A method for synthesizing triphenylmethylolmesartan medoxomil
By controlling the generation of impurity A through hydrolysis and condensation reactions in a toluene/C1-C4 lower alcohol mixed solvent, the problem of high impurity A content in the synthesis of triphenylmethylolmesartan medoxomil was solved, and the production of triphenylmethylolmesartan medoxomil with high purity and high yield was achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- ZHEJIANG TIANYU PHARMA
- Filing Date
- 2023-09-28
- Publication Date
- 2026-06-30
AI Technical Summary
In the existing technology, the content of impurity A is high during the synthesis of olmesartan medoxomil, which is difficult to control effectively and affects the quality of olmesartan medoxomil.
Hydrolysis and condensation reactions are carried out in a toluene/C1-C4 lower alcohol mixed solvent. The high-temperature elimination reaction of hydroxyl groups is suppressed by a protic alcohol solvent, and the generation of impurity A is controlled by a base and a phase transfer catalyst.
It effectively reduced the content of impurity A to 0.04%, improved the purity and yield of triphenylmethylolmesartan medoxomil, simplified the production process, and reduced production costs.
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Figure CN117343051B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical synthesis, and more specifically to a method for synthesizing triphenylmethylolmesartan medoxomil, an intermediate of olmesartan medoxomil. Background Technology
[0002] Olmesartan Medoxomil, a novel angiotensin B receptor (AT1) inhibitor (ARB) jointly developed by Sankyo (Japan) and Forest Laboratories (USA), was approved by the US FDA in May 2002 under the brand name Benicar. It was approved in Germany in August 2002. It was registered and approved in China in 2013 under the brand name Aotan, and was included in the second batch of national centralized procurement catalogs in 2020.
[0003]
[0004] In existing production technologies, olmesartan medoxomil is mainly obtained by removing the triphenylmethyl group (CPh3) from the key intermediate triphenylmethylolmesartan medoxomil.
[0005]
[0006] Triphenylmethylolmesartan medoxomil is mainly obtained through a two-step chemical reaction, which involves hydrolyzing compound 2 to obtain an intermediate sodium salt and then directly condensing it with compound 3.
[0007]
[0008] Chinese patent CN107311990A discloses a method for synthesizing olmesartan medoxomil, in which a single aprotic solvent such as THF, acetone, acetonitrile, or dioxane is used to convert compound 2 into triphenylmethylolmesartan medoxomil via a one-pot method.
[0009] Although the synthesis method disclosed in Chinese patent CN107311990A achieves one-pot direct acquisition of triphenylmethylolmesartan medoxomil, the inventors found that the control of impurity A in the method was not ideal when repeating the method. Its content in the synthesis solution was high, and the structure of this impurity was very similar to that of triphenylmethylolmesartan medoxomil, making it difficult to remove in the triphenylmethylolmesartan medoxomil intermediate. The content of impurity A in the finished triphenylmethylolmesartan medoxomil product was too high. This impurity was converted into olefin impurities in the pharmacopoeia standard in subsequent processes, which seriously affected the quality of olmesartan medoxomil raw material.
[0010] Summary of the Invention
[0011] This invention provides a method for synthesizing triphenylmethylolmesartan ester that overcomes the shortcomings of existing technologies and effectively reduces the content of impurity A.
[0012] Through long-term and in-depth research on the synthesis method of triphenylmethylolmesartan medoxomil, the inventors discovered that impurity A in the synthesis method of triphenylmethylolmesartan medoxomil is mainly produced by the removal of one molecule of water from the tertiary alcohol hydroxyl group in compound 2 during hydrolysis and condensation in a strongly alkaline aprotic solvent through a high-temperature elimination reaction. The generation of impurity A is closely related to the choice of solvent system and reaction temperature. If a small amount of protic lower alcohol solvent is present in the reaction system, the hydrogen of the ortho-methyl group of the hydroxyl group that tends to be eliminated will be quickly replenished by the lower alcohol in the system by providing protons to restore it to the original methyl group. In this way, the elimination reaction is significantly inhibited. Therefore, adding an appropriate amount of C1-C4 lower alcohol such as ethanol to the aprotic solvent toluene will significantly reduce the generation of this impurity.
[0013] The technical solution of the present invention is proposed based on the above-mentioned technical discoveries, as follows:
[0014] A method for synthesizing triphenylmethylolmesartan medoxomil includes the following steps:
[0015]
[0016] In a mixed solvent of toluene and C1-C4 lower alcohols, compound 2 is hydrolyzed under the action of an alkali at 60-75°C to obtain a synthesis solution of intermediate sodium salt; carbonate and phase transfer catalyst are added to the synthesis solution of intermediate sodium salt, and then compound 3 is added at 35-47°C, and a condensation reaction is carried out at this temperature to obtain triphenylmethylolmesartan ester.
[0017] According to the method of the present invention, in the hydrolysis step, the hydrolysis reaction is carried out at 65-70°C.
[0018] According to the method of the present invention, in the hydrolysis step, the base is sodium hydroxide and / or potassium hydroxide.
[0019] According to the method of the present invention, in the hydrolysis step, the C1-C4 lower alcohol is one or more of methanol, ethanol, isopropanol, and tert-butanol, preferably ethanol.
