Green synthesis process of ezetimibe intermediate
Through the asymmetric reduction reaction catalyzed by Fuke-K alkylation reaction, acylation reaction and immobilized carbonyl reductase, the Ezemel intermediate was successfully prepared, solving the problems of many by-products, low yields and large environmental pollution, and achieving an efficient and environmentally friendly production process.
Patent Information
- Application Number
- CN202411968285.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-30
- Publication Date
- 2025-03-28
AI Technical Summary
The existing preparation process of Ezemmaibu intermediates has problems such as many by-products, low yields and great environmental pollution.
The compound of formula III is produced by Fuke-K alkylation reaction, followed by acylation reaction with (S)-4-phenyl-2-oxazolidinone, and finally asymmetric reduction reaction under the catalysis of immobilized carbonyl reductase to obtain the Ezemebu intermediate.
It improves the efficient utilization of raw materials and minimizes energy consumption, improves production efficiency and product quality, and reduces environmental pollution.
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Figure CN119709903A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a green synthesis process of an ezetimibe intermediate, and belongs to the technical field of drug intermediate synthesis. Background Art
[0002] Ezetimibe Tablets is a cholesterol absorption inhibitor developed jointly by Merck & Co. and Schering-Plough Corporation of the United States. Unlike other lipid-lowering drugs, it can be used in combination with statins to treat primary hypercholesterolemia. It does not increase bile secretion, nor inhibit the synthesis of cholesterol in the liver, and has a long duration of effect. It is an ideal lipid-lowering drug and has occupied an important position in the market since its launch, with broad prospects.
[0003] In the conventional preparation process of ezetimibe intermediates, the production process is limited and the synthesis conditions of the process route are relatively harsh, which makes the production operation difficult. There are many by-products in the production process, the yield is not high, and the pollution to the environment is relatively large. At the same time, factors such as high raw material prices also make the production cost of ezetimibe relatively expensive, which is not conducive to its widespread popularization.
[0004] The published document "Study on the Synthesis Process of the Lipid-lowering Drug Ezetimibe" by Wu Guiying discloses a synthetic route for Ezetimibe, the main mechanism of which is: first asymmetric reduction to introduce the side chain S-hydroxyl group, and then form a β-lactam ring to prepare the Ezetimibe API. The specific scheme is: using p-fluoroaniline and p-hydroxybenzaldehyde as raw materials for addition reaction to obtain the imine 4-(4-fluorophenylimino)cresol (imine compound III), and another raw material (4S)-3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone (compound I) is selectively asymmetric reduced to (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4-phenyl-2-oxazolidinone under the catalysis of (R)-MeCBS. Phenyl-2-oxazolidinone (amide compound II), compound II and compound III are condensed to form (4S)-3-[(2R, 5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl)amino][4-(trimethylsilyloxy)phenyl]yl]-1-oxo-(5-trimethylsilyloxy)pentyl]-4-phenyl-2-oxazolidinone (compound IV), compound IV is cyclized by BSA to obtain (3R, 4S)-1-(4-fluorophenyl)-3-[(S)-3-(4-fluorophenyl-3-(trimethylsilyloxy)propyl)-4-(4-(trimethylsilyloxy)phenyl]azetidine-2-one (compound V), compound V is deprotected by TBAF and recrystallized to obtain ezetimibe, and its synthetic route is as follows:
[0005]
[0006] In the above scheme, (4S)-3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone (compound I) is selectively asymmetric reduced to (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4-phenyl-2-oxazolidinone (amide compound II) under the catalytic action of (R)-MeCBS. The prepared intermediate compound II is the same as the final product in the present application. However, the catalytic process is relatively complicated and the production difficulty is relatively high. Summary of the invention
[0007] In view of the defects existing in the above prior art, the present invention provides a green synthesis process of an ezetimibe intermediate, which solves the problems of more by-products, low yield and greater pollution to the environment.
