] After dissolution, the temperature was lowered to 5°C and kept warm for 3 hours to allow crystals to precipitate. The mixture was then filtered, and the filter cake was washed with about 1.5L of cold methanol to obtain wet product 1 of compound (1). The filtrate was distilled under reduced pressure to a volume of about 1.5L, cooled to 5℃, kept warm for 3 hours to allow crystals to precipitate, and then filtered to obtain wet product 2 of compound (1).
[0036] Wet sample 1 and wet sample 2 of compound (1) were mixed and dried to obtain approximately 2.8 kg of compound (1) with a purity of 94.2% and a total impurity of approximately 3.1%. Comparative Example 3
[0037] Take approximately 800 L of the irbesartan stock solution obtained according to the method described in Example 1.
[0038] The mother liquor of irbesartan was directly concentrated to dryness under reduced pressure at room temperature to obtain about 5 kg of oily residue. 2.5 L of ethyl acetate was added to the residue and stirred to dissolve it.
[0039] After dissolution, the temperature was lowered to 5°C and kept warm for 3 hours to allow crystals to precipitate. The mixture was then filtered, and the filter cake was washed with about 1.5 L of cold ethyl acetate to obtain wet product 1 of compound (1). The filtrate was distilled under reduced pressure to a volume of about 1.5L, cooled to 5℃, kept warm for 3 hours to allow crystals to precipitate, and then filtered to obtain wet product 2 of compound (1).
[0040] Wet sample 1 and wet sample 2 of compound (1) were mixed and dried to obtain approximately 2.1 kg of compound (1) with a purity of 92.1% and a total impurity of approximately 4.7%. Comparative Example 4
[0041] Take approximately 800 L of the irbesartan stock solution obtained according to the method described in Example 1.
[0042] At room temperature, 300 L of saturated sodium bicarbonate solution was added to the mother liquor of irbesartan for washing, followed by separation, and the toluene layer was retained. The obtained toluene layer solution was then concentrated to dryness under reduced pressure to obtain approximately 5 kg of oily residue. 2.5 L of ethyl acetate was added to the residue and stirred to dissolve.
[0043] After dissolution, the temperature was lowered to 5°C and kept warm for 3 hours to allow crystals to precipitate. The mixture was then filtered, and the filter cake was washed with about 1.5 L of cold ethyl acetate to obtain wet product 1 of compound (1). The filtrate was distilled under reduced pressure to a volume of about 1.5L, cooled to 5℃, kept warm for 3 hours to allow crystals to precipitate, and then filtered to obtain wet product 2 of compound (1).
[0044] Wet sample 1 and wet sample 2 of compound (1) were mixed and dried to obtain approximately 1.9 kg of compound (1) with a purity of 95.9% and a total impurity of approximately 3.6%.
[0045] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, equivalent changes, and alterations made by those skilled in the art to the above embodiments based on the technical essence of the present invention shall still fall within the scope of the present invention.
Claims
1. A method for recovering irbesartan mother liquor (1) The method of compound, characterized in that, Follow the steps below: (1) Add 0.1-0.5 times the volume of alkaline solution to the irbesartan mother liquor for washing, let stand for separation, retain the organic layer and concentrate under reduced pressure to dryness to obtain the residue. Add solvent a to the obtained residue at a ratio of 0.4L-1L per kilogram of residue, stir to dissolve, and obtain the first solution; the alkaline solution is an aqueous solution of sodium hydroxide or potassium hydroxide, pH=11-14. (2) Cool the first solution to 5℃-10℃, keep it warm to crystallize, filter, take the filter cake and wash it with solvent b at 5℃-10℃ to obtain solid wet product 1; combine the solvent b used to wash the filter cake and the filtrate to obtain the second solution; (3) Take the second solution and concentrate it to 1 / 4-1 / 2 of the original volume, cool it to 5-10℃, keep it warm to precipitate crystals, filter it, and take the filter cake to obtain solid wet product 2; combine solid wet product 1 and solid wet product 2 and dry them to obtain the compound product of formula (1); The irbesartan mother liquor is derived from the following process: Formula (1) The compound is reacted in a toluene solution with 1.8-2.2 equivalents of sodium azide and 1.8-2.2 equivalents of triethylamine, heated to 85°C-110°C. After the reaction is complete, the reaction solution is cooled, and 1-2 equivalents of sodium azide with a mass concentration of 10%-20% hydrochloric acid is added to quench the reaction solution. The reaction solution is then extracted with a 10%-35% aqueous solution of sodium hydroxide or potassium hydroxide. The organic phase solution obtained by separation is the irbesartan mother liquor. The volume ratio of the sodium hydroxide or potassium hydroxide aqueous solution to the toluene solution is 1:10-1:
5.
2. The method for recovering formula (1) from irbesartan mother liquor as described in claim 1. The method of compound, characterized in that, Solvent a and solvent b are both selected from ethanol and ethyl acetate.
3. The method for recovering formula (1) from irbesartan mother liquor as described in claim 1. The method of compound, characterized in that, The volume ratio of the second solution to the first solution is 1:1 to 3:
1.
4. The method for recovering formula (1) from irbesartan mother liquor as described in claim 1. The method of compound, characterized in that, The irbesartan mother liquor described herein is of formula (1) The concentration of the compound was 0.005 kg / L - 0.012 kg / L.