[0020] According to the method of the present invention, in the hydrolysis step, the volume ratio of toluene to C1-C4 lower alcohol is 10-15:1, preferably 10-12:1, and more preferably 10:1.
[0021] According to the method of the present invention, in the hydrolysis step, the mass-to-volume ratio (g / mL) of compound 2 to toluene is 1:10 to 15, preferably 1:10 to 13, and more preferably 1:12.
[0022] According to the method of the present invention, in the hydrolysis step, the molar ratio of compound 2 to base is 1:1.0 to 1.2, preferably 1.0 to 1.1, and more preferably 1:1.05.
[0023] According to the method of the present invention, in the condensation step, the condensation reaction is carried out at 40-45°C.
[0024] According to the method of the present invention, in the condensation step, the carbonate is sodium carbonate and / or potassium carbonate, preferably sodium carbonate.
[0025] According to the method of the present invention, in the condensation step, the phase transfer catalyst is one or more of benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride, tetrabutylammonium bisulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride, preferably tetrabutylammonium bromide.
[0026] According to the method of the present invention, the molar ratio of compound 2 to carbonate and phase transfer catalyst is 1:0.4-0.6:0.06-0.1, preferably 1:0.4-0.5:0.06-0.08, and more preferably 1:0.5:0.08.
[0027] According to the method of the present invention, the molar ratio of compound 2 to compound 3 is 1:1.1 to 1.3, preferably 1:1.2.
[0028] According to the method of the present invention, after the condensation reaction is completed, the synthesis solution is cooled to room temperature, water is added, the layers are separated, the organic layer (e.g., toluene layer) is washed with a saturated sodium chloride aqueous solution, and the organic layer (e.g., toluene layer) is concentrated to dryness under reduced pressure to obtain crude triphenylmethylolmesartan medoxomil; preferably, the obtained crude triphenylmethylolmesartan medoxomil is recrystallized by a crystallization solvent to obtain the finished triphenylmethylolmesartan medoxomil; preferably, the crystallization solvent is one or more of acetone, methanol, ethanol, isopropanol, and acetonitrile.
[0029] Beneficial effects
[0030] The method for synthesizing olmesartan medoxomil provided by this invention has the following significant advantages compared with the prior art:
[0031] 1) By using a mixed solvent system of toluene / C1-C4 lower alcohols, this invention effectively controls the content of impurity A in the product by inhibiting the high-temperature elimination reaction of hydroxyl groups by protic alcohol solvents. The content of impurity A can be effectively controlled to as low as 0.04%.
[0032] 2) This invention completes all preparation processes in a "one-pot method", resulting in a short production cycle, simple process, and no need to change or add new solvents during the process. This facilitates the recycling and reuse of solvents in industrial production and effectively reduces production costs.
[0033] 3) The synthesis method of olmesartan medoxomil described in this invention has a high overall yield (pure product yield up to 92%), high production efficiency, simple product purification (pure product purity up to 99.5%), and good quality control. Detailed Implementation
[0034] The present invention will be further described below with reference to specific embodiments, but the implementation of the present invention is not limited thereto.
[0035] Unless otherwise specified, the instruments used in this invention are conventional instruments, and the reagents used are conventional reagents.
[0036] Impurity A in olmesartan medoxomil was analyzed by HPLC under the following chromatographic conditions:
[0037] Instrument: Agilent 1200
[0038] Column: Zorbax SB-C18, 50 x 4.6 mm, 188 μm.
[0039] Flow rate: F = 1.0 ml / min
[0040] Column temperature: T = 26℃
[0041] Detection wavelength: λ = 220 nm
[0042] Mobile phase: A = 0.01 mol / L potassium dihydrogen phosphate solution (dissolve 1.36 g of potassium dihydrogen phosphate in 1000 ml of water), B = acetonitrile.
[0043] Example 1
[0044]
[0045] 71.7 g of compound 2, 4.2 g of sodium hydroxide, 860 mL of toluene, and 86 mL of ethanol were added to a three-necked flask. The reaction solution was heated to 65–70 °C and stirred for 12 hours. The reaction solution was then cooled to 40–45 °C, and 5.3 g of sodium carbonate and 2.5 g of tetrabutylammonium bromide were added directly. Then, 17.8 g of compound 3 was added dropwise at 42 °C over 2 hours. The reaction was then carried out at this temperature for 8 hours. After the reaction was completed, the synthesis solution was cooled to room temperature, and 800 mL of water was added. The layers were separated, and the toluene layer was washed twice with 800 mL of saturated sodium chloride aqueous solution. The toluene layer was concentrated to dryness under reduced pressure to obtain crude triphenylmethylolmesartan medoxomil. HPLC analysis showed that the content of impurity A in the crude product was 0.08%. The crude product was recrystallized from 360 mL of acetone to obtain 73.7 g of the finished triphenylmethylolmesartan medoxomil product, with a yield of 92%, a purity of 99.5%, and an impurity A content of 0.04%.
