CN110818606B - Preparation method of ezetimibe and intermediate thereof - Google Patents

Preparation method of ezetimibe and intermediate thereof Download PDF

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CN110818606B
CN110818606B CN201810894024.4A CN201810894024A CN110818606B CN 110818606 B CN110818606 B CN 110818606B CN 201810894024 A CN201810894024 A CN 201810894024A CN 110818606 B CN110818606 B CN 110818606B
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ezetimibe
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ezetimibe intermediate
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陈健
邹宝勤
应述欢
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Shanghai Xinlitai Pharmaceutical Co ltd
Shanghai Yunshengyan Neoplasm Technology Co ltd
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Shanghai Bocimed Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
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Abstract

The invention discloses a preparation method of ezetimibe and an intermediate thereof. The invention provides a preparation method of an ezetimibe intermediate IV, which comprises the following steps: in an organic solvent, under the existence of trialkyl chlorosilane, organic alkali, a chiral catalyst and lithium diisopropylamide, carrying out cyclization reaction on an ezetimibe intermediate II and an ezetimibe intermediate III to obtain an ezetimibe intermediate IV; r is methyl, ethyl or propyl. The preparation method has the advantages of short route steps, mild reaction conditions, simple post-treatment steps, avoidance of connecting chiral group substrates, high purity of the prepared product, achievement of the raw material drug standard, high yield, low production cost, high atom utilization rate and suitability for industrial production.

Description

Preparation method of ezetimibe and intermediate thereof
Technical Field
The invention relates to a preparation method of ezetimibe and an intermediate thereof.
Background
Ezetimibe (I) produced by Merchy Sharp (Merck Sharp)&Dohme, MSD) was developed and approved by the united states Food and Drug Administration (FDA) at 25/10/2002, and later approved by the japan pharmaceutical and medical instrumentation complex (PMDA) at 18/4/2007, and marketed by moesha dong under the trade name morsha
Figure BDA0001757644980000011
Figure BDA0001757644980000012
Ezetimibe is a cholesterol absorption inhibitor. It inhibits the absorption of cholesterol in the small intestine, reduces the cholesterol content in the liver cells, promotes the increase of the absorption of cholesterol in the circulation, and thus reduces the cholesterol content in the blood. Is mainly used for adjuvant diet treatment of primary hyperlipidemia, mixed hyperlipidemia, homozygous familial hypercholesterolemia and homozygous sitosterolemia (phytosterolemia).
Ezetimibe is an oral tablet containing 10mg of ezetimibe per tablet. The recommended dosage is 1 time daily, 10mg each time, with meal or empty stomach.
The ezetimibe combined with the low-strength statins can inhibit the absorption and synthesis of cholesterol at the same time, the two mechanisms are complementary and synergistic, the range of the density lipoprotein cholesterol is reduced by more than 50 percent, and a novel choice is provided for the clinical intensified lipid-lowering treatment; and the safety and the tolerance of the combined drug are equivalent to that of statin single drug treatment. For patients who fail to reach cholesterol levels or tolerate greater statin doses using statins alone, a combination therapy of ezetimibe and a medium to low dose statin may also be selected.
The published and reported synthetic method of ezetimibe under the prior art conditions is reported in patent CN99814140.2, namely ezetimibe I is obtained by coupling, cyclizing and dissociating (4S) -3- [ (5S) -5- (4-fluorophenyl) -5-hydroxypentanoyl ] -4-phenyl-1, 3-oxaziridine-2-ketone and 4- [ [ (4-fluorophenyl) imine ] methyl ] -phenol which are used as starting materials.
Figure BDA0001757644980000021
The key steps of the preparation route are coupling and ring closing, chiral groups are required to be connected with a substrate, the optical purity of a ring closing product is controlled by the chiral groups, and then the chiral groups are removed. The total yield is lower and is only 46.6%; more impurities are generated in the reaction, the product quality is difficult to control (the maximum impurity is 0.56 percent), and the impurities need to be crystallized and removed for many times; the connection and the removal of chiral groups are not embodied in drug molecules, so that the atom economy is poor; the substrate connected with the chiral group is also expensive and high in cost, and is not suitable for industrial production. Therefore, the prior art conditions need to be changed urgently, a preparation method which is simple and convenient to operate needs to be found for preparing ezetimibe, a substrate connected with a chiral group is avoided, the steps are short, and the ezetimibe meeting the raw material medicine standard is obtained in high yield.
Disclosure of Invention
The invention aims to overcome the defects of long steps, low yield, poor purity of prepared products, poor atom economy, high production cost, unsuitability for industrial production and the like of the preparation method of ezetimibe in the prior art, and provides the preparation method of the ezetimibe and the intermediate thereof. The preparation method has the advantages of short route steps, mild reaction conditions, simple post-treatment steps, avoidance of connecting chiral group substrates, high purity of the prepared product, achievement of the raw material drug standard (the purity is more than 99.5 percent, and the single impurity is less than 0.1 percent), high total yield (56-61 percent), low production cost and high atom utilization rate, and is suitable for industrial production.
