The invention relates to 4apos; novel preparation process of-O-Benzyloxy Ezetimibe

Abstract

The invention discloses a preparation method of 4 '; the novel preparation process comprises the following steps: under the protection of inert gas, dissolving a chiral ligand and a metal salt in an organic solvent, stirring the mixture for 30 minutes to 1 hour at room temperature, adding a solution of a compound II into a catalyst solution, stirring for 15-30 minutes at a low temperature of-40 DEG C, adding a compound I, an activating agent and an alkali reagent, stirring for 15-30 minutes at a low temperature of-40 DEG C, and reacting for 1-2 hours to obtain a compound I; and continuously stirring at-40 DEG C to react for 6-8 hours, monitoring the proceeding of the reaction by HPLC (High Performance Liquid Chromatography), and separating a product after the reaction is completed to obtain a compound III. The method has the beneficial effects that the operation is simple, the reaction steps can be effectively reduced, the reaction route is short, the raw materials are easy to obtain, the reaction time is short, and the production cost and the labor cost can be effectively reduced; the product yield is high, the reaction selectivity is good, the product purity is high, the reaction product yield is high, the selectivity is good, the target product can be obtained at a high yield, and meanwhile, the post-treatment difficulty of the product is reduced.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically a novel process for preparing 4'-O-BenzyloxyEzetimibe. Background Technology

[0002] Ezetimibe, also known as ezetimibe or ezetimibe, is the first selective cholesterol absorption inhibitor jointly developed by Schering-Plough and Merck. It was the first selective cholesterol absorption inhibitor to be approved by the US FDA. It was first launched in Germany in November 2002, simultaneously in the United States.

[0003] Ezetimibe is the first selective inhibitor of intestinal cholesterol absorption. Its mechanism of action differs from other lipid-lowering drugs (such as statins, bile acid sequestrants, phenoxy acid derivatives, and phytosterol esters). It can be used alone or in combination with HMG-CoA reductase inhibitors (statins) to treat primary (heterozygous familial or non-familial) hypercholesterolemia, homozygous familial hypercholesterolemia (HoFH), and homozygous sitosterolemia (or phytosterolemia). Ezetimibe does not increase bile secretion (like bile acid sequestrants) nor inhibit cholesterol synthesis in the liver (like statins), and its effects are long-lasting. Since its market launch, ezetimibe has become a blockbuster drug in the lipid-lowering drug market with a promising market prospect. Therefore, developing and producing this drug will have significant social and economic benefits.

[0004] Schering-Plough currently holds patents protecting the compounds and synthesis process of ezetimibe (CN100475829C, CN1130342C, US5767115). Patent US5767115 discloses a method for synthesizing ezetimibe where the compound does not react with (4-benzyloxy-benzyloxy)-(4-fluorophenyl-amine) and methyl 4-chloroformylbutyrate. The acyl chloride is prepared by hydrolysis, then reacted with p-fluorophenyl zinc chloride under palladium catalysis, and finally hydrogenated by chiral reduction catalysis to obtain ezetimibe. This process involves column chromatography purification, which is unsuitable for industrial production. Patent document CN1130342C describes the reaction of 5-(4-fluorophenyl)-5-oxopentanoic acid and pivaloyl chloride to obtain a mixed acid anhydride, which then undergoes a nucleophilic substitution reaction with (4S)-4-phenyl-oxazolidinone to yield 4S)-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-4-phenyl-2- Oxazolidinone was asymmetrically reduced to (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-2-oxazolidinone, which was condensed with 4-(4-fluorophenylimino)phenol to give (7). Further cyclization and removal of the protecting group gave ezetimibe. The whole route has harsh reaction conditions, many reaction steps, and low yield and purity.

[0005] Based on the aforementioned process defects, this invention develops a new process for synthesizing ezetimibe intermediate and ezetimibe. Summary of the Invention

[0006] To address the above shortcomings, the present invention provides the following technical solution: A novel process for preparing 4'-O-Benzyloxy Ezetimibe includes the following steps: Under inert gas protection, the chiral ligand and metal salt were dissolved in an organic solvent, and the mixture was stirred at room temperature for 30 minutes to 1 hour. The solution of compound II was added to the above solution, and the mixture was stirred at -40°C for 15-30 minutes. Then, compound I, an activator, and an alkaline reagent were added, and the reaction was continued to be stirred at -40°C for 6-8 hours. The reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound III.

