CN105622661A - Molecular sieve catalytic synthesis method of ezetimibe midbody - Google Patents

Molecular sieve catalytic synthesis method of ezetimibe midbody Download PDF

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CN105622661A
CN105622661A CN201511016734.XA CN201511016734A CN105622661A CN 105622661 A CN105622661 A CN 105622661A CN 201511016734 A CN201511016734 A CN 201511016734A CN 105622661 A CN105622661 A CN 105622661A
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zsm
molecular sieve
compound
ezetimibe
raw
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CN201511016734.XA
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CN105622661B (en
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王勇
李立忠
苏志强
昝建强
武晋
姚荷云
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山西普德药业股份有限公司
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    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J29/00Catalysts comprising molecular sieves
    • B01J29/04Catalysts comprising molecular sieves having base-exchange properties, e.g. crystalline zeolites
    • B01J29/06Crystalline aluminosilicate zeolites; Isomorphous compounds thereof
    • B01J29/40Crystalline aluminosilicate zeolites; Isomorphous compounds thereof of the pentasil type, e.g. types ZSM-5, ZSM-8 or ZSM-11, as exemplified by patent documents US3702886, GB1334243 and US3709979, respectively
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J29/00Catalysts comprising molecular sieves
    • B01J29/04Catalysts comprising molecular sieves having base-exchange properties, e.g. crystalline zeolites
    • B01J29/06Crystalline aluminosilicate zeolites; Isomorphous compounds thereof
    • B01J29/40Crystalline aluminosilicate zeolites; Isomorphous compounds thereof of the pentasil type, e.g. types ZSM-5, ZSM-8 or ZSM-11, as exemplified by patent documents US3702886, GB1334243 and US3709979, respectively
    • B01J29/42Crystalline aluminosilicate zeolites; Isomorphous compounds thereof of the pentasil type, e.g. types ZSM-5, ZSM-8 or ZSM-11, as exemplified by patent documents US3702886, GB1334243 and US3709979, respectively containing iron group metals, noble metals or copper
    • B01J29/46Iron group metals or copper
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D205/00Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06Heterocyclic 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
    • C07D205/08Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02Silicon compounds
    • C07F7/08Compounds having one or more C—Si linkages
    • C07F7/18Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804Compounds having Si-O-C linkages
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2229/00Aspects of molecular sieve catalysts not covered by B01J29/00
    • B01J2229/10After treatment, characterised by the effect to be obtained
    • B01J2229/18After treatment, characterised by the effect to be obtained to introduce other elements into or onto the molecular sieve itself
    • B01J2229/186After treatment, characterised by the effect to be obtained to introduce other elements into or onto the molecular sieve itself not in framework positions
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/584Recycling of catalysts

Abstract

The invention discloses a synthesis method of an ezetimibe midbody 3-[(2R, 5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl (amino)]][4-R1oxygroup] phenyl] methyl]-1- oxo-5-[(trimethylsilyl) oxygen] phenyl]-4-phenyl-(4S)-2-oxazolidinone.A solid H-ZSM-5 molecular sieve based catalysts and/or a Co-ZSM-5 molecular sieve based catalysts are/is adopted to replace an original titanium tetrachloride and isopropyl titanate catalyst, so that the environmental pollution and the requirement on production equipment are reduced, the separation and recovery problems of the catalyst are solved, and a foundation is laid for large-scale continuous production of ezetimibe.

Description

The molecular sieve catalytic synthetic method of a kind of Ezetimibe intermediate
Technical field
The application relates to a kind of Ezetimibe intermediate 3-[(2R, 5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl (amino)]] [4-R1Oxygen base] phenyl] methyl]-1-oxo-5-[(trimethylammonium silicon) oxygen] phenyl] preparation method of-4-phenyl-(4S)-2-oxazolidone, belong to pharmaceutical synthesis field.
Background technology
Ezetimibe sheet is a novel anticholesteremic agent of class, is a kind of selectivity cholesterol absorption inhibitor, the main external source absorption features blocking cholesterol. It suppresses the absorption of enteron aisle inner cholesterol by acting on cholesterol transport albumen. Further, Ezetimibe f hardlyes pass through cytochrome P 450 enzymes metabolism, and interaction between other drug is few, and security and tolerance are good.
Ezetimibe (Ezetimibe) is called according to ezetimibe, Zetia, jointly develops successfully by Schering Plough (Schering Plough) company and Merck (Merck) company the earliest. U.S. FDA approval listing on October 25th, 2002, commodity are called Ai ZetingAfter in Canada, Japan, European Union, China etc. all list. Commodity in China's listing benefit by name is suitable pureFormulation is tablet, specification: 10mg/ sheet, for the treatment of primary hypercholesterolemia, homozygote familial hypercholesterolemia, homozygote Sitosterolemia.
The synthesis of Ezetimibe and intermediate thereof mainly taking titanium tetrachloride and titanium isopropylate as the homogeneous catalysis methodology of organic synthesis of catalyzer, its exist cost height, environmental pollution, to the requirement height of production unit and feed moisture content, be difficult to successive reaction, catalyzer be difficult to the problems such as recovery.
Summary of the invention
An aspect according to the application, it is provided that a kind of Ezetimibe intermediate 3-[(2R, 5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl (amino)]] [4-R1Oxygen base] phenyl] methyl]-1-oxo-5-[(trimethylammonium silicon) oxygen] phenyl] preparation method of-4-phenyl-(4S)-2-oxazolidone, by adopting solid H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst to instead of original titanium tetrachloride and titanium isopropylate catalyzer, reduce environmental pollution and the requirement to production unit, solve separation and the recovery problem of catalyzer, make the large scale continuous prod of Ezetimibe become possibility.
Ezetimibe intermediate described in the application is the intermediate being produced Ezetimibe technique by following step:
The first step: condensation reaction
2nd step: ring-closure reaction
3rd step: hydrolysis reaction
4th step: recrystallization is purified
By organic dissolution to the crude product after hydrolysis reaction, carry out recrystallization purification, obtain the Ezetimibe of high purity.
The preparation method of Ezetimibe intermediate described in the application, the first step being in above-mentioned steps, it is characterised in that, by containing the raw material of compound A and compound B, with H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts, prepare described Ezetimibe intermediate;
Described compound A is (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl base]-4-phenyl-1,3-oxazolidine-2-ketone, and structural formula is such as formula shown in I:
Described compound B is 4-(4-fluorophenyl imines) methylphenol, and structural formula is such as formula shown in II:
Described Ezetimibe intermediate is 3-[(2R, 5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl (amino)]] [4-R1Oxygen base] phenyl] methyl]-1-oxo-5-[(trimethylammonium silicon) oxygen] phenyl]-4-phenyl-(4S)-2-oxazolidone, structural formula is as shown in formula III:
Wherein, R1At least one being selected from the group with structural formula shown in formula IV:
Wherein, R11, R12, R13Separately it is selected from the alkyl that carbonatoms is no more than 10.
Preferably, the R in formula IV11, R12, R13In have at least one to be methyl. Further preferably, the R in formula IV11, R12, R13It it is all methyl.
Preferably, in described H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst, the weight percentage of H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is not less than 30%. Further preferably, in described H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst, the weight percentage of H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is 50%��100%.
Preferably, the sial atomic ratio Si/Al in described H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is no more than 50.
Further preferably, the sial atomic ratio Si/Al in described H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is 25��50.
Described Co-ZSM-5 molecular sieve is obtained by ion exchange method or pickling process.
Preferably, in described Co-ZSM-5 molecular sieve, the weight percentage of cobalt element in Co-ZSM-5 molecular sieve is 0.1��5wt%. Further preferably, in described Co-ZSM-5 molecular sieve, the weight percentage of cobalt element in Co-ZSM-5 molecular sieve is 0.5��2wt%.
Preferably, the sial atomic ratio Si/Al in described Co-ZSM-5 molecular sieve is no more than 50. Further preferably, the sial atomic ratio Si/Al in described Co-ZSM-5 molecular sieve is 25��50.
The technician of this area, it is possible to according to the needs of the needs of actual production and concrete technique, select the ratio of H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst and raw material. Preferably, weight ratio 1:1��100 of compound A in H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst and raw material. Further preferred, weight ratio 1:3��30 of compound A in H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst and raw material.
Preferably, in described raw material, the mol ratio of compound A and compound B is 1:1��3. Further preferably, in described raw material