CN107488164B - Ezetimibe intermediate compound - Google Patents
Ezetimibe intermediate compound Download PDFInfo
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- CN107488164B CN107488164B CN201610405336.5A CN201610405336A CN107488164B CN 107488164 B CN107488164 B CN 107488164B CN 201610405336 A CN201610405336 A CN 201610405336A CN 107488164 B CN107488164 B CN 107488164B
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- C07—ORGANIC CHEMISTRY
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- C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
- C07D339/02—Five-membered rings
- C07D339/06—Five-membered rings having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
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Abstract
The invention provides a novel ezetimibe intermediate and a preparation method thereof. The method comprises the following steps: 4- (4-fluoro-benzoyl) -butyric acid is converted to 4- [2- (4-fluoro-phenyl) - [1,3] dithiolan-2-yl ] -butyric acid by means of an unseparated intermediate compound. The method is simple, cheap and efficient, and in order to better protect functional groups, the method uses the protective groups which can be selectively removed, so that the generated impurities are few, the purity is high and the yield is high.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to an ezetimibe intermediate compound.
Background
Ezetimibe is the first selective cholesterol absorption inhibitor that interferes with both the absorption of food-derived cholesterol and cholesterol synthesized by the liver in the hepatic-intestinal circulation, without affecting the absorption of other nutritional components. The pharmacology of the compound only acts on the small intestine, and the cholesterol in the intestinal tract is reduced to be transported to the liver by inhibiting the absorption of the cholesterol, so that the storage of the cholesterol is reduced; can enhance the removal of cholesterol from the blood, thereby lowering the plasma cholesterol level. It can be used in combination with statins to reduce the frequency of high-dose statin drugs, with a potency 8 times that of the cholesterol-lowering effect of statin alone.
Patent US5767115 provides a route for synthesizing ezetimibe, which uses (4-benzyloxy-benzylidene) - (4-fluorophenyl) -amine and 4-chloroformyl methyl butyrate as raw materials, hydrolyzes the obtained product to prepare acyl chloride, reacts with p-fluorophenyl zinc chloride under the condition of using palladium tetratriphenylphosphine as a catalyst, and finally carries out chiral reduction and catalytic hydrogenation to obtain ezetimibe.
Patent WO2007072088 provides another synthetic route to ezetimibe, the specific synthetic route is as follows:
in patent WO2007072088, hydroxyl on chiral carbon on a 3-position branched chain in an ezetimibe synthetic route is obtained by chiral reduction of carbonyl, before the achiral reduction, the carbonyl is protected by ethylene glycol so as to destroy the carbonyl during other chemical reactions, the obtained intermediate compounds IV and VI are relatively fine solid substances and are relatively difficult to crystallize during post-treatment, impurities are easily separated out during the crystallization process due to relatively fine granularity, a small part of products flow out along with filtrate in the filtration process, the quality of the products is poor, the subsequent reactions are relatively difficult to complete, the yield is low, and the production cost is increased.
Patent WO200810175806 provides another synthetic route for ezetimibe, and the specific synthetic route is shown in the following formula:
reacting the compound I with substituted 1, 3-propanediol to generate a compound II; reacting the compound II with pivaloyl chloride to generate a compound III, and then reacting the compound III with the compound A to generate a compound IV; reacting the compound IV with a compound V under the condition of a titanium compound catalyst to generate a compound VI; the compound VI is cyclized to generate a compound VII with beta-lactam; hydrolyzing the compound VII to obtain a compound VIII; the compound VIII is reduced into a compound IX ezetimibe by a borane chiral reducing agent.
The compound I reacts with the substituted 1, 3-propanediol to generate a compound II, a six-membered heterocycle is generated, and the six-membered heterocycle is relatively stable and difficult to damage, so that the reaction is incomplete, impurities are large, the yield is low, the production cost is increased, and the industrialized mass production is not facilitated.
The synthetic methods of ezetimibe have problems, such as low yield, large impurities, high technical requirements and increased production cost, and are not suitable for industrial mass production.
Disclosure of Invention
The invention aims to provide an intermediate for synthesizing ezetimibe and a synthesis method of the intermediate.
It is another object of the present invention to provide a novel route for the synthesis of ezetimibe using the above intermediates. The route is simple, cheap and efficient, and in order to better protect functional groups, the route uses protective groups which can be selectively removed.