[0007] Furthermore, the solvent used in the reaction is dichloromethane.

[0008] Furthermore, the activator used in the reaction is (chloromethylene)dimethylammonium chloride.

[0009] Furthermore, the molar ratio of the reactant compound I to compound II is 1:1.1 to 1.2.

[0010] Furthermore, the chiral ligand used in the reaction is (S,S)-t-Bu-Box.

[0011] Furthermore, the amount of the activator is 1.2-1.5 eq of compound I.

[0012] Furthermore, the metal salt is Mg(OTf)2.

[0013] Furthermore, the amount of the metal salt used is 5 to 10 mol of compound I.

[0014] Furthermore, the base reagent is triethylamine, and the amount of triethylamine used is 2.5 to 3.0 eq of compound I.

[0015] Furthermore, the ratio of the metal salt to the chiral ligand is 1:1 to 1.2.

[0016] The beneficial effects of this invention are: 1. The technical solution of this application is simple to operate, can effectively reduce reaction steps, has a short reaction route, readily available raw materials, and short reaction time, which can effectively reduce production costs and labor costs; the product yield is high, the reaction selectivity is good, the product purity is high, and it is easy to produce stable intermediates of pharmaceutical ezetimibe; 2. The technical solution of this invention can produce intermediate compounds of the corresponding configuration with high selectivity, avoid the generation of more isomers, prevent isomer products from affecting the purity of the overall product, the reaction product yield is high, the selectivity is good, the target product can be obtained in high yield, and the shorter route and higher selectivity ensure fewer by-products, effectively saving reagent consumption and reducing the difficulty of product post-processing. Attached Figure Description

[0017] Figure 1 This is a schematic diagram of the reaction route and process route of the present invention. Detailed Implementation

[0018] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0019] Example 1 Under nitrogen protection, 0.005 mol of chiral ligand (S,S)-t-Bu-Box and 0.005 mol of metal salt Mg(OTf)₂ were dissolved in 500 ml of anhydrous dichloromethane. The mixture was stirred at room temperature for 30 minutes to 1 hour. 0.11 mol (33.6 g) of compound II was dissolved in 100 ml of anhydrous dichloromethane and then added to the above solution. The mixture was stirred at -40°C for 15-30 minutes. 0.1 mol (21.0 g) of compound I was then added, along with 0.12 mol of activator (chloromethylene)dimethylammonium chloride. Add 0.25 mol of triethylamine as a base reagent, and stir continuously at -40°C for 6–8 h. Monitor the reaction progress with HPLC. After the reaction is complete, slowly raise the temperature to room temperature and slowly add dilute hydrochloric acid to quench the reaction. Pour the reaction mixture into a separatory funnel, add 100 ml of water and 100 ml of ethyl acetate as an organic solvent, separate the layers, extract the aqueous phase with the organic solvent 2–3 times, combine all organic phases, wash 2–3 times with saturated brine, dry with anhydrous sodium sulfate, filter, and recrystallize the product with 50 ml of toluene to give 46.6 g of compound III, with a yield of 93.8% and a purity of 98.8%.