The invention provides a preparation method of an ezetimibe intermediate IV, which comprises the following steps: in an organic solvent, under the existence of trialkyl chlorosilane, organic alkali, a chiral catalyst and lithium diisopropylamide, carrying out cyclization reaction on an ezetimibe intermediate II and an ezetimibe intermediate III to obtain an ezetimibe intermediate IV; r is methyl, ethyl or propyl; the trialkyl chlorosilane is trimethyl chlorosilane, triethyl chlorosilane or tripropyl chlorosilane;
Figure BDA0001757644980000031
the ezetimibe intermediate IV can be prepared by conventional methods of this type of ring closure reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
the preparation method of the ezetimibe intermediate IV is preferably carried out under the protection of protective gas, and the protective gas is preferably nitrogen and/or argon.
In the preparation method of the ezetimibe intermediate IV, the organic solvent is preferably an ether solvent; the ether solvent is preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane.
In the preparation method of the ezetimibe intermediate IV, the volume-to-mass ratio of the organic solvent to the ezetimibe intermediate II is preferably 5mL/g to 40mL/g, more preferably 10mL/g to 20mL/g, such as 10mL/g, 15mL/g or 20 mL/g.
In the preparation method of the ezetimibe intermediate IV, the organic base is preferably one or more of diisopropylethylamine, triethylamine and tri-n-butylamine.
In the preparation method of the ezetimibe intermediate IV, the molar ratio of the organic base to the ezetimibe intermediate II is preferably 1.2 to 10.0, more preferably 2.0 to 3.5, such as 3.0, 2.6, or 3.4.
In the preparation method of the ezetimibe intermediate IV, the molar ratio of the ezetimibe intermediate III to the ezetimibe intermediate II is preferably 1.0 to 3.0, and further 1.2 to 1.8, for example, 1.2, 1.5 or 1.8.
In the preparation method of the ezetimibe intermediate IV, the chiral catalyst is preferably (+) -N-benzyl- (3R,4R) -bis (diphenylphosphino) pyrrolidine
Figure BDA0001757644980000041
In the preparation method of the ezetimibe intermediate IV, the molar ratio of the chiral catalyst to the ezetimibe intermediate II is preferably 0.001 to 0.1, and further 0.005 to 0.02, for example, 0.005, 0.01 or 0.02.
In the preparation method of the ezetimibe intermediate IV, the molar ratio of the trialkylchlorosilane to the ezetimibe preparation II is preferably 1.1 to 6.0, further 1.5 to 2.5, such as 2.4, 3.1 or 2.7.
In the preparation method of ezetimibe intermediate IV, the molar ratio of lithium diisopropylamide to ezetimibe preparation II is preferably 1.1 to 6.0, further 1.0 to 2.5, for example 2.0 or 1.5.
In the preparation method of the ezetimibe intermediate IV, the temperature of the cyclization reaction is preferably-50 ℃ to 20 ℃, more preferably-20 ℃ to 10 ℃, for example-20 ℃ to-10 ℃, 10 ℃ to 0 ℃ or 0 ℃ to 10 ℃.
In the method for producing the ezetimibe intermediate IV, the cyclization reaction is preferably carried out for 1 to 10 hours, more preferably for 1 to 5 hours, for example, for 1 to 2 hours, 2 to 3 hours, or 3 to 4 hours.
The preparation method of the ezetimibe intermediate IV preferably comprises the following steps: and adding organic alkali and trialkylchlorosilane into a mixture of an organic solvent, the ezetimibe intermediate II and the ezetimibe intermediate III, then adding a chiral catalyst, then adding lithium diisopropylamide, and carrying out cyclization reaction to obtain the ezetimibe intermediate IV. The temperature of the "mixture of the organic solvent, the ezetimibe intermediate II and the ezetimibe intermediate III" is preferably-50 ℃ to 20 ℃, more preferably-20 ℃ to 10 ℃, for example-20 ℃ to-10 ℃, 10 ℃ to 0 ℃, or 0 ℃ to 10 ℃. The preferable dropping mode of the lithium diisopropylamide is dropping, and the dropping speed is subject to the condition that the temperature of the reaction system is not more than 0 ℃. After "adding the organic base and the trialkylsilane", the mixture is preferably stirred for 1 to 10 hours, more preferably for 1 to 5 hours, for example for 1 to 2 hours, 2 to 3 hours or 3 to 4 hours. After "adding lithium diisopropylamide", stirring is preferably performed for 1 to 10 hours, more preferably for 1 to 5 hours, for example, for 1 to 2 hours, 2 to 3 hours, or 3 to 4 hours.
The preparation method of the ezetimibe intermediate IV preferably adopts the following post-treatment steps: and after the reaction is finished, quenching the reaction, removing the solvent, extracting, washing and drying to obtain a crude product of the ezetimibe intermediate IV.