An intermediate compound for synthesizing ezetimibe is shown as a formula IV, and the structural formula is as follows:
a preparation method of an intermediate IV comprises the following steps: 4- (4-fluoro-benzoyl) -butyric acid II is converted by means of the unseparated intermediate compound III into 4- [2- (4-fluoro-phenyl) - [1,3] dithiolan-2-yl ] -butyric acid IV,
the preparation method of the intermediate IV specifically comprises the following steps: reacting 4- (4-fluoro-benzoyl) -butyric acid (II) with ethanedithiol at 20-25 ℃ in an organic solvent A in the presence of a Lewis acid and a water-binding auxiliary material; adding sodium bicarbonate to terminate the reaction; the solvent was changed to methanol and compound (iii) was hydrolyzed with a base a solution; concentrating, acidifying with tartaric acid, extracting with organic solvent B, and separating the 4- [2- (4-fluoro-phenyl) - [1,3] dithiolane-2-yl ] -butyric acid (IV).
The organic solvent A is selected from one or more of aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, alkanes, ethers, amides, glycol derivatives, ester solvents and phenol; preferably, the organic solvent A is selected from one or more of benzene, toluene, cyclohexane, methanol, ethanol, tert-butanol, dichloromethane, diethyl ether, acetone, trichloroethylene, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate and DMF; further preferred is tetrahydrofuran, or dichloromethane, or a mixed solvent of the two; most preferably a mixed solvent of tetrahydrofuran and dichloromethane in a ratio of 1: 3.
The Lewis acid is selected from ZnCl2/HCl、NH3、H2O、CO2、CH3One of OH, halide, hydroxide, alkoxide, alkene and hydride; preferably ZnCl2/HCl。
The base A is preferably an inorganic base selected from one of potassium hydroxide, sodium hydroxide, lithium hydroxide and cesium hydroxide, most preferably potassium hydroxide; the concentration of the inorganic base is preferably 10 to 30%.
A method for synthesizing ezetimibe from an intermediate IV comprises the following steps:
step 1:
conversion of 4- (4-fluoro-benzoyl) -butyric acid (II) to 4- [2- (4-fluoro-phenyl) - [1,3] dithiolan-2-yl ] -butyric acid (IV) by means of the unseparated intermediate compound (III)
Step 2:
acylation of chiral oxazolidinones (V) with 4- [2- (4-fluoro-phenyl) - [1,3] dithiolan-2-yl ] -butyric acid (IV) to give oxazolidinone derivatives (VI)
And step 3:
the following acylated oxazolidinones (VI) are reacted with imines (VII) to isolate the compounds of formula (VIII)
And 4, step 4:
protected azetidinone (IX) obtained by cyclization of a compound of formula (VIII)
And 5:
obtaining a compound of formula (X) by hydrolysis of the ketal group of a compound of formula (IX)
The above steps are described in detail in the following sections:
step 1:
in an organic solvent A, in the presence of Lewis acid and water combined auxiliary materials, 4- (4-fluoro-benzoyl) -butyric acid (II) reacts with ethanedithiol at a certain temperature, and an alkaline reagent is added to terminate the reaction; the temperature is preferably 20-25 ℃, most preferably 20 ℃; the alkaline reagent is one of sodium carbonate, sodium acetate, sodium phosphate or sodium bicarbonate, and sodium bicarbonate is preferred.
The solvent was changed to methanol and compound (iii) was hydrolyzed with a base a solution. Concentrating, acidifying with tartaric acid, extracting with organic solvent B, and separating the 4- [2- (4-fluoro-phenyl) - [1,3] dithiolane-2-yl ] -butyric acid (IV).
The organic solvent A in the step 1 is selected from one or more of aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, alkanes, ethers, amides, glycol derivatives, ester solvents and phenol; more preferably one or more of benzene, toluene, cyclohexane, methanol, ethanol, tert-butanol, dichloromethane, diethyl ether, acetone, trichloroethylene, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate and DMF; further preferred is tetrahydrofuran, or dichloromethane, or a mixed solvent of the two; most preferably a mixed solvent of tetrahydrofuran and dichloromethane in a ratio of 1: 3.