[0008] The object of the present invention is achieved by the following technical scheme, a green synthesis process of an ezetimibe intermediate, the method comprising the following steps:
[0009] S1: subjecting fluorobenzene and glutaric anhydride to Friedel-Crafts alkylation reaction in an organic solvent I at low temperature to generate a compound of formula III;
[0010] S2: subjecting the compound of formula III to an acylation reaction with (S)-4-phenyl-2-oxazolidinone in an organic solution II to generate a compound of formula II;
[0011] S3: subjecting the compound of formula II to an asymmetric reduction reaction under the catalysis of an immobilized carbonyl reductase to obtain a compound of formula I, i.e., an ezetimibe intermediate;
[0012] The (S)-4-phenyl-2-oxazolidinone is mixed with DMAP and DMF and then added into the reaction system;
[0013] The immobilization carrier of the carbonyl reductase is a polyvinyl alcohol film;
[0014] The amino acid sequence of the carbonyl reductase is shown in SEQ ID NO.1;
[0015] The structural formula of the compound of formula I is:
[0016]
[0017] The structural formula of the compound of formula II is:
[0018]
[0019] The structural formula of the compound of formula III is:
[0020]
[0021] Preferably, in step S1, the organic solvent I is selected from at least one of dichloromethane, toluene and tetrahydrofuran.
[0022] Most preferably, tetrahydrofuran is used as the reaction solvent because the reaction stability is better and less by-products are generated.
[0023] Preferably, in the step S1, the mass ratio of the fluorobenzene to the glutaric anhydride is 1:1 to 1.1.
[0024] Most preferably, when the feed mass ratio of fluorobenzene to glutaric anhydride is 1:1.1, fluorobenzene can react completely.
[0025] Preferably, in the step S1, anhydrous aluminum chloride is added as a catalyst, and the mass ratio of the fluorobenzene to the anhydrous aluminum chloride is 1:1.6-2.2.
[0026] As the most preferred option, when the feed mass ratio of fluorobenzene to anhydrous aluminum chloride is 1:2, there is a small amount of tolerance for water absorption and inactivation.
[0027] Preferably, in the step S1, the low temperature condition ranges from 0 to 5°C, and the Friedel-Crafts alkylation reaction is carried out in an ice bath.
[0028] Most preferably, when the low temperature condition is 0°C, the reaction is milder.
[0029] Preferably, in step S2, the organic solution II is selected from at least one of DMSO, dichloromethane and tetrahydrofuran.
[0030] Most preferably, the organic solution II is DMSO, which can slightly reduce the generation of by-products.
[0031] Preferably, in the step S2, the acylation reaction is carried out in an alkaline environment, and at least one of triethylamine and pyridine is selected as the alkaline additive.
[0032] Most preferably, the alkaline additive is triethylamine.
[0033] Preferably, in step S2, the acylation reaction catalyst is an acyl chloride, and at least one of acetyl chloride and oxalyl chloride is selected as the acyl chloride catalyst.
[0034] Most preferably, the acyl chloride catalyst is acetyl chloride.
[0035] Preferably, in step S2, the acyl chloride catalyst is added dropwise to the reaction system at room temperature.
[0036] Preferably, in the step S2, the mass ratio of the compound of formula III to the (S)-4-phenyl-2-oxazolidinone is 1:1 to 1.2.
[0037] Most preferably, the mass ratio of the compound of formula III to the (S)-4-phenyl-2-oxazolidinone is 1:1.2, and the compound of formula III can react completely.
[0038] In summary, compared with the prior art, the present invention has the following advantages:
[0039] In the scheme of the present invention, by adopting an optimized process flow, efficient utilization of raw materials and minimization of energy consumption are achieved. In addition, the process has reached a high level in production efficiency and product quality, providing solid technical support for the large-scale production of ezetimibe API. BRIEF DESCRIPTION OF THE DRAWINGS
[0040] Figure 1 This is the synthetic route of the present invention. DETAILED DESCRIPTION
[0041] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.