The quenching, solvent removal, extraction, washing, drying and concentration can be carried out by methods conventional in the art for such procedures. The quenching reaction is preferably carried out using an aqueous ammonium chloride solution. The mass concentration of the ammonium chloride aqueous solution is preferably 1% to 10%, for example, 5%, and the mass concentration refers to the mass percentage of ammonium chloride to the total mass of the ammonium chloride aqueous solution. The solvent removal is preferably carried out by vacuum concentration. The temperature of the vacuum concentration is preferably 35 to 55 ℃, for example 35 to 45 ℃. The pressure of the vacuum concentration is preferably-0.085 MPa to-0.095 MPa. The solvent used for extraction is preferably an ester solvent; the ester solvent is preferably ethyl acetate. The washing is preferably performed by using an aqueous sodium bicarbonate solution and brine in this order. The mass concentration of the sodium bicarbonate aqueous solution is preferably 5-30%, for example 10%, and the mass concentration refers to the mass percentage of sodium bicarbonate in the total mass of the sodium bicarbonate aqueous solution. The salt solution preferably has a mass concentration of 5% to 30%, for example 15%, the mass concentration being the mass percentage of sodium chloride to the total mass of the sodium chloride solution. The drying is preferably vacuum drying or desiccant drying. The drying agent is preferably anhydrous sodium sulfate. The temperature of the vacuum drying is preferably 45-55 ℃. The pressure of the vacuum drying is preferably-0.01 MPa to-0.1 MPa. The time for vacuum drying is preferably 12 to 16 hours.
And preferably recrystallizing the crude ezetimibe intermediate IV to obtain the ezetimibe intermediate IV. The recrystallization preferably adopts the following steps: and mixing the solution formed by the ezetimibe intermediate IV crude product and the organic solvent with a poor solvent, and cooling and crystallizing to obtain the ezetimibe intermediate IV. The organic solvent is preferably an ester solvent; the ester solvent is preferably ethyl acetate. The temperature of the solution of the crude ezetimibe intermediate IV and the organic solvent is preferably 60-90 ℃, for example 70-80 ℃. The cooling crystallization temperature is preferably-5 ℃ to 20 ℃, for example, 0 ℃ to 10 ℃. The cooling crystallization time is preferably 1 hour to 5 hours, for example, 1 hour to 2 hours. The poor solvent is preferably an alkane solvent; the alkane solvent is preferably n-heptane. The volume ratio of the organic solvent to the poor solvent is preferably 0.1 to 10, more preferably 0.5 to 2, for example 1.
The invention also provides a preparation method of ezetimibe I, which comprises the following steps: after the ezetimibe intermediate IV is prepared according to the preparation method, the ezetimibe intermediate IV and fluoride are subjected to nucleophilic substitution reaction in an organic solvent to obtain ezetimibe I:
Figure BDA0001757644980000061
in the preparation method of the ezetimibe I, the organic solvent is preferably an alcohol solvent; the alcohol solvent is preferably one or more of isopropanol, ethanol and n-propanol.
In the preparation method of ezetimibe I, the volume-to-mass ratio of the organic solvent to the ezetimibe intermediate IV is preferably 1mL/g to 40mL/g, more preferably 5mL/g to 10mL/g, such as 5mL/g, 7.5mL/g or 10 mL/g.
In the preparation method of ezetimibe I, the fluoride is preferably tetra-n-butylammonium fluoride, benzyltrimethylammonium fluoride (preferably benzyltrimethylammonium fluoride monohydrate), or an aqueous hydrofluoric acid solution.
In the preparation method of ezetimibe I, the molar ratio of the fluoride to the ezetimibe preparation IV is preferably 1.0 to 10.0, further 2.0 to 4.0, for example, 2.5, 3.0 or 4.0.
In the preparation method of ezetimibe I, the temperature of the nucleophilic substitution reaction is preferably-20 ℃ to 50 ℃, more preferably 0 ℃ to 30 ℃, for example, 0 ℃ to 10 ℃, 10 ℃ to 20 ℃, or 20 ℃ to 30 ℃.
In the preparation method of ezetimibe I, the progress of the nucleophilic substitution reaction can be monitored by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and generally the end point of the reaction is the time when the ezetimibe intermediate IV disappears, and the time of the nucleophilic substitution reaction is preferably 1 hour to 10 hours, more preferably 1 hour to 5 hours, such as 1 hour to 2 hours, 2 hours to 3 hours, or 3 hours to 4 hours.
The preparation method of the ezetimibe I is preferably carried out under the protection of protective gas, and the protective gas is preferably nitrogen and/or argon.
The preparation method of the ezetimibe I preferably adopts the following post-treatment steps: and after the reaction is finished, adding water, stirring, filtering, washing and drying to obtain a crude product of ezetimibe I. The stirring, filtering, washing and drying can be carried out by methods conventional in the art for such operations. The washing is preferably water washing. The drying is preferably vacuum drying. The temperature of the vacuum drying is preferably 45-55 ℃. The pressure of the vacuum drying is preferably-0.01 MPa to-0.1 MPa. The time for vacuum drying is preferably 12 to 16 hours.