The Lewis acid is selected from ZnCl2/HCl、NH3、H2O、CO2、CH3One of OH, halide, hydroxide, alkoxide, alkene and hydride; preferably ZnCl2/HCl。
The base A is preferably an inorganic base selected from one of potassium hydroxide, sodium hydroxide, lithium hydroxide and cesium hydroxide, most preferably potassium hydroxide; the concentration of the inorganic base is preferably 10 to 30%.
The organic solvent B is selected from ethyl acetate and alkanes; further, one selected from ethyl acetate, dichloromethane, n-hexane, heptane and n-butane is preferable.
Step 2:
4- [2- (4-fluoro-phenyl) - [1,3] dithiolan-2-yl ] -butyric acid (IV) is converted into a mixed anhydride using pivaloyl chloride in an organic solvent A in the presence of triethylamine at-10 ℃. Adding lithium chloride, adding 4-phenyl-2-oxazolidinone, stirring the reaction liquid for 5-7 hours, and extracting and crystallizing to obtain an intermediate VI.
The organic solvent A in the step 2 is selected from one of aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, alkanes, ethers, amides, glycol derivatives, ester solvents and phenol; more preferably one of benzene, toluene, cyclohexane, methanol, ethanol, t-butanol, dichloromethane, diethyl ether, acetone, trichloroethylene, tetrahydrofuran, methyl t-butyl ether, ethyl acetate and DMF; tetrahydrofuran is most preferred.
And step 3:
reacting a compound VI with a compound VII in an organic solvent A, controlling the temperature to be 30 ℃ below zero, adding titanium tetrachloride and diisopropylethylamine, reacting for 2 hours, adding isopropanol to quench the reaction, extracting and separating a product (VIII), distilling, and stirring and refining methanol.
Step 3, the organic solvent A is selected from one of aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, alkanes, ethers, amides, glycol derivatives, ester solvents and phenol; more preferably one of benzene, toluene, cyclohexane, methanol, ethanol, t-butanol, dichloromethane, diethyl ether, acetone, trichloroethylene, tetrahydrofuran, methyl t-butyl ether, ethyl acetate and DMF; most preferred is dichloromethane.
And 4, step 4:
and (3) silanizing the product (VIII) obtained in the step (3) by using a silanizing agent bis (trimethyl-silyl) -acetamide in acetonitrile at the temperature of 25 ℃ for 1-3 hours, adding tetrabutylammonium-fluoride-trihydrate into the reaction liquid by a catalytic amount, stirring for 2 hours, adding water to quench the reaction, adding an organic solvent B to extract, and concentrating an organic phase to obtain a compound IX.
The acetonitrile in step 4 can also be methanol or ethanol.
Step 4, the organic solvent B is selected from ethyl acetate and alkanes; further, one selected from ethyl acetate, dichloromethane, n-hexane, heptane and n-butane is preferable, and n-hexane is most preferable.
And 5:
dissolving the product compound IX in the step 4 in an organic solvent A, controlling the temperature to be below 0 ℃, adding pyridinium p-toluenesulfonate, carrying out heat preservation reaction for 8 hours, concentrating and evaporating the solvent after the reaction is finished, adding a mixture of ethanol and water, controlling the temperature to be 0 ℃, stirring, crystallizing, filtering and drying to obtain a product X.
The organic solvent A in the step 5 is selected from one of aromatic hydrocarbon, aliphatic hydrocarbon, alicyclic hydrocarbon, halogenated hydrocarbon, alcohol, alkane, ether, amide, glycol derivative, ester solvent and phenol; more preferably one of benzene, toluene, cyclohexane, methanol, ethanol, t-butanol, dichloromethane, diethyl ether, acetone, trichloroethylene, tetrahydrofuran, methyl t-butyl ether, ethyl acetate and DMF; tetrahydrofuran is most preferred.
The invention has the advantages that:
the ethanedithiol can protect carbonyl with large steric hindrance, the reaction condition is mild, and the risk of operators is reduced by using Lewis acid to replace concentrated sulfuric acid; and the ethanedithiol is easy to be completely deprotected, and has the advantages of less generated impurities, high purity and high yield.
In a word, the method is efficient, economical and simple in production operation, and completely meets the requirement of industrial mass production.
Detailed Description
The present invention will be further explained with reference to specific examples, which are not intended to limit the invention itself in any manner.