[0020] Example 2 Under nitrogen protection, 0.005 mol of chiral ligand (S,S)-t-Bu-Box and 0.005 mol of metal salt Mg(OTf)₂ were dissolved in 500 ml of anhydrous dichloromethane. The mixture was stirred at room temperature for 30 minutes to 1 hour. 0.12 mol (36.6 g) of compound II was dissolved in 100 ml of anhydrous dichloromethane and then added to the above solution. The mixture was stirred at -40°C for 15-30 minutes. 0.1 mol (21.0 g) of compound I was then added, along with 0.12 mol of activator (chloromethylene)dimethylammonium chloride. Add 0.25 mol of triethylamine as a base reagent, and stir continuously at -40°C for 6–8 h. Monitor the reaction progress by HPLC. After the reaction is complete, slowly raise the temperature to room temperature and slowly add dilute hydrochloric acid to quench the reaction. Pour the reaction mixture into a separatory funnel, add 100 ml of water and 100 ml of ethyl acetate as an organic solvent, separate the layers, extract the aqueous phase with the organic solvent 2–3 times, combine all organic phases, wash 2–3 times with saturated brine, dry with anhydrous sodium sulfate, filter, and recrystallize the product with 50 ml of toluene to give 46.5 g of compound III, with a yield of 93.5% and a purity of 98.6%.

[0021] Example 3 Under nitrogen protection, 0.006 mol of chiral ligand (S,S)-t-Bu-Box and 0.005 mol of metal salt Mg(OTf)₂ were dissolved in 500 ml of anhydrous dichloromethane. The mixture was stirred at room temperature for 30 minutes to 1 hour. 0.11 mol (33.6 g) of compound II was dissolved in 100 ml of anhydrous dichloromethane and then added to the above solution. The mixture was stirred at -40°C for 15-30 minutes. 0.1 mol (21.0 g) of compound I was then added, along with 0.12 mol of activator (chloromethylene)dimethylammonium chloride. Add 0.25 mol of triethylamine as a base reagent, and stir continuously at -40°C for 6–8 h. Monitor the reaction progress by HPLC. After the reaction is complete, slowly raise the temperature to room temperature and slowly add dilute hydrochloric acid to quench the reaction. Pour the reaction mixture into a separatory funnel, add 100 ml of water and 100 ml of ethyl acetate as an organic solvent, separate the layers, extract the aqueous phase with the organic solvent 2–3 times, combine all organic phases, wash 2–3 times with saturated brine, dry with anhydrous sodium sulfate, filter, and recrystallize the product with 50 ml of toluene to give 46.8 g of compound III, with a yield of 94.1% and a purity of 98.9%.

[0022] Example 4 Under nitrogen protection, 0.010 mol of chiral ligand (S,S)-t-Bu-Box and 0.010 mol of metal salt Mg(OTf)₂ were dissolved in 500 ml of anhydrous dichloromethane. The mixture was stirred at room temperature for 30 minutes to 1 hour. 0.11 mol (33.6 g) of compound II was dissolved in 100 ml of anhydrous dichloromethane and then added to the above solution. The mixture was stirred at -40°C for 15-30 minutes. 0.1 mol (21.0 g) of compound I was then added, along with 0.12 mol of activator (chloromethylene)dimethylammonium chloride. Add 0.25 mol of triethylamine as a base reagent, and stir continuously at -40°C for 6–8 h. Monitor the reaction progress by HPLC. After the reaction is complete, slowly raise the temperature to room temperature and slowly add dilute hydrochloric acid to quench the reaction. Pour the reaction mixture into a separatory funnel, add 100 ml of water and 100 ml of ethyl acetate as an organic solvent, separate the layers, extract the aqueous phase with the organic solvent 2–3 times, combine all organic phases, wash 2–3 times with saturated brine, dry with anhydrous sodium sulfate, filter, and recrystallize the product with 50 ml of toluene to give 46.7 g of compound III, with a yield of 93.9% and a purity of 98.7%.

[0023] Example 5 Under nitrogen protection, 0.005 mol of chiral ligand (S,S)-t-Bu-Box and 0.005 mol of metal salt Mg(OTf)₂ were dissolved in 500 ml of anhydrous dichloromethane. The mixture was stirred at room temperature for 30 minutes to 1 hour. 0.11 mol (33.6 g) of compound II was dissolved in 100 ml of anhydrous dichloromethane and then added to the above solution. The mixture was stirred at -40°C for 15-30 minutes. 0.1 mol (21.0 g) of compound I was then added, along with 0.15 mol of activator (chloromethylene)dimethylammonium chloride. Add 0.25 mol of triethylamine as a base reagent, and stir continuously at -40°C for 6–8 h. Monitor the reaction progress by HPLC. After the reaction is complete, slowly raise the temperature to room temperature and slowly add dilute hydrochloric acid to quench the reaction. Pour the reaction mixture into a separatory funnel, add 100 ml of water and 100 ml of ethyl acetate as an organic solvent, separate the layers, extract the aqueous phase with the organic solvent 2–3 times, combine all organic phases, wash 2–3 times with saturated brine, dry with anhydrous sodium sulfate, filter, and recrystallize the product with 50 ml of toluene to give 46.1 g of compound III, with a yield of 92.7% and a purity of 98.3%.