The ezetimibe I crude product is preferably recrystallized to obtain ezetimibe I. The solvent used for recrystallization is preferably an alcohol solvent and/or water; the alcohol solvent is preferably isopropanol. The volume ratio of the alcohol solvent to the water is preferably 1-5, more preferably 2-4, such as 2, 3 or 4.
In the invention, the preparation method of the ezetimibe I preferably adopts the following route:
Figure BDA0001757644980000071
the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.
The positive progress effects of the invention are as follows: the preparation method has the advantages of short route steps, mild reaction conditions, simple post-treatment steps, avoidance of connecting chiral group substrates, high purity of the prepared product, achievement of the raw material drug standard (the purity is more than 99.5 percent, and the single impurity is less than 0.1 percent), high total yield (56-61 percent), low production cost and high atom utilization rate, and is suitable for industrial production.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Detailed Description
Example 1: preparation of ezetimibe intermediate IV (R ═ methyl)
Figure BDA0001757644980000081
Under nitrogen protection, 23.0g (0.102mol) of ezetimibe intermediate II (5S-5- (4-fluorophenyl) -5-hydroxypentanoic acid methyl ester) and 32.9g (0.153mol) of ezetimibe intermediate III (4- [ [ (4-fluorophenyl) imine ] methyl ] -phenol) were added to 345mL of tetrahydrofuran, cooled to-10 ℃ to 0 ℃, and then added with 39.5g (0.306mol) of diisopropylethylamine and 29.9g (0.275mol) of trimethylchlorosilane, and stirred at-10 ℃ to 0 ℃ for 2 hours to 3 hours. 0.54g (0.00102mol) of (+) -N-benzyl- (3R,4R) -bis (diphenylphosphino) pyrrolidine was added, and 102mL (0.204mol) of a 2.0mol/L lithium diisopropylamide tetrahydrofuran/ethylbenzene/heptane solution was slowly added, followed by stirring at-10 ℃ to 0 ℃ for 1 hour to 2 hours. Adding 200mL of 5% ammonium chloride aqueous solution (the mass concentration refers to the mass percentage of ammonium chloride in the total mass of the ammonium chloride aqueous solution), vacuum concentrating to remove most of organic solvent (35-45 ℃, and minus 0.085 MPa-minus 0.095MPa), extracting with 150mL of ethyl acetate for three times, combining organic phases, washing with 10% sodium bicarbonate aqueous solution (the mass concentration refers to the mass percentage of sodium bicarbonate in the total mass of the sodium bicarbonate aqueous solution) and 15% saline solution (the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution), and drying with anhydrous sodium sulfate. Filtering the mixture by a funnel filled with 100g of silica gel, washing the mixture by 200mL of ethyl acetate, carrying out vacuum concentration to remove a solvent (35-55 ℃, minus 0.085MPa to minus 0.095MPa) to obtain a crude product of the ezetimibe intermediate IV, cooling the crude product, adding 250mL of ethyl acetate, heating the crude product to 70-80 ℃, stirring the crude product for 1 hour, dropwise adding 250mL of n-heptane, slowly cooling the crude product to 0-10 ℃, stirring the crude product for 1 hour to 2 hours, filtering the crude product, washing the crude product by the n-heptane for 2 times, and carrying out vacuum drying (45-55 ℃, minus 0.01MPa to minus 0.1MPa) for 12 hours to 16 hours to obtain 44.5g of the ezetimibe intermediate IV (R is methyl), wherein the yield is 79.0 percent and the HPLC purity is 99.07.
