WO2017143628A1

WO2017143628A1 - Method for preparing hypolipidemic drug ezetimibe and intermediate thereof

Info

Publication number: WO2017143628A1
Application number: PCT/CN2016/075539
Authority: WO
Inventors: 郭乙杰
Original assignee: 常州制药厂有限公司
Priority date: 2016-02-26
Filing date: 2016-03-03
Publication date: 2017-08-31
Also published as: CN107129452A

Abstract

The present invention relates to a method for preparing an industrially-produced method for preparing a hypolipidemic drug Ezetimibe and an intermediate thereof.

Description

Preparation method of hypolipidemic drug ezetimibe and its key intermediates

Technical field

The invention relates to a preparation method of ezetimibe (formula I) with optimized synthesis conditions, and a preparation method of key intermediates.

Background technique

Ezetimibe is a new type of lipid-lowering drug that inhibits cholesterol absorption developed by Merck and Schering-Plough. Its chemical name is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxybenzene) Base)-2-azetidinone. Ezetimibe belongs to the β-lactam family and is the first monocyclic β-lactam cholesterol absorption inhibitor successfully developed.

Ezetimibe is a white crystalline powder, very soluble in ethanol, methanol and acetone, insoluble in water, melting point is about 163 ° C, stable at room temperature. Ezetimibe can reduce blood TC by inhibiting TC absorption in the small intestine brush border, and it also has a weak lipid-lowering effect. After oral absorption, it is combined with glucuronic acid to form the active substance, ezetimibe-glucuronic acid, which is excreted by bile and kidney. After oral administration, the peak concentration of blood was reached within 4 to 12 hours, Cmax was 3.4-5.8 mg/ml, bioavailability was between 35% and 60%, and t _{l/2 was} about 22 h. The binding ratio of ezetimibe and ezetimibe-glucuronic acid to plasma protein is higher than 90%.

Ezetimibe was first launched in Germany in November 2002 and was listed in the US, Switzerland, the UK and Sweden. The market size report for major lipid-lowering (cholesterol-lowering) products in the world market in 2003 showed that ezetimibe/simvastatin had global sales of $471 million in 2003. Inegy (ezetimibe/simvastatin) was approved by the German government for the treatment of hyperlipidemia in 2004. Inegy is also the world's first lipid-lowering drug with a dual mechanism of blocking liver cholesterol synthesis and inhibiting intestinal cholesterol absorption. Due to good drug efficacy and low side effects, ezetimibe is getting more and more people's attention and the market prospect is broad.

Studies have shown that ezetimibe is an effective cholesterol absorption inhibitor, especially in combination with statin lipid-lowering drugs. The combination of ezetimibe with statins is eight times more effective than statins in producing cholesterol-lowering effects. There is no potential pharmacokinetic/pharmacodynamic interaction between ezetimibe and statins and other commonly used oral drugs, ezetimibe Administration alone or in combination with statins was well tolerated and the incidence of adverse events was similar to placebo. The advantage of ezetimibe in combination with statins is that it significantly enhances the lipid-lowering effect, is safer to use, and reduces the risk of rhabdomyolysis and hepatotoxicity and muscle pain caused by high-dose medications. This provides hope for many patients with lipid disorders who are unable to tolerate high doses of statins and fail to achieve the desired lipid targets.

The preparation method of ezetimibe is first disclosed in U.S. Patent No. 5,767,115, the route of which is as follows.

The disclosed preparation method comprises: ring-opening esterification of glutaric acid under the action of methanol to obtain monomethyl glutarate, monomethyl glutarate and (4S)-4-phenyl-oxazolidinone Acid amination reaction to obtain (4S)-3-(4-carboxylic acid formyl-1-oxobutyl)-4-phenyl-2-oxazolidinone in titanium tetrachloride, tetraisopropyl The reverse condensation reaction with N-(4-fluorophenyl)-4-benzyloxybenzylidene is carried out by the combination of titanium alkoxide and DIPEA to form (6), and then by BSA/TBAF (tetrabutylamine fluoride) The ring closure is obtained (7), and then hydrolyzed by LiOH to obtain (8), (8) by oxalyl chloroformyl chloride (9), (9) by fluorophenylmagnesium bromide in ZnC1 ₂ and Pd(PPh ₃ ) ₄ The (10) is obtained, and the carbonyl group is asymmetrically reduced by CBS/BH ₃ , and the benzyl group is removed by Pd/C to obtain ezetimibe. The key intermediates in the method disclosed in the patent need to be purified by column chromatography. The difficulty and cost of industrial production are increased, and in the final step, when palladium carbon is used to remove the benzyl group, the fluorine on the benzene ring is easily removed, thereby generating impurities. The risk of residual heavy metal palladium in the final product is reduced by palladium on carbon. In summary, the disadvantages are therefore not suitable for industrial production.

The invention is based on the process route of the patent US 5,767,115, which is improved and optimized to obtain a synthetic method suitable for industrial production, which has the advantages of simple operation, mild reaction conditions and high selectivity of the asymmetric reduction configuration of the intermediate. The reaction steps are short, the quality of the intermediate is high, the production cost is low, and the product quality meets the advantages of the quality requirements of the raw materials in the ICH guidelines.

Summary of the invention

The object of the present invention is to provide a preparation method for the optimization of ezetimibe, which provides a simple method for preparing high-purity intermediate compound 2 by accurately controlling pH, and provides a simple method for preparing high-purity intermediate compound 2 by accurately controlling pH. The key intermediate compound 4 is prepared by a coupling reaction in a suitable solvent; the ezetimibe palladium is prepared by using bistriphenylphosphine palladium dichloride as a coupling catalyst and adsorbing residual palladium by using activated carbon. The content is controlled below 5ppm; in the process of asymmetric reduction to prepare intermediate compound 5, we reduce the catalytic amount and the borane dimethyl sulfide reducing agent by adding a catalytic amount of trifluoroacetic anhydride. Its content of diastereomers. The synthetic route of the invention is as follows:

The content covered by the present invention includes the following aspects:

(1) Providing an optimized method for preparing a high-purity intermediate (Compound 2)

By precisely controlling the pH value of the solution and successively acidifying, due to the difference in the basicity of the compound 2 and the compound 2', the compound 2 is preferentially released during the acidification process, and the impurity compound 2' remains in the water as a monosodium salt or a double sodium salt. The purpose of removing impurities and purifying the intermediate compound 2 is achieved; the base for hydrolysis may be one or a mixture of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and most preferably hydrogen hydroxide. Sodium; the acid used for neutralizing the mother liquor can use inorganic acid or organic acid. The inorganic acid includes hydrochloric acid, sulfuric acid, phosphoric acid, and the organic acid includes p-toluenesulfonic acid, acetic acid, and propionic acid;

(2) Providing a method for preparing compound compound 4

Compound 2 is dissolved in an inert solvent, and reacted with a chlorinating reagent under the action of a catalytic amount of DMF to obtain an acid chloride compound. For the chlorinating agent, oxalyl chloride, thionyl chloride or the like can be used. The inert solvent is dichloromethane, chloroform, tetrahydrofuran, diethyl ether, ethyl acetate, toluene or xylene;

The acid chloride compound is then coupled with a Grignard reagent brominated p-fluorophenylmagnesium in an inert solvent in the presence of zinc chloride in the presence of a catalyst to provide intermediate compound 4. The inert solvent is one or a mixture of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, acetonitrile, ethyl acetate, toluene, xylene;

The catalyst is palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium dichloride, preferably bistriphenylphosphine palladium dichloride;

When the catalyst selected is bistriphenylphosphine palladium dichloride, the amount of the catalyst is 0.5% to 2% by weight of the compound 2;

(3) A method for preparing a compound 5 (ezetimibe)

The asymmetric reduction of the carbonyl group in the compound 4 with the reducing agent borane dimethyl sulfide in the presence of a catalytic amount of trifluoroacetic anhydride in an inert solvent gives the highly pure compound ezetimibe with high selectivity. It is characterized in that the reaction solvent is one or a mixture of tetrahydrofuran, dichloroethane, chloroform, dichloromethane, toluene or xylene, preferably dichloromethane or tetrahydrofuran.

detailed description

1. Preparation of Compound 2

Method A: 100 ml of dichloromethane was added to a 1000 ml reaction flask, 100.0 g (0.259 mol) of compound 1 was added, stirred, and the reaction temperature was maintained at 0 to 5 ° C, and sodium hydroxide solution (21.79 g (0.545 mol) of sodium hydroxide was added dropwise. - 300 ml of water), the dropping rate was controlled to maintain the temperature of the reaction solution at 0-5 ° C, and the dropwise addition was completed in about 3 hours. The dropwise addition was completed, and the reaction temperature was maintained at 0 to 5 ° C for 4 hours, and the conversion of the compound 1 was completed by TLC. 250 ml of water and 500 ml of ethyl acetate were added to the reaction mixture, and the mixture was stirred for 10 to 15 minutes, and the mixture was allowed to stand for separation. The aqueous layer was extracted with 250 ml of ethyl acetate, and the mixture was allowed to stand for separation. The aqueous layer was separated and the organic layer was discarded. Slowly add 1N HCl solution, control the pH value of 7-8, stir for 30 minutes, extract with 1000ml, 250ml of ethyl acetate, let stand for layering, separate the organic phase, organic phase TLC detection shows no impurity compound 2' Spotted spots, the water layer is discarded. The organic layer was dried over anhydrous sodium sulfate, filtered and filtered, and evaporated to dryness

Method B: 100 mg of dichloromethane was added to a 1000 ml reaction flask, 100.0 g (0.259 mol) of compound 1 was added, stirred, and the reaction temperature was maintained at 0 to 5 ° C, and potassium hydroxide solution (30.57 g (0.545 mol) of hydroxide was added dropwise. Potassium - 300 ml of water), controlling the dropping rate to maintain the temperature of the reaction solution at 0-5 ° C, about 3 hours, and the end of the dropwise addition, keeping the reaction temperature at 0 to 5 ° C for 4 hours, TLC detection showed complete conversion of compound 1. 250 ml of water and 500 ml of ethyl acetate were added to the reaction mixture, and the mixture was stirred for 10 to 15 minutes, and the mixture was allowed to stand for separation. The aqueous layer was extracted with 250 ml of ethyl acetate, and the mixture was allowed to stand for separation. The aqueous layer was separated and the organic layer was discarded. Slowly add 1N sulfuric acid solution, control the pH value of 8-9, stir for 30 minutes, extract with 1000ml, 250ml of ethyl acetate, let stand layering, separate the organic phase, organic phase TLC detection shows no impurity compound 2' Spotted spots, the water layer is discarded. The organic layer was dried over anhydrous sodium sulfate, filtered and filtered, and evaporated to dryness

2. Preparation of Compound 4

Method A: 100 ml of dichloromethane, and 20 g (60.7 mmol) of compound 2 and 0.1 ml of DMF were added to a 500 ml reaction flask, and an oxalyl chloride-methylene chloride solution (11.5 g (91.1 mmol) of oxalyl chloride - 50 ml) was added dropwise with stirring. Dichloromethane), the dropping rate was controlled to maintain the temperature of the reaction solution at 0 to 5 ° C, and the dropwise addition was completed, and the reaction was carried out at room temperature of 15 to 20 ° C for 6 hours. After completion of the reaction, the reaction mixture was evaporated to dryness mjjjjjjjj

To another 500 ml reaction flask, 180 ml of dichloromethane, 2.2 g (91.4 mmol) of magnesium and 0.1 g of iodine were added, and the mixture was heated under nitrogen, stirred and heated to a temperature of 30 to 40 ° C, and 16 g (91.4 mmol) of p-fluorobromobenzene was added dropwise. The drip acceleration is controlled to maintain the reaction temperature of 20 to 25 ° C, and after the completion of the dropwise addition, the reaction is kept at 20 to 25 ° C for 1 hour until the magnesium disappears. The mixture was cooled to 0 to 5 ° C, and 25 g of zinc chloride was added thereto, and the mixture was kept at 0 to 5 ° C for 3 hours; 0.1 g of bistriphenylphosphine palladium dichloride was added, and the mixture was stirred for 30 minutes, and the above-mentioned acid chloride ether was added dropwise to the reaction liquid. The solution was incubated at 0 to 5 ° C for 2 hours after the completion of the dropwise addition. The reaction was completed, suction filtration, the filter cake was washed with dichloromethane, the filter cake was discarded, the filtrate was combined, dried over anhydrous sodium sulfate and activated charcoal, filtered, filtered, and concentrated to dryness to dryness to dryness. It was refined in an alcohol and dried in vacuo to give 15.6 g of an off-white solid, yield: 62%.

Method B: 100 ml of tetrahydrofuran, and 20 g (60.7 mmol) of compound 2 and 0.1 ml of DMF were added to a 500 ml reaction flask, and an oxalyl chloride-tetrahydrofuran solution (11.5 g (91.1 mmol) of oxalyl chloride - 50 ml of tetrahydrofuran) was added dropwise with stirring. The dropping rate was maintained at 0 to 5 ° C to maintain the temperature of the reaction solution, and the reaction was continued at room temperature for 15 hours at 15 to 20 ° C for 6 hours. After completion of the reaction, the reaction mixture was concentrated to dryness to dryness crystals.

To another 500ml reaction flask, 180ml of tetrahydrofuran, 2.2g (91.4mmol) of magnesium and 0.1g of iodine were added, protected by nitrogen, heated to a temperature of 30-40 ° C under stirring, and 16 g (91.4 mmol) of p-fluorobromobenzene was added dropwise. The dropping rate was maintained at a reaction temperature of 20 to 25 ° C, and after the completion of the dropwise addition, the reaction was kept at 20 to 25 ° C for 1 hour until the magnesium disappeared. The mixture was cooled to 0 to 5 ° C, and 25 g of zinc chloride was added thereto, and the mixture was kept at 0 to 5 ° C for 3 hours; 0.1 g of bistriphenylphosphine palladium dichloride was added thereto, and the mixture was stirred for 30 minutes, and the above-mentioned acid chloride tetrahydrofuran was added dropwise to the reaction liquid. The solution was incubated at 0 to 5 ° C for 2 hours after the completion of the dropwise addition. The reaction was completed, suction filtration, the filter cake was washed with tetrahydrofuran, the filter cake was discarded, the filtrate was combined, dried over anhydrous sodium sulfate and activated carbon, suction filtered, and the mother liquid was concentrated under reduced pressure to dryness to oil. It was purified and dried in vacuo to give 17.1 g of an off-white solid, yield: 68%.

Method C: 100 ml of dichloromethane, and 20 g (60.7 mmol) of compound 2 and 0.1 ml of DMF were added to a 500 ml reaction flask, and an oxalyl chloride-methylene chloride solution (11.5 g (91.1 mmol) of oxalyl chloride - 50 ml) was added dropwise with stirring. Dichloromethane), the dropping rate was controlled to maintain the temperature of the reaction solution at 0 to 5 ° C, and the dropwise addition was completed, and the reaction was carried out at room temperature of 15 to 20 ° C for 6 hours. After completion of the reaction, the reaction mixture was evaporated to dryness mjjjjjjjj

To another 500 ml reaction flask, 180 ml of dichloromethane, 2.2 g (91.4 mmol) of magnesium and 0.1 g of iodine were added, and the mixture was heated under nitrogen, stirred and heated to a temperature of 30 to 40 ° C, and 16 g (91.4 mmol) of p-fluorobromobenzene was added dropwise. The drip acceleration is controlled to maintain the reaction temperature of 20 to 25 ° C, and after the completion of the dropwise addition, the reaction is kept at 20 to 25 ° C for 1 hour until the magnesium disappears. Stirring to 0 to 5 ° C, stirring 25 g of zinc chloride, maintaining 0 to 5 ° C for 3 hours; adding 1 g of tetrakistriphenylphosphine palladium, stirring for 30 minutes, adding the above-mentioned acid chloride ether solution to the reaction solution, adding dropwise After the completion, the temperature was kept at 0 to 5 ° C for 2 hours. After completion of the reaction, the mixture was filtered with suction, and the filter cake was washed with methylene chloride. The filter cake was discarded, and the filtrate was combined, dried over anhydrous sodium sulfate, filtered, filtered and evaporated to dryness. It was purified and dried in vacuo to give 12.6 g of an off-white solid, yield: 50%, and palladium.

3. Preparation of Compound 5

Method A: 100 ml of dichloromethane, 10.0 g (24.5 mmol) of compound 4, 0.05 g of trifluoroacetic anhydride were added to a 500 ml reaction flask, protected with nitrogen, cooled to -20 to -25 ° C, and added to 6.6 ml (R-Methyl). CBS) toluene solution (6.8 g (R-Methyl CBS) - 35 ml toluene). 4 ml of borane dimethyl sulfide was added dropwise to the reaction solution, and the dropping rate was controlled to keep the temperature of the reaction solution at -20 to -25 ° C. After the completion of the dropwise addition, the reaction was carried out at -20 to -25 ° C for 3 hours, and TLC detection showed that the reaction liquid was in the reaction liquid. Compound 4 was completely reacted. After completion of the reaction, 15 ml of ethanol was added dropwise to the reaction mixture, and the dropping rate was controlled to keep the temperature of the reaction solution at -20 to -25 ° C, and the temperature was raised to 0 to 5 ° C for 1 hour. 18 ml of 1 N HCl solution was continuously added dropwise, and the mixture was stirred at a temperature of 5 to 10 ° C for 1 hour. The reaction mixture was extracted with ethyl acetate (60 ml), EtOAc (EtOAc m. The solid was dried to dryness in vacuo to give a white solid, 9 g, yield: 90%.

Method B: Add 100 ml of tetrahydrofuran, 10.0 g (24.5 mmol) of compound 4, 0.05 g of trifluoroacetic anhydride to a 500 ml reaction flask, protect with nitrogen, cool to -20 to -25 ° C with stirring, and add 6.6 ml (R-Methyl CBS). Toluene solution (6.8 g (R-Methyl CBS) - 35 ml toluene). 4 ml of borane dimethyl sulfide was added dropwise to the reaction solution, and the dropping rate was controlled to keep the temperature of the reaction solution at -20 to -25 ° C. After the completion of the dropwise addition, the reaction was carried out at -20 to -25 ° C for 3 hours, and TLC detection showed that the reaction liquid was in the reaction liquid. Compound 4 was completely reacted. After completion of the reaction, 15 ml of ethanol was added dropwise to the reaction mixture, and the dropping rate was controlled to keep the temperature of the reaction solution at -20 to -25 ° C, and the temperature was raised to 0 to 5 ° C for 1 hour. 18 ml of 1 N HCl solution was continuously added dropwise, and the mixture was stirred at a temperature of 5 to 10 ° C for 1 hour. The reaction mixture was extracted with ethyl acetate (60 ml), EtOAc (EtOAc m. The solid was dried to dryness in vacuo to give 8.8 g of white solid.

Method C: Add 100 ml of toluene, 10.0 g (24.5 mmol) of compound 4, 0.05 g of trifluoroacetic anhydride to a 500 ml reaction flask, protect with nitrogen, cool to -20 to -25 ° C with stirring, and add 6.6 ml (R-Methyl CBS). Toluene solution (6.8 g (R-Methyl CBS) - 35 ml toluene). 4 ml of borane dimethyl sulfide was added dropwise to the reaction solution, and the dropping rate was controlled to keep the temperature of the reaction solution at -20 to -25 ° C. After the completion of the dropwise addition, the reaction was carried out at -20 to -25 ° C for 3 hours, and TLC detection showed that the reaction liquid was in the reaction liquid. Compound 4 was completely reacted. After completion of the reaction, 15 ml of ethanol was added dropwise to the reaction mixture, and the dropping rate was controlled to keep the temperature of the reaction solution at -20 to -25 ° C, and the temperature was raised to 0 to 5 ° C for 1 hour. 18 ml of 1 N HCl solution was continuously added dropwise, and the mixture was stirred at a temperature of 5 to 10 ° C for 1 hour. The reaction mixture was extracted with ethyl acetate (60 ml), EtOAc (EtOAc m. The solid was dried to dryness in vacuo to give a white solid, 7 g, yield: 70%.

Claims

A method for preparing a compound 2, which is characterized in that the basic difference of the compound 2 and 2' (lactam ring-opening impurities) is utilized, and the product compound 2 is purified by accurately controlling the pH of the mother liquid to make the impurity compound 2' salt. Form residual mother liquor.
The method for preparing the compound 2 according to claim 1, wherein the selected base is a mixture of one or more of an inorganic base, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate. Most preferred is sodium hydroxide.
A process for the preparation of a compound 2 according to claim 1, characterized in that the pH of the mother liquor is controlled to be from 7 to 10, most preferably to a pH of from 7 to 8.
A method for preparing compound 4, which is characterized in that first, compound 2 is acylated with thionyl chloride or oxalyl chloride under a catalytic amount of DMF to obtain compound 3, and then compound 3 is present in zinc chloride and a catalyst. Coupling with p-fluorophenyl magnesium bromide in an inert solvent to give compound 4.
The process for producing a compound 4 according to claim 4, wherein the compound 3 is subjected to a direct coupling reaction without isolation.
The process for producing a compound 4 according to claim 4, wherein the acylating agent selected for the preparation of the compound 3 is thionyl chloride or oxalyl chloride, preferably oxalyl chloride.
The process for producing a compound 4 according to claim 4, wherein the compound 3 is prepared at an acylation temperature of 0 to 50 ° C, preferably 0 to 5 ° C.
The method for preparing the compound 4 according to claim 4, wherein the solvent 3 is prepared by using an inert solvent such as dichloromethane, chloroform, tetrahydrofuran, diethyl ether, acetonitrile, ethyl acetate, toluene, xylene and a mixture thereof, preferably. Tetrahydrofuran.
The method for preparing compound 4 according to claim 4, wherein the catalyst selected for the preparation of compound 4 is palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium dichloride, preferably double. Triphenylphosphine palladium dichloride.
The process for the preparation of the compound 4 according to claim 4, wherein the catalyst selected for the preparation of the compound 4 is bistriphenylphosphinepalladium dichloride, and the amount of the catalyst is from 0.5% to 2% by weight based on the compound 2.
The method for preparing the compound 4 according to claim 4, wherein the solvent 4 is prepared by using an inert solvent such as dichloromethane, chloroform, tetrahydrofuran, diethyl ether, acetonitrile, ethyl acetate, toluene, xylene and a mixture thereof, preferably Tetrahydrofuran.
The method for producing a compound 4 according to claim 4, wherein a trace amount of residual palladium is removed when the compound 4 is prepared, and adsorption may be carried out by using activated carbon, silica gel or aluminum trichloride, preferably activated carbon.
A process for preparing compound 5 ezetimibe, which is mainly characterized in that compound 4 and a reducing agent borane dimethyl sulfide are asymmetric with respect to a carbonyl group in compound 4 in the presence of a catalytic amount of trifluoroacetic anhydride in an inert solvent. The high-purity compound ezetimibe is obtained by reduction and high selectivity.
The method according to claim 12, wherein ezetimibe is prepared, wherein the reaction solvent is one or a mixture of tetrahydrofuran, dichloroethane, chloroform, dichloromethane, toluene or xylene, preferably dichloro Methane or tetrahydrofuran.