Example one
Step 1:
180ml of tetrahydrofuran and dichloromethane mixed solvent (the ratio of the tetrahydrofuran to the dichloromethane is 1:3) is weighed and added into a 500ml round-bottom flask, and 0.8g of ZnCl is added2And 2ml of HCl, 32ml of trimethylorthoformate are added and 4- (4-fluoro-benzoyl) -butyric acid (II) is reacted with ethanedithiol at 20 ℃ for 4 hours. 5g of sodium hydrogencarbonate was added to terminate the reaction. The solvent was evaporated off, the residue was dissolved in 150ml of methanol and placed in an ice-water bath to coolWhile cooling, 100ml of 10% potassium hydroxide solution was added, and the mixture was stirred for 30 minutes while controlling the temperature at 25 ℃. Concentrating, adding 300ml of 10% tartaric acid solution to enable the pH value to reach 3-4, extracting twice by using 200ml of ethyl acetate and 100ml of ethyl acetate, washing an organic phase to be neutral by using water, drying by using anhydrous sodium sulfate, filtering, evaporating to dryness, and recrystallizing by using n-hexane to obtain 4- [2- (4-fluoro-phenyl) - [1,3] n-hexane]Dithiolan-2-yl]-butyryl-4-phenyl-oxazolidin-2-one (IV). The yield thereof was found to be 94.6%.
Step 2:
adding 38g of 4- [2- (4-fluoro-phenyl) - [1,3] dithiolane-2-yl ] -butyric acid (IV) in an anhydrous oxygen-free environment, adding 300ml of tetrahydrofuran, adding 50ml of triethylamine, controlling the temperature to be-20 to-10 ℃, dropwise adding a mixture of 20ml of pivaloyl chloride and 50ml of tetrahydrofuran, and reacting for 2 hours. 6.5g of anhydrous lithium chloride is added, stirring is carried out for 2 hours, 28g of 4-phenyl-2-oxazolidone is added, the reaction liquid is stirred for 5-7 hours, and intermediate VI is obtained through extraction and crystallization, wherein the yield is 95.2%.
And step 3:
dissolving 40g of a compound VI and 60g of a compound VII in 300ml of dichloromethane, controlling the temperature to be 30 ℃ below zero, adding 3ml of titanium tetrachloride and 5g of diisopropylethylamine, reacting for 2 hours, adding 30ml of isopropanol, stirring for 30 minutes, quenching the reaction, pouring the reaction solution into 110ml of tartrate buffer solution with the pH value of 6-7, stirring for 15 minutes, carrying out phase separation, extracting with 50ml of multiplied by 3 dichloromethane, washing the combined dichloromethane phase with 100ml of water, drying with anhydrous sodium sulfate, filtering, evaporating the solvent, and recrystallizing with methanol to obtain a product (VIII), wherein the yield is 92.5%.
And 4, step 4:
adding 25g of the product (VIII) obtained in the step 3 into 450ml of acetonitrile, controlling the temperature to be 25 ℃, adding 16.8ml of a silanization agent bis (trimethyl-silyl) -acetamide, controlling the temperature to be 20-25 ℃ for silanization for 2 hours, adding 0.1g of tetrabutylammonium-fluoride-trihydrate, keeping the temperature and stirring for 2 hours, clarifying the solution, adding 500ml of water for quenching reaction, adding 500ml of n-hexane for extracting an acetonitrile phase, drying the acetonitrile phase with anhydrous sodium sulfate, filtering, and concentrating an organic phase to obtain a compound IX, wherein the yield is 93.2%.
And 5:
dissolving 20g of the product compound IX in the step 4 in 400ml of tetrahydrofuran, controlling the temperature to be below-5-0 ℃, adding 0.4g of pyridinium p-toluenesulfonate, carrying out heat preservation reaction for 8 hours, concentrating and evaporating the solvent after the reaction is finished, adding a mixture of 50ml of ethanol and 50ml of water, controlling the temperature to be 0 ℃, stirring and crystallizing, filtering and drying to obtain the product X, wherein the yield is 95.8 percent, and the purity is 99.5 percent.