Example 2: preparation of ezetimibe intermediate IV (R ═ ethyl)
Figure BDA0001757644980000091
To 230mL of 2-methyltetrahydrofuran, 23.0g (0.102mol) of ezetimibe intermediate II (5S-5- (4-fluorophenyl) -5-hydroxypentanoic acid methyl ester) and 26.4g (0.123mol) of ezetimibe intermediate III (4- [ [ (4-fluorophenyl) imine ] methyl ] -phenol) were added under nitrogen protection, and then the mixture was cooled to 0 ℃ to 10 ℃, 49.2g (0.265mol) of tri-n-butylamine and 36.9g (0.245mol) of triethylchlorosilane were added, and the mixture was stirred at 0 ℃ to 10 ℃ for 1 hour to 2 hours. 0.27g (0.00051mol) of (+) -N-benzyl- (3R,4R) -bis (diphenylphosphino) pyrrolidine was added, and 77mL (0.154mol) of a 2.0mol/L lithium diisopropylamide tetrahydrofuran/ethylbenzene/heptane solution was slowly added, followed by stirring at 0 ℃ to 10 ℃ for 2 hours to 3 hours. Adding 200mL of 5% ammonium chloride aqueous solution (the mass concentration refers to the mass percentage of ammonium chloride in the total mass of the ammonium chloride aqueous solution), vacuum concentrating to remove most of organic solvent (35-45 ℃, and minus 0.085 MPa-minus 0.095MPa), extracting with 150mL of ethyl acetate for three times, combining organic phases, washing with 10% sodium bicarbonate aqueous solution (the mass concentration refers to the mass percentage of sodium bicarbonate in the total mass of the sodium bicarbonate aqueous solution) and 15% saline solution (the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution), and drying with anhydrous sodium sulfate. Filtering the mixture by a funnel filled with 100g of silica gel, washing the mixture by 200mL of ethyl acetate, carrying out vacuum concentration to remove a solvent (35-55 ℃, minus 0.085MPa to minus 0.095MPa) to obtain a crude product of the ezetimibe intermediate IV, cooling the crude product, adding 250mL of ethyl acetate, heating the crude product to 70-80 ℃, stirring the crude product for 1 hour, dropwise adding 250mL of n-heptane, slowly cooling the crude product to 0-10 ℃, stirring the crude product for 1 hour to 2 hours, filtering the crude product, washing the crude product by the n-heptane for 2 times, and carrying out vacuum drying (45-55 ℃, minus 0.01MPa to minus 0.1MPa) for 12 hours to 16 hours to obtain 50.8g of the ezetimibe intermediate IV (R is ethyl), wherein the yield is 78.3% and the HPLC purity is 99.18.
Example 3: preparation of ezetimibe intermediate IV (R ═ propyl)
Figure BDA0001757644980000101
Under the protection of nitrogen, 23.0g (0.102mol) of ezetimibe intermediate II (5S-5- (4-fluorophenyl) -5-hydroxy methyl valerate) and 39.5g (0.183mol) of ezetimibe intermediate III (4- [ [ (4-fluorophenyl) imine ] methyl ] -phenol) are added into 460mL of 1, 4-dioxane, cooled to-20 ℃ to-10 ℃, 35.0g (0.346mol) of triethylamine and 60.9g (0.316mol) of tripropyl chlorosilane are added, and the mixture is stirred at-20 ℃ to-10 ℃ for 3 hours to 4 hours. 1.08g (0.00204mol) of (+) -N-benzyl- (3R,4R) -bis (diphenylphosphino) pyrrolidine was added, 102mL (0.204mol) of a 2.0mol/L lithium diisopropylamide tetrahydrofuran/ethylbenzene/heptane solution was slowly added, and the mixture was stirred at-20 ℃ to-10 ℃ for 3 to 4 hours. Adding 200mL of 5% ammonium chloride aqueous solution (the mass concentration refers to the mass percentage of ammonium chloride in the total mass of the ammonium chloride aqueous solution), vacuum concentrating to remove most of organic solvent (35-45 ℃, and minus 0.085 MPa-minus 0.095MPa), extracting with 150mL of ethyl acetate for three times, combining organic phases, washing with 10% sodium bicarbonate aqueous solution (the mass concentration refers to the mass percentage of sodium bicarbonate in the total mass of the sodium bicarbonate aqueous solution) and 15% saline solution (the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution), and drying with anhydrous sodium sulfate. Filtering the mixture by a funnel filled with 100g of silica gel, washing the mixture by 200mL of ethyl acetate, carrying out vacuum concentration to remove a solvent (35-55 ℃, minus 0.085MPa to minus 0.095MPa) to obtain a crude product of the ezetimibe intermediate IV, cooling the crude product, adding 250mL of ethyl acetate, heating the crude product to 70-80 ℃, stirring the crude product for 1 hour, dropwise adding 250mL of n-heptane, slowly cooling the crude product to 0-10 ℃, stirring the crude product for 1 hour to 2 hours, filtering the crude product, washing the crude product by the n-heptane for 2 times, and carrying out vacuum drying (45-55 ℃, minus 0.01MPa to minus 0.1MPa) for 12 hours to 16 hours to obtain 56.3g of the ezetimibe intermediate IV (R is propyl), wherein the yield is 76.7 percent and the HPLC purity is 98.83.
Example 4: preparation of Ezetimibe I
Figure BDA0001757644980000111
Under the protection of nitrogen, 40g (0.0722mol, HPLC purity 99.07%) of the ezetimibe intermediate IV prepared in example 1 and 47.2g (0.181mol) of tetra-n-butylammonium fluoride are added to 300mL of isopropanol, stirred at 10-20 ℃ for 2-3 hours, added with 600mL of water and stirred for 1 hour, filtered, washed with water and dried under vacuum (45-55 ℃ and-0.01 MPa-0.1 MPa) for 12-16 hours to obtain 28.7g of crude ezetimibe I, the yield is 97.0%, and the HPLC purity is 98.67%. The crude ezetimibe I product is recrystallized from isopropanol/water (volume ratio of 3:1) and vacuum dried (45-55 ℃ C., -0.01 MPa-0.1 MPa) for 12-16 hours to obtain 23.0g of ezetimibe I with yield of 80.1% (total yield 61.4%, calculated as 5S-5- (4-fluorophenyl) -5-hydroxypentanoic acid methyl ester), HPLC purity 99.86% and maximum single impurity 0.04%.
Example 5: preparation of Ezetimibe I
Figure BDA0001757644980000121
Under the protection of nitrogen, 45g (0.0705mol, the HPLC purity is 99.18%) of the ezetimibe intermediate IV (R ═ ethyl) prepared in example 2 is added into 225mL of ethanol, the mixture is cooled to 0-10 ℃, a hydrofluoric acid aqueous solution with the mass concentration of 20% (the mass concentration refers to the mass percentage of hydrogen fluoride in the total mass of the hydrofluoric acid aqueous solution) is added dropwise, the mixture is stirred for 1-2 hours at 0-10 ℃, 450mL of water is added and stirred for 1 hour, the mixture is filtered, washed with water and dried in vacuum (45-55 ℃, minus 0.01 MPa-minus 0.1MPa) for 12-16 hours, and then 27.8g of coarse ezetimibe I is obtained, the yield is 96.3%, and the HPLC purity is 98.53%. The crude ezetimibe I product is recrystallized from isopropanol/water (volume ratio 4:1) and vacuum dried (45-55 ℃ C., -0.01 MPa-0.1 MPa) for 12-16 hours to obtain 22.4g of ezetimibe I with a yield of 80.6% (total yield 60.8%, based on 5S-5- (4-fluorophenyl) -5-hydroxypentanoic acid methyl ester), an HPLC purity of 99.83% and a maximum single impurity of 0.07%.
Example 6: preparation of Ezetimibe I
Figure BDA0001757644980000122
To 500mL of n-propanol, 50g (0.0692mol, HPLC purity 98.83%) of the ezetimibe intermediate IV prepared in example 3 and 38.9g (0.208mol) of benzyltrimethylammonium fluoride monohydrate were stirred at 20 ℃ to 30 ℃ for 3 hours to 4 hours under nitrogen protection, 1000mL of water was added and stirred for 1 hour, filtered, washed with water and dried under vacuum (45 ℃ to 55 ℃, from-0.01 MPa to-0.1 MPa) for 12 hours to 16 hours to obtain 27.7g of crude ezetimibe I, yield 97.7%, HPLC purity 98.14%. The crude ezetimibe I product is recrystallized from isopropanol/water (volume ratio of 2:1) and vacuum dried (45-55 ℃ C., -0.01 MPa-0.1 MPa) for 12-16 hours to obtain 20.8g of ezetimibe I with a yield of 75.1% (total yield 56.3%, based on 5S-5- (4-fluorophenyl) -5-hydroxypentanoic acid methyl ester), HPLC purity 99.84% and maximum single impurity 0.06%.
Comparative example: preparation of Ezetimibe (method according to patent CN 99814140.2)
Figure BDA0001757644980000131
Under nitrogen protection, 36.4g (0.102mol) of (4S) -3- [ (5S) -5- (4-fluorophenyl) -5-hydroxypentanoyl ] -4-phenyl-1, 3-oxazepin-2-one and 32.9g (0.153mol) of 4- [ [ (4-fluorophenyl) imine ] methyl ] -phenol were added to 345mL of methylene chloride, cooled to-10 ℃ to 0 ℃, and then, 39.5g (0.306mol) of diisopropylethylamine and 29.9g (0.275mol) of trimethylchlorosilane were added thereto, followed by stirring at-10 ℃ to 0 ℃ for 2 hours to 3 hours. Cooling to-30 to-25 ℃, dripping 12.7mL of titanium tetrachloride, and stirring for 3 to 4 hours at-30 to-25 ℃. Slowly adding 17mL of acetic acid, heating to 0-10 ℃, adding 300mL of tartaric acid aqueous solution with the mass concentration of 7% (the mass concentration refers to the mass percentage of tartaric acid in the total mass of the tartaric acid aqueous solution), stirring, standing and layering; after the organic phase is separated out, the organic phase is washed by sodium sulfite aqueous solution with the mass concentration of 10% (the mass concentration refers to the mass percentage of the sodium sulfite to the total mass of the sodium sulfite aqueous solution) and salt water with the mass concentration of 15% (the mass concentration refers to the mass percentage of the sodium chloride to the total mass of the salt aqueous solution) in sequence, and dried by anhydrous sodium sulfate. Filtering, cooling, vacuum concentrating to remove most of solvent (35-45 deg.C, -0.05 MPa-0.085 MPa), adding 18mL of bis-trimethyl silicane acetamide, and stirring at 30-40 deg.C for 0.5-1 hr. Vacuum concentration is carried out to remove the solvent (35-45 ℃ and minus 0.05MPa to minus 0.085MPa), 250mL of ethyl acetate is added after cooling, the mixture is heated to 70-80 ℃ and stirred for 1 hour, 250mL of n-heptane is dropwise added, then the mixture is slowly cooled to 0-10 ℃ and stirred for 1 hour-2 hours, filtration is carried out, the n-heptane is washed for 2 times, and vacuum drying (45-55 ℃ and minus 0.01MPa to minus 0.1MPa) is carried out for 12 hours-16 hours to obtain 48.6g of the ezetimibe intermediate V, the yield is 66.6%, and the HPLC purity is 98.72%.
Under the protection of nitrogen, 480mL of methyl tert-butyl ether is added with 48.0g of ezetimibe intermediate V, 0.1g of tetra-n-butylammonium fluoride and 29mL of bistrimethylsilyl acetamide, stirred at 20-30 ℃ for 2-3 hours, and then 2.5mL of acetic acid is added. Vacuum concentration is carried out to remove the solvent (35-45 ℃ and minus 0.075MPa to minus 0.095MPa) and remove the solvent, thus obtaining a crude product of the ezetimibe intermediate IV, 300mL of isopropanol and 70mL of 4mol/L sulfuric acid aqueous solution are directly added, the mixture is stirred for 2 hours to 3 hours at 10-20 ℃, 600mL of water is added and stirred for 1 hour, the mixture is filtered, washed by water and dried in vacuum (45-55 ℃ and minus 0.01MPa to minus 0.1MPa) for 12 hours to 16 hours, thus obtaining 24.9g of crude product of ezetimibe I, the yield is 90.8 percent, and the HPLC purity is 98.35 percent. The crude ezetimibe I product is recrystallized from isopropanol/water and dried in vacuo (45 ℃ C. -55 ℃ C., -0.01 MPa. about. -0.1MPa) for 12 h-16 h to give 19.2g of ezetimibe I in 77.1% yield, 46.6% overall yield (based on (4S) -3- [ (5S) -5- (4-fluorophenyl) -5-hydroxypentanoyl ] -4-phenyl-1, 3-oxazepan-2-one), 99.23% HPLC purity and 0.56% maximum monohetero.

Claims (10)

1. A preparation method of an ezetimibe intermediate IV is characterized by comprising the following steps: in an organic solvent, under the existence of trialkyl chlorosilane, organic alkali, a chiral catalyst and lithium diisopropylamide, carrying out cyclization reaction on an ezetimibe intermediate II and an ezetimibe intermediate III to obtain an ezetimibe intermediate IV; r is methyl, ethyl or propyl; the trialkyl chlorosilane is trimethyl chlorosilane, triethyl chlorosilane or tripropyl chlorosilane; the chiral catalyst is (+) -N-benzyl- (3R,4R) -bis (diphenylphosphino) pyrrolidine;
Figure FDA0002941301450000011
2. a process for the preparation of ezetimibe intermediate IV according to claim 1, wherein:
in the preparation method of the ezetimibe intermediate IV, the volume-mass ratio of the organic solvent to the ezetimibe intermediate II is 5 mL/g-40 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the organic base to the ezetimibe intermediate II is 1.2-10.0;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the ezetimibe intermediate III to the ezetimibe intermediate II is 1.0-3.0;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the chiral catalyst to the ezetimibe intermediate II is 0.001-0.1;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the trialkyl chlorosilane to the ezetimibe intermediate II is 1.1-6.0;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the lithium diisopropylamide to the ezetimibe intermediate II is 1.0-6.0;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the temperature of the cyclization reaction is-50-20 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the cyclization reaction time is 1-10 hours;
and/or the presence of a gas in the gas,
the preparation method of the ezetimibe intermediate IV is carried out under the protection of protective gas.
3. A process for the preparation of ezetimibe intermediate IV according to claim 2, wherein:
in the preparation method of the ezetimibe intermediate IV, the volume-mass ratio of the organic solvent to the ezetimibe intermediate II is 10 mL/g-20 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the organic base to the ezetimibe intermediate II is 2.0-3.5;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the ezetimibe intermediate III to the ezetimibe intermediate II is 1.2-1.8;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the chiral catalyst to the ezetimibe intermediate II is 0.005-0.02;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the trialkyl chlorosilane to the ezetimibe intermediate II is 1.5-3.1;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the lithium diisopropylamide to the ezetimibe intermediate II is 1.1-2.5;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the temperature of the cyclization reaction is-20-10 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the cyclization reaction time is 1-5 hours;
and/or the presence of a gas in the gas,
when the preparation method of the ezetimibe intermediate IV is carried out under the protection of protective gas, the protective gas is nitrogen and/or argon.
4. A process for the preparation of ezetimibe intermediate IV according to claim 3, wherein:
in the preparation method of the ezetimibe intermediate IV, the volume-mass ratio of the organic solvent to the ezetimibe intermediate II is 10mL/g, 15mL/g or 20 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the organic base to the ezetimibe intermediate II is 2.6, 3.0 or 3.4;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the ezetimibe intermediate III to the ezetimibe intermediate II is 1.2, 1.5 or 1.8;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the chiral catalyst to the ezetimibe intermediate II is 0.005, 0.01 or 0.02;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the trialkylchlorosilane to the ezetimibe intermediate II is 2.4, 3.1 or 2.7;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the molar ratio of the lithium diisopropylamide to the ezetimibe intermediate II is 2.0 or 1.5;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the temperature of the cyclization reaction is-20 to-10 ℃, 10 ℃ to 0 ℃ or 0 ℃ to 10 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the cyclization reaction time is 1-2 hours, 2-3 hours or 3-4 hours.
5. A process for the preparation of ezetimibe intermediate IV according to claim 1, wherein:
in the preparation method of the ezetimibe intermediate IV, the organic solvent is an ether solvent;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe intermediate IV, the organic base is one or more of diisopropylethylamine, triethylamine and tri-n-butylamine;
and/or the presence of a gas in the gas,
the preparation method of the ezetimibe intermediate IV comprises the following steps: adding organic alkali and trialkyl chlorosilane into a mixture of an organic solvent, an ezetimibe intermediate II and an ezetimibe intermediate III, then adding a chiral catalyst, then adding lithium diisopropylamide, and carrying out cyclization reaction to obtain an ezetimibe intermediate IV;
and/or the presence of a gas in the gas,
the preparation method of the ezetimibe intermediate IV comprises the following post-treatment steps: and after the reaction is finished, quenching the reaction, removing the solvent, extracting, washing and drying to obtain a crude product of the ezetimibe intermediate IV.
6. The process for the preparation of ezetimibe intermediate IV according to claim 5, wherein:
in the preparation method of the ezetimibe intermediate IV, the ether solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane.
7. The preparation method of ezetimibe I is characterized by comprising the following steps: preparing an ezetimibe intermediate IV according to the preparation method of any one of claims 1 to 4, and then carrying out nucleophilic substitution reaction on the ezetimibe intermediate IV and fluoride in an organic solvent to obtain ezetimibe I:
Figure FDA0002941301450000051
8. a process for the preparation of ezetimibe I according to claim 7, wherein:
in the preparation method of ezetimibe I, the organic solvent is an alcohol solvent;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe I, the volume-mass ratio of the organic solvent to the ezetimibe intermediate IV is 1 mL/g-40 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of ezetimibe I, the fluoride is tetra-n-butylammonium fluoride, benzyltrimethylammonium fluoride monohydrate or hydrofluoric acid aqueous solution;
and/or the presence of a gas in the gas,
in the preparation method of ezetimibe I, the molar ratio of the fluoride to the ezetimibe intermediate IV is 1.0-10.0;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe I, the temperature of the nucleophilic substitution reaction is-20-50 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe I, the time of the nucleophilic substitution reaction is 1-10 hours;
and/or the presence of a gas in the gas,
the preparation method of the ezetimibe I is carried out under the protection of protective gas;
and/or the presence of a gas in the gas,
the preparation method of the ezetimibe I comprises the following post-treatment steps: and after the reaction is finished, adding water, stirring, filtering, washing and drying to obtain a crude product of ezetimibe I.
9. A process for the preparation of ezetimibe I according to claim 8, wherein:
in the preparation method of ezetimibe I, the alcohol solvent is one or more of isopropanol, ethanol and n-propanol;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe I, the volume-mass ratio of the organic solvent to the ezetimibe intermediate IV is 5 mL/g-10 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of ezetimibe I, the molar ratio of the fluoride to the ezetimibe intermediate IV is 2.0-4.0;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe I, the temperature of the nucleophilic substitution reaction is 0-30 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe I, the time of the nucleophilic substitution reaction is 1-5 hours;
and/or the presence of a gas in the gas,
when the preparation method of the ezetimibe I is carried out under the protection of protective gas, the protective gas is nitrogen and/or argon;
and/or the presence of a gas in the gas,
and recrystallizing the ezetimibe I crude product to obtain ezetimibe I.
10. A process for the preparation of ezetimibe I according to claim 9, wherein:
in the preparation method of ezetimibe I, the volume-to-mass ratio of the organic solvent to the ezetimibe intermediate IV is 5mL/g, 7.5mL/g or 10 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of ezetimibe I, the molar ratio of the fluoride to the ezetimibe intermediate IV is 2.5, 3.0 or 4.0;
and/or the presence of a gas in the gas,
in the preparation method of the ezetimibe I, the temperature of the nucleophilic substitution reaction is 0-10 ℃, 10-20 ℃ or 20-30 ℃;
and/or the presence of a gas in the gas,
in the preparation method of ezetimibe I, the time of the nucleophilic substitution reaction is 1 to 2 hours, 2 to 3 hours or 3 to 4 hours;
and/or the presence of a gas in the gas,
the solvent adopted by recrystallization is an alcohol solvent and/or water.
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Publication number Priority date Publication date Assignee Title
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CN1805926A (en) * 2003-05-05 2006-07-19 兰贝克赛实验室有限公司 Process for the preparation of trans-isomers of diphenylazetidinone derivatives

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