[0042] Example 1
[0043] Preparation of compounds of formula III:
[0044] In the reaction bottle, add 53.34g anhydrous AlCl3 (0.4mol), 19.22mL fluorobenzene (0.2mol) and 150mL tetrahydrofuran, cool to 0℃, stir evenly, control the temperature and add 25.1g solid glutaric anhydride (0.22mol) in 3 batches, keep warm until the reaction is completed. Quench with dilute hydrochloric acid, pour the reaction solution into ice water, stir, filter, wash and dissolve the filtered solid with 100mL saturated sodium bicarbonate solution, adjust the pH value of the filtered filtrate to acidic with dilute hydrochloric acid, filter, wash the filter cake with water, and dry to obtain 37.98g of compound III, the product yield is 90.4%, and the product purity is 96%;
[0045] Preparation of compounds of formula II:
[0046] In a reaction flask, add 21g of compound III (0.1mol), 10.12g of TEA (0.1mol) and 100mL of DMSO, stir until completely dissolved, add 8.56mL of acetyl chloride (0.12mol) dropwise at room temperature, stir after dripping, then add 19.56g of (S)-4-phenyl-2-oxazolidinone (0.12mol), 9.77g of DMAP (0.08mol) and 50mL of DMF, and heat to react until the reaction is complete. Pour the reaction solution into dilute hydrochloric acid to quench, stir and layer, extract the water layer, combine the organic layers and wash them with 100mL of saturated sodium bicarbonate solution and 150mL of saturated brine respectively, desolvate the organic layer under reduced pressure to dryness, add solvent, stir and heat until completely dissolved, slowly stir and cool to crystallize, filter, filter and dry to obtain 31.6g of compound II, the product yield is 89%, and the product purity is 99%;
[0047] Carbonyl reductase immobilization:
[0048] 5 g of freeze-dried carbonyl reductase enzyme powder was dissolved in 250 mL of PBS buffer solution to obtain a carbonyl reductase solution, 25 g of polyvinyl alcohol was dissolved in 100 mL of solvent deionized water to obtain a polyvinyl alcohol solution, the polyvinyl alcohol solution was added to the carbonyl reductase solution to obtain a mixed solution, the mixture was stirred and mixed evenly, 2.5 mL (1 mg / mL) of a cross-linking agent in a glutaraldehyde aqueous solution was gradually added in 3 batches, the initial addition was stirred for 20 to 30 minutes, the rotation speed was maintained at 300 r / min, and then the stirring reaction time was gradually extended by 10 to 15 minutes. After the reaction was completed, centrifugation was performed, the buffer solution was washed, and low-temperature drying was performed to obtain 29 g of a polyvinyl alcohol film-coated carbonyl reductase product, i.e., a carbonyl reductase-polyvinyl alcohol film complex, with an immobilization rate of 96.7%;
[0049] Preparation of compounds of formula I:
[0050] In a reaction flask, add 17.76g of compound II (0.05mol), 100mL of isopropanol, 2g of fixed carbonyl reductase, 0.8g of isopropanol dehydrogenase and 1g of NADP, and keep warm until the reaction is completed. Add 100mL of ethyl acetate for extraction, wash the organic layer with saturated brine, desolventize the organic layer to dryness under reduced pressure, add toluene, stir and heat until completely dissolved, slowly stir and cool to crystallize, filter, filter and dry, and obtain 16.28g of compound I, with a product yield of 91.2%, a product purity of 99%, and a total product yield of 73.3%.
[0051] Example 2
[0052] In the reaction bottle, add 53.34g anhydrous AlCl3 (0.4mol), 19.22mL fluorobenzene (0.2mol) and 150mL dichloromethane, cool to 0°C, stir evenly, control the temperature and add a total of 25.1g solid glutaric anhydride (0.22mol) in 3 batches, add and keep warm until the reaction is completed. Quench with dilute hydrochloric acid, pour the reaction solution into ice water and stir, filter, wash and dissolve the filtered solid with 100mL saturated sodium bicarbonate solution, adjust the pH value of the filtered filtrate to acidic with dilute hydrochloric acid, filter, wash the filter cake with water, and dry to obtain 37.47g of formula III compound, the product yield is 89.1%, and the product purity is 95.7%.
[0053] Example 3
[0054] In the reaction bottle, add 53.34g anhydrous AlCl3 (0.4mol), 19.22mL fluorobenzene (0.2mol) and 150mL toluene, cool to 0°C, stir evenly, control the temperature and add a total of 25.1g solid glutaric anhydride (0.22mol) in 3 batches, add and keep warm until the reaction is completed. Quench with dilute hydrochloric acid, pour the reaction solution into ice water and stir, filter, wash and dissolve the filtered solid with 100mL saturated sodium bicarbonate solution, adjust the pH value of the filtered filtrate to acidic with dilute hydrochloric acid, filter, wash the filter cake with water, and dry to obtain 37.6g of formula III compound, the product yield is 89.5%, and the product purity is 96%.