Example two
Step 1:
180ml of tetrahydrofuran and dichloromethane mixed solvent (the ratio of the tetrahydrofuran to the dichloromethane is 1:3) is weighed and added into a 500ml round-bottom flask, and 0.8g of ZnCl is added2And 2ml of HCl, 32ml of trimethylorthoformate are added and 4- (4-fluoro-benzoyl) -butyric acid (II) is reacted with ethanedithiol at 20 ℃ for 4 hours. 5g of sodium hydrogencarbonate was added to terminate the reaction. The solvent was evaporated off, the residue was dissolved in 150ml of methanol and cooled in an ice-water bath, 100ml of 20% sodium hydroxide solution was added during cooling, the temperature was controlled at 25 ℃ and stirring was carried out for 30 minutes. Concentrating, adding 300ml of 10% tartaric acid solution to enable the pH value to reach 3-4, extracting twice with 200ml of dichloromethane and 100ml of dichloromethane, washing an organic phase to be neutral, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and recrystallizing with n-hexane to obtain 4- [2- (4-fluoro-phenyl) - [1,3]]Dithiolan-2-yl]-butyryl-4-phenyl-oxazolidin-2-one (IV). The yield thereof was found to be 95.5%.
Step 2:
in an anhydrous and oxygen-free environment, 36g of 4- [2- (4-fluoro-phenyl) - [1,3] dithiolane-2-yl ] -butyric acid (IV) is added, 300ml of dichloromethane is added, 50ml of triethylamine is added, the temperature is controlled between minus 20 ℃ and minus 10 ℃, a mixture of 20ml of pivaloyl chloride and 50ml of tetrahydrofuran is added dropwise, and the reaction is carried out for 2 hours. 6.4g of anhydrous lithium chloride is added, stirring is carried out for 2 hours, 27g of 4-phenyl-2-oxazolidinone is added, the reaction liquid is stirred for 5-7 hours, and intermediate VI is obtained through extraction and crystallization, wherein the yield is 96.1%.
And step 3:
dissolving 40g of a compound VI and 60g of a compound VII in 300ml of tetrahydrofuran, controlling the temperature to be 30 ℃ below zero, adding 3ml of titanium tetrachloride and 5g of diisopropylethylamine, reacting for 2 hours, adding 30ml of isopropanol, stirring for 30 minutes, quenching the reaction, pouring the reaction solution into 110ml of tartrate buffer solution with the pH value of 6-7, stirring for 15 minutes, carrying out phase separation, extracting with 50ml of multiplied by 3 dichloromethane, washing the combined dichloromethane phase with 100ml of water, drying with anhydrous sodium sulfate, filtering, evaporating the solvent, and recrystallizing with methanol to obtain a product (VIII), wherein the yield is 93.6%.
And 4, step 4:
adding 25g of the product (VIII) obtained in the step 3 into 450ml of methanol, controlling the temperature to be 25 ℃, adding 16.8ml of a silanization agent bis (trimethyl-silyl) -acetamide, controlling the temperature to be 20-25 ℃ for silanization for 2 hours, adding 0.1g of tetrabutylammonium-fluoride-trihydrate, keeping the temperature and stirring for 2 hours, clarifying the solution, adding 500ml of water for quenching reaction, adding 500ml of n-hexane for extracting an acetonitrile phase, drying the acetonitrile phase with anhydrous sodium sulfate, filtering, and concentrating an organic phase to obtain a compound IX, wherein the yield is 95.0%.
And 5:
dissolving 20g of the product compound IX in the step 4 in 400ml of tetrahydrofuran, controlling the temperature to be below-5-0 ℃, adding 0.4g of pyridinium p-toluenesulfonate, carrying out heat preservation reaction for 8 hours, concentrating and evaporating the solvent after the reaction is finished, adding a mixture of 50ml of ethanol and 50ml of water, controlling the temperature to be 0 ℃, stirring and crystallizing, filtering and drying to obtain the product X, wherein the yield is 93.8 percent, and the purity is 99.5 percent.