[0046] Examples 2-6
[0047] Triphenylmethylolmesartan medoxomil was synthesized using the procedure described in Example 1. With only the solvent type and its ratio changed and the other parameters remaining the same as in Example 1, the results of HPLC detection of impurity A are summarized in Table 1 below.
[0048] Table 1
[0049] Example solvent system yield purity The content of impurity A in the crude product The content of impurity A in the finished product Example 2 Toluene 83％ 99.1％ 2.5％ 1.4％ Example 3 Toluene:ethanol = (15:1) 90％ 99.3％ 0.10％ 0.06％ Example 4 Toluene:Methanol = (10:1) 89％ 98.8％ 0.13％ 0.07％ Example 5 Toluene:Isopropanol = (10:1) 87％ 99.2％ 0.11％ 0.08％ Example 6 Toluene: tert-butanol = (10:1) 85％ 98.6％ 0.15％ 0.10％
[0050] Comparative Examples 1-3
[0051] Triphenylmethylolmesartan medoxomil was synthesized in Comparative Examples 1-3 under the condition that only the reaction temperature was changed and all other parameters remained the same as those in Example 1 with the optimal conditions. The contents of impurity A are shown in Table 2 below.
[0052] Table 2
[0053] Comparative Example hydrolysis temperature Condensation temperature Volume ratio of toluene to ethanol The content of impurity A in the finished product of triphenylmethylolmesartan medoxomil Comparative Example 1 75～80℃ 40～45℃ 10：1 0.28％ Comparative Example 2 65～70℃ 48～52℃ 10：1 0.32％ Comparative Example 3 65～70℃ 55～60℃ 10：1 0.38％
[0054] Comparative Examples 4-6
[0055] Triphenylmethylolmesartan medoxomil was synthesized using the operating steps of Examples 1-3 disclosed in Chinese Patent CN107311990A, corresponding to Comparative Examples 4-6 in this application. The relevant impurities were analyzed by HPLC and are shown in Table 3 below.
[0056] Table 3
[0057]
[0058] The synthesis method of olmesartan medoxomil proposed in this invention has been described through examples. Those skilled in the art can obviously modify or appropriately change and combine the olmesartan medoxomil preparation method described herein without departing from the content, spirit, and scope of this invention to achieve the technical solution of this invention. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the spirit, scope, and content of this invention.
Claims
1. A method for synthesizing triphenylmethylolmesartan medoxomil, comprising the following steps: In a mixed solvent of toluene and C1-C4 lower alcohols, compound 2 is hydrolyzed under the action of an alkali at 60-75°C to obtain a synthesis solution of intermediate sodium salt; carbonate and phase transfer catalyst are added to the synthesis solution of intermediate sodium salt, and then compound 3 is added at 35-47°C, and a condensation reaction is carried out at this temperature to obtain triphenylmethylolmesartan ester; The volume ratio of toluene to C1-C4 lower alcohols is 10-15:
1. In the hydrolysis step, the base is sodium hydroxide; In the condensation step, the carbonate is sodium carbonate and / or potassium carbonate; the phase transfer catalyst is one or more of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride.
2. The method of claim 1, wherein, In the hydrolysis step, the hydrolysis reaction is carried out at 65~70℃.
3. The method of claim 1 or 2, wherein, In the hydrolysis step, the C1-C4 lower alcohol is one or more of methanol, ethanol, isopropanol, and tert-butanol.
4. The method of claim 3, wherein, In the hydrolysis step, the C1-C4 lower alcohol is ethanol.
5. The method of claim 1 or 2, wherein, In the hydrolysis step, the volume ratio of toluene to C1-C4 lower alcohols is 10-12:
1.
6. The method according to claim 5, wherein, In the hydrolysis step, the volume ratio of toluene to C1-C4 lower alcohols is 10:
1.
7. The method according to claim 1 or 2, wherein, In the hydrolysis step, the mass-to-volume ratio of compound 2 to toluene is 1:10~15.
8. The method according to claim 7, wherein, In the hydrolysis step, the mass-to-volume ratio of compound 2 to toluene is 1:10~13.
9. The method according to claim 1 or 2, wherein, In the hydrolysis step, the molar ratio of compound 2 to the base is 1:1.0~1.
2.
10. The method according to claim 9, wherein, In the hydrolysis step, the molar ratio of compound 2 to the base is 1:1.0~1.
1.
11. The method according to claim 1 or 2, wherein, In the condensation step, the condensation reaction is carried out at 40~45℃.
12. The method according to claim 1, wherein, In the condensation step, the carbonate is sodium carbonate.
13. The method according to claim 1, wherein, In the condensation step, the phase transfer catalyst is tetrabutylammonium bromide.
14. The method according to claim 1 or 2, wherein, The molar ratio of compound 2 to carbonate and phase transfer catalyst is 1:0.4-0.6:0.06-0.
1.
15. The method according to claim 14, wherein, The molar ratio of compound 2 to carbonate and phase transfer catalyst is 1:0.4-0.5:0.06-0.
08.
16. The method according to claim 1 or 2, wherein, The molar ratio of compound 2 to compound 3 is 1:1.1~1.
3.
17. The method according to claim 16, wherein, The molar ratio of compound 2 to compound 3 is 1:1.2.