[0055] Example 4
[0056] In the reaction bottle, add 53.34g anhydrous AlCl3 (0.4mol), 19.22mL fluorobenzene (0.2mol) and 150mL tetrahydrofuran, cool to 0°C, stir evenly, control the temperature and add a total of 22.82g solid glutaric anhydride (0.2mol) in 3 batches, add and keep warm until the reaction is completed. Quench with dilute hydrochloric acid, pour the reaction solution into ice water and stir, filter, wash and dissolve the filtered solid with 100mL saturated sodium bicarbonate solution, adjust the pH value of the filtered filtrate to acidic with dilute hydrochloric acid, filter, wash the filter cake with water, and dry to obtain 35.83 formula III compound, the product yield is 85.3%, and the product purity is 96%.
[0057] Example 5
[0058] In a reaction flask, add 21g of compound III (0.1mol), 10.12g of TEA (0.1mol) and 100mL of DCM, stir until completely dissolved, add 8.56mL of acetyl chloride (0.12mol) dropwise at room temperature, stir after dripping, then add 19.56g of (S)-4-phenyl-2-oxazolidinone (0.12mol), 9.77g of DMAP (0.08mol) and 50mL of DMF, and heat to react until the reaction is completed. Pour the reaction solution into dilute hydrochloric acid to quench, stir and layer, extract the water layer, combine the organic layers and wash them with 100mL of saturated sodium bicarbonate solution and 150mL of saturated brine respectively, desolvate the organic layer under reduced pressure to dryness, add solvent, stir and heat until completely dissolved, slowly stir and cool to crystallize, filter, filter and dry to obtain 30.96g of compound II, with a product yield of 87.2% and a product purity of 99%.
[0059] Example 6
[0060] In a reaction flask, add 21g of compound III (0.1mol), 10.12g of TEA (0.1mol) and 100mL of THF, stir until completely dissolved, add 8.56mL of acetyl chloride (0.12mol) dropwise at room temperature, stir after dripping, then add 19.56g of (S)-4-phenyl-2-oxazolidinone (0.12mol), 9.77g of DMAP (0.08mol) and 50mL of DMF, and heat to react until the reaction is complete. Pour the reaction solution into dilute hydrochloric acid to quench, stir and layer, extract the aqueous layer, combine the organic layers and wash with 100mL of saturated sodium bicarbonate solution and 150mL of saturated brine respectively, desolvate the organic layer under reduced pressure to dryness, add solvent, stir and heat until completely dissolved, slowly stir and cool to crystallize, filter, filter and dry to obtain 31.18g of compound II, with a product yield of 87.8% and a product purity of 99%.
[0061] Example 7
[0062] In a reaction flask, add 21g of compound III (0.1mol), 7.91g of pyridine (0.1mol) and 100mL of DMSO, stir until completely dissolved, add 8.56mL of acetyl chloride (0.12mol) dropwise at room temperature, stir after dripping, then add 19.56g of (S)-4-phenyl-2-oxazolidinone (0.12mol), 9.77g of DMAP (0.08mol) and 50mL of DMF, and heat to react until the reaction is completed. Pour the reaction solution into dilute hydrochloric acid to quench, stir and layer, extract the water layer, combine the organic layers and wash them with 100mL of saturated sodium bicarbonate solution and 150mL of saturated brine respectively, desolvate the organic layer under reduced pressure to dryness, add solvent, stir and heat until completely dissolved, slowly stir and cool to crystallize, filter, filter and dry to obtain 30.93g of compound II, with a product yield of 87.1% and a product purity of 99%.
[0063] Example 8
[0064] In a reaction flask, add 21g of compound III (0.1mol), 10.12g of TEA (0.1mol) and 100mL of DMSO, stir until completely dissolved, add 9.52mL of oxalyl chloride (0.12mol) dropwise at room temperature, stir after dripping, then add 19.56g of (S)-4-phenyl-2-oxazolidinone (0.12mol), 9.77g of DMAP (0.08mol) and 50mL of DMF, and heat to react until the reaction is complete. Pour the reaction solution into dilute hydrochloric acid to quench, stir and layer, extract the water layer, combine the organic layers and wash with 100mL of saturated sodium bicarbonate solution and 150mL of saturated brine respectively, desolvate the organic layer under reduced pressure to dryness, add solvent, stir and heat until completely dissolved, slowly stir and cool to crystallize, filter, filter and dry to obtain 31.07g of compound II, with a product yield of 87.5% and a product purity of 99%.