EXAMPLE III
Step 1:
180ml of tetrahydrofuran are weighed into a 500ml round-bottom flask, 0.8g of ZnCl is added2And 2ml of HCl, 32ml of trimethylorthoformate are added and 4- (4-fluoro-benzoyl) -butyric acid (II) is reacted with ethanedithiol at 20 ℃ for 4 hours. 5g of sodium hydrogencarbonate was added to terminate the reaction. The solvent was evaporated off, the residue was dissolved in 150ml of methanol and cooled in an ice-water bath, and 100ml of 30% lithium hydroxide solution was added during cooling, the temperature was controlled at 25 ℃ and stirring was carried out for 30 minutes. Concentrating, adding 300ml of 10% tartaric acid solution to enable the pH value to reach 3-4, extracting twice by using 200ml of n-hexane and 100ml of n-hexane, washing an organic phase to be neutral by using water, drying by using anhydrous sodium sulfate, filtering, evaporating to dryness, and recrystallizing by using n-hexane to obtain 4- [2- (4-fluoro-phenyl) - [1,3]]Dithiolan-2-yl]-butyryl-4-phenyl-oxazolidin-2-one (IV). The yield thereof was found to be 93.9%.
Step 2:
under anhydrous and anaerobic conditions, 39g of 4- [2- (4-fluoro-phenyl) - [1,3] dithiolan-2-yl ] -butyric acid (IV) was added, 300ml of dichloromethane was added, 50ml of triethylamine was added, the temperature was controlled at-20 ℃ to-10 ℃, and a mixture of 20ml of pivaloyl chloride and 50ml of tetrahydrofuran was added dropwise to react for 2 hours. 6.5g of anhydrous lithium chloride is added, stirring is carried out for 2 hours, 28g of 4-phenyl-2-oxazolidinone is added, the reaction liquid is stirred for 5-7 hours, and intermediate VI is obtained through extraction and crystallization, wherein the yield is 94.9%.
And step 3:
dissolving 40g of a compound VI and 60g of a compound VII in 300ml of DMF, controlling the temperature to be 30 ℃ below zero, adding 3ml of titanium tetrachloride and 5g of diisopropylethylamine, reacting for 2 hours, adding 30ml of isopropanol, stirring for 30 minutes, quenching the reaction, pouring the reaction solution into 110ml of tartrate buffer solution with the pH value of 6-7, stirring for 15 minutes, carrying out phase separation, extracting with 50ml of multiplied by 3 dichloromethane, washing the combined dichloromethane phase with 100ml of water, drying with anhydrous sodium sulfate, filtering, evaporating the solvent, and recrystallizing with methanol to obtain a product (VIII), wherein the yield is 95.5%.
And 4, step 4:
adding 25g of the product (VIII) obtained in the step (3) into 450ml of ethanol, controlling the temperature to be 25 ℃, adding 16.8ml of a silanization agent bis (trimethyl-silyl) -acetamide, controlling the temperature to be 20-25 ℃ for silanization for 2 hours, adding 0.1g of tetrabutylammonium-fluoride-trihydrate, preserving the temperature and stirring for 2 hours, clarifying the solution, adding 500ml of water for quenching reaction, adding 500ml of n-butane for extracting an acetonitrile phase, drying by anhydrous sodium sulfate, filtering, and concentrating an organic phase to obtain a compound IX, wherein the yield is 94.3%.
And 5:
dissolving 20g of the product compound IX in the step 4 in 400ml of DMF, controlling the temperature to be below-5-0 ℃, adding 0.4g of pyridinium p-toluenesulfonate, carrying out heat preservation reaction for 8 hours, concentrating and evaporating the solvent after the reaction is finished, adding a mixture of 50ml of ethanol and 50ml of water, controlling the temperature to be 0 ℃, stirring and crystallizing, filtering and drying to obtain the product X, wherein the yield is 93.9 percent, and the purity is 99.4 percent.
Example four
Step 1:
180ml of ethyl acetate are weighed into a 500ml round-bottom flask, 0.8g of ZnCl is added2And 2ml of HCl, 32ml of trimethylorthoformate are added and 4- (4-fluoro-benzoyl) -butyric acid (II) is reacted with ethanedithiol at 20 ℃ for 4 hours. 5g of sodium hydrogencarbonate was added to terminate the reaction. Evaporating off the solvent and removing the residueDissolving in 150ml isopropanol, cooling in ice water bath, adding 100ml 10% potassium hydroxide solution while cooling, controlling temperature at 25 deg.C, and stirring for 30 min. Concentrating, adding 200ml of 10% acetic acid solution to enable the pH value to reach 4-5, extracting twice with 200ml of cyclohexane and 100ml of cyclohexane, washing an organic phase to be neutral, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and recrystallizing with n-hexane to obtain 4- [2- (4-fluoro-phenyl) - [1,3]]Dithiolan-2-yl]-butyryl-4-phenyl-oxazolidin-2-one (IV). The yield thereof was found to be 73.0%.
Step 2:
under anhydrous and anaerobic conditions, 38g of 4- [2- (4-fluoro-phenyl) - [1,3] dithiolane-2-yl ] -butyric acid (IV) is added, 300ml of acetone and 50ml of triethylamine are added, the temperature is controlled between-20 ℃ and-10 ℃, and a mixture of 10ml of pivaloyl chloride and 50ml of tetrahydrofuran is added dropwise for reaction for 2 hours. And adding 5.5g of anhydrous lithium chloride, stirring for 2 hours, adding 28g of 4-phenyl-2-oxazolidinone, stirring the reaction liquid for 5-7 hours, and extracting and crystallizing to obtain an intermediate VI with the yield of 72.8%.
And step 3:
dissolving 40g of a compound VI and 60g of a compound VII in 300ml of ethyl acetate, controlling the temperature to be 30 ℃ below zero, adding 3ml of titanium tetrachloride and 5g of diisopropylethylamine, reacting for 2 hours, adding 20ml of isopropanol, stirring for 30 minutes, quenching the reaction, pouring the reaction solution into 110ml of tartrate buffer solution with the pH value of 6-7, stirring for 15 minutes, carrying out phase separation, extracting with 50ml of multiplied by 3 ethyl acetate, washing the combined dichloromethane phase with 100ml of water, drying with anhydrous sodium sulfate, filtering, evaporating the solvent, and recrystallizing with methanol to obtain a product (VIII) with the yield of 80.1%.
And 4, step 4:
adding 25g of the product (VIII) obtained in the step 3 into 450ml of methyl tert-butyl ether, controlling the temperature to be 25 ℃, adding 12ml of a silanization agent bis (trimethyl-silyl) -acetamide, controlling the temperature to be 20-25 ℃ for silanization for 2 hours, adding 0.1g of tetrabutylammonium-fluoride-trihydrate, preserving the temperature and stirring for 2 hours, clarifying the solution, adding 500ml of water for quenching reaction, adding 500ml of heptane for extracting an acetonitrile phase, drying the acetonitrile phase by anhydrous sodium sulfate, filtering, and concentrating an organic phase to obtain a compound IX, wherein the yield is 66.9%.
And 5:
dissolving 20g of the product compound IX in the step 4 in 400ml of heptane, controlling the temperature to be below 0-5 ℃, adding 0.3g of pyridine hydrobromide, keeping the temperature for reaction for 8 hours, concentrating and evaporating the solvent after the reaction is finished, adding 100ml of ethanol, controlling the temperature to be 0 ℃, stirring and crystallizing, filtering and drying to obtain the product X, wherein the yield is 70.1%, and the purity is 98.0%.
EXAMPLE five
Step 1:
weighing 180ml of acetone, adding the acetone into a 500ml round-bottom flask, and adding 0.5g of ZnCl2And 2ml of HCl, 25ml of trimethylorthoformate are added and 4- (4-fluoro-benzoyl) -butyric acid (II) is reacted with ethanedithiol at 20 ℃ for 4 hours. 5g of sodium hydrogencarbonate was added to terminate the reaction. The solvent was evaporated off, the residue was dissolved in 150ml of methanol and cooled in an ice-water bath, 100ml of 40% potassium hydroxide solution was added during cooling, the temperature was controlled at 25 ℃ and stirring was carried out for 30 minutes. Concentrating, adding 300ml of 10% tartaric acid solution to enable the pH value to reach 3-4, extracting twice with 200ml of cyclohexane and 100ml of cyclohexane, washing an organic phase to be neutral with water, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and recrystallizing with n-hexane to obtain 4- [2- (4-fluoro-phenyl) - [1,3] n-hexane]Dithiolan-2-yl]-butyryl-4-phenyl-oxazolidin-2-one (IV). The yield thereof was found to be 80.8%.
Step 2:
adding 36g of 4- [2- (4-fluoro-phenyl) - [1,3] dithiolane-2-yl ] -butyric acid (IV) in an anhydrous oxygen-free environment, adding 300ml of tetrahydrofuran, adding 50ml of triethylamine, controlling the temperature to be-20 ℃ to-10 ℃, dropwise adding a mixture of 20ml of pivaloyl chloride and 50ml of tetrahydrofuran, and reacting for 2 hours. Adding 6.4g of anhydrous lithium chloride, stirring for 2 hours, adding 20g of 4-phenyl-2-oxazolidinone, stirring the reaction liquid for 5-7 hours, and extracting and crystallizing to obtain an intermediate VI with the yield of 78.1%.
And step 3:
dissolving 40g of a compound VI and 40g of a compound VII in 300ml of ethyl acetate, controlling the temperature to be 30 ℃ below zero, adding 3ml of titanium tetrachloride and 5g of diisopropylethylamine, reacting for 2 hours, adding 30ml of isopropanol, stirring for 30 minutes, quenching the reaction, pouring the reaction solution into 100ml of tartrate buffer solution with the pH value of 7-8, stirring for 15 minutes, carrying out phase separation, extracting with 50ml of x 3 ethyl acetate, washing the combined dichloromethane phase with 100ml of water, drying with anhydrous sodium sulfate, filtering, evaporating the solvent, and recrystallizing with methanol to obtain a product (VIII), wherein the yield is 82.2%.
And 4, step 4:
adding 25g of the product (VIII) obtained in the step 3 into 450ml of acetonitrile, controlling the temperature to be 25 ℃, adding 16.8ml of a silanization agent bis (trimethyl-silyl) -acetamide, controlling the temperature to be 20-25 ℃ for silanization for 2 hours, adding 0.1g of tetrabutylammonium-fluoride-trihydrate, keeping the temperature and stirring for 2 hours, clarifying the solution, adding 500ml of water for quenching reaction, adding 300ml of heptane to extract an acetonitrile phase, drying the acetonitrile phase with anhydrous sodium sulfate, filtering the solution, and concentrating an organic phase to obtain a compound IX, wherein the yield is 72.4%.
And 5:
dissolving 20g of the product compound IX obtained in the step 4 in 400ml of heptane, controlling the temperature to be below-5-0 ℃, adding 0.4g of pyridinium p-toluenesulfonate, carrying out heat preservation reaction for 8 hours, concentrating and evaporating to remove the solvent after the reaction is finished, adding a mixture of 30ml of ethanol and 50ml of water, controlling the temperature to be 0 ℃, stirring and crystallizing, filtering and drying to obtain the product X, wherein the yield is 69.9%, and the purity is 96.2%.
Claims (8)
1. An intermediate compound for synthesizing ezetimibe is shown as a formula IV, and the structural formula is as follows:
2. a process for the preparation of an intermediate compound as claimed in claim 1, which process comprises the steps of: 4- (4-fluoro-benzoyl) -butyric acid II is converted by means of the unseparated intermediate compound III into 4- [2- (4-fluoro-phenyl) - [1,3] dithiolan-2-yl ] -butyric acid IV,
3. the process for the preparation of an intermediate compound according to claim 2, characterized in that the process comprises in particular the steps of: reacting 4- (4-fluoro-benzoyl) -butyric acid (II) with ethanedithiol at 20-25 ℃ in an organic solvent A in the presence of a Lewis acid and a water-binding auxiliary material; adding sodium bicarbonate to terminate the reaction; the solvent was changed to methanol and compound (iii) was hydrolyzed with a base a solution; concentrating, acidifying with tartaric acid, extracting with organic solvent B, and separating the 4- [2- (4-fluoro-phenyl) - [1,3] dithiolane-2-yl ] -butyric acid (IV).
4. The method for preparing an intermediate compound according to claim 3, wherein the organic solvent A is selected from one or more of benzene, toluene, cyclohexane, methanol, ethanol, tert-butanol, dichloromethane, diethyl ether, acetone, trichloroethylene, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate and DMF.
5. Process for the preparation of the intermediate compounds according to claim 3, characterized in that the Lewis acid is ZnCl2/HCl。
6. A process for the preparation of an intermediate compound according to claim 3, wherein the base a is selected from one of potassium hydroxide, sodium hydroxide, lithium hydroxide and cesium hydroxide.
7. A process for the preparation of an intermediate compound according to claim 3, wherein the base a is selected from potassium hydroxide.
8. The method for preparing an intermediate compound according to claim 3, wherein the organic solvent B is selected from one of ethyl acetate, dichloromethane, n-hexane, heptane, n-butane.
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