[0024] Example 6 Under nitrogen protection, 0.005 mol of chiral ligand (S,S)-t-Bu-Box and 0.005 mol of metal salt Mg(OTf)₂ were dissolved in 500 ml of anhydrous dichloromethane. The mixture was stirred at room temperature for 30 minutes to 1 hour. 0.11 mol (33.6 g) of compound II was dissolved in 100 ml of anhydrous dichloromethane and then added to the above solution. The mixture was stirred at -40°C for 15-30 minutes. 0.1 mol (21.0 g) of compound I was then added, along with 0.12 mol of activator (chloromethylene)dimethylammonium chloride. Add 0.3 mol of triethylamine as a base reagent, and stir continuously at -40°C for 6–8 h. Monitor the reaction progress by HPLC. After the reaction is complete, slowly raise the temperature to room temperature and slowly add dilute hydrochloric acid to quench the reaction. Pour the reaction mixture into a separatory funnel, add 100 ml of water and 100 ml of ethyl acetate as an organic solvent, separate the layers, extract the aqueous phase with the organic solvent 2–3 times, combine all organic phases, wash 2–3 times with saturated brine, dry with anhydrous sodium sulfate, filter, and recrystallize the product with 50 ml of toluene to give 46.3 g of compound III, with a yield of 93.1% and a purity of 98.7%.

[0025] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0026] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A novel process for preparing 4'-O-Benzyloxy Ezetimibe, characterized in that... Includes the following steps: Under inert gas protection, the chiral ligand and metal salt were dissolved in an organic solvent, and the mixture was stirred at room temperature for 30 minutes to 1 hour. The solution of compound II was added to the above solution, and the mixture was stirred at -40°C for 15-30 minutes. Then, compound I, an activator, and an alkaline reagent were added, and the reaction was continued to be stirred at -40°C for 6-8 hours. The reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound III.

2. The novel preparation process of 4'-O-Benzyloxy Ezetimibe according to claim 1, characterized in that: The solvent used in the reaction is dichloromethane.

3. The novel preparation process of 4'-O-Benzyloxy Ezetimibe according to claim 1, characterized in that: The activator used in the reaction is (chloromethylene)dimethylammonium chloride.

4. The novel preparation process of 4'-O-Benzyloxy Ezetimibe according to claim 1, characterized in that: The molar ratio of compound I to compound II in the reaction is 1:1.1 to 1.

2.

5. The novel preparation process of 4'-O-Benzyloxy Ezetimibe according to claim 1, characterized in that: The chiral ligand used in the reaction is (S,S)-t-Bu-Box.

6. The novel preparation process of 4'-O-Benzyloxy Ezetimibe according to claim 1, characterized in that: The amount of the activator used is 1.2-1.5 eq of compound I.

7. The novel preparation process of 4'-O-Benzyloxy Ezetimibe according to claim 1, characterized in that: The metal salt is Mg(OTf)2.

8. The novel preparation process of 4'-O-Benzyloxy Ezetimibe according to claim 1, characterized in that: The amount of the metal salt used is 5 to 10 mol of compound I.

9. A novel process for preparing 4'-O-Benzyloxy Ezetimibe according to claim 1, characterized in that: The alkaline reagent is triethylamine, and the amount of triethylamine used is 2.5 to 3.0 eq of compound I.

10. A novel process for preparing 4'-O-Benzyloxy Ezetimibe according to claim 1, characterized in that: The ratio of the metal salt to the chiral ligand is 1:1 to 1.2.

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