[0065] Example 9
[0066] In a reaction flask, add 21g of compound III (0.1mol), 10.12g of TEA (0.1mol) and 100mL of DMSO, stir until completely dissolved, add 8.56mL of acetyl chloride (0.12mol) dropwise at room temperature, stir after dripping, then add 16.3g of (S)-4-phenyl-2-oxazolidinone (0.1mol), 9.77g of DMAP (0.08mol) and 50mL of DMF, and heat to react until the reaction is completed. Pour the reaction solution into dilute hydrochloric acid to quench, stir and layer, extract the water layer, combine the organic layers and wash them with 100mL of saturated sodium bicarbonate solution and 150mL of saturated brine respectively, desolvate the organic layer under reduced pressure to dryness, add solvent, stir and heat until completely dissolved, slowly stir and cool to crystallize, filter, filter and dry to obtain 30.64g of compound II, with a product yield of 86.3% and a product purity of 99%.
[0067] The implementation of the present invention is not limited to the above-mentioned embodiments. Without departing from the spirit and scope of the present invention, ordinary technicians in this field can make various changes and improvements to the present invention in form and detail, and these are considered to fall within the protection scope of the present invention.
Claims
1. A green synthesis process of an ezetimibe intermediate, characterized in that: The method comprises the following steps: S1: subjecting fluorobenzene and glutaric anhydride to Friedel-Crafts alkylation reaction in an organic solvent I at low temperature to generate a compound of formula III; S2: subjecting the compound of formula III to an acylation reaction with (S)-4-phenyl-2-oxazolidinone in an organic solution II to generate a compound of formula II; S3: subjecting the compound of formula II to an asymmetric reduction reaction under the catalysis of an immobilized carbonyl reductase to obtain a compound of formula I, i.e., an ezetimibe intermediate; The (S)-4-phenyl-2-oxazolidinone is mixed with DMAP and DMF and then added into the reaction system; The immobilization carrier of the carbonyl reductase is a polyvinyl alcohol film; The amino acid sequence of the carbonyl reductase is shown in SEQ ID NO.1; The structural formula of the compound of formula I is: The structural formula of the compound of formula II is: The structural formula of the compound of formula III is:
2. The green synthesis process of an ezetimibe intermediate according to claim 1, characterized in that: In the step S1, the organic solvent I is selected from at least one of dichloromethane, toluene and tetrahydrofuran.
3. The green synthesis process of an ezetimibe intermediate according to claim 1, characterized in that: In the step S1, the mass ratio of the fluorobenzene to the glutaric anhydride is 1:1 to 1.
1.
4. The green synthesis process of an ezetimibe intermediate according to claim 1, characterized in that: In the step S1, anhydrous aluminum chloride is added as a catalyst, and the feed mass ratio of the fluorobenzene to the anhydrous aluminum chloride is 1:1.6-2.
2.
5. The green synthesis process of an ezetimibe intermediate according to claim 1, characterized in that: In the step S1, the low temperature condition ranges from 0 to 5°C, and the Friedel-Crafts alkylation reaction is carried out in an ice bath.
6. The green synthesis process of an ezetimibe intermediate according to claim 1, characterized in that: In the step S2, the organic solution II is selected from at least one of DMSO, dichloromethane and tetrahydrofuran.
7. The green synthesis process of an ezetimibe intermediate according to claim 1, characterized in that: In the step S2, the acylation reaction is carried out in an alkaline environment, and at least one of triethylamine and pyridine is selected as the alkaline additive.
8. The green synthesis process of an ezetimibe intermediate according to claim 1, characterized in that: In the step S2, the acylation reaction catalyst is an acyl chloride, and at least one of acetyl chloride and oxalyl chloride is selected as the acyl chloride catalyst.
9. The green synthesis process of an ezetimibe intermediate according to claim 1, characterized in that: In the step S2, the acyl chloride catalyst is added dropwise to the reaction system at room temperature.
10. The green synthesis process of an ezetimibe intermediate according to claim 1, characterized in that: In the step S2, the mass ratio of the compound of formula III to the (S)-4-phenyl-2-oxazolidinone is 1:1 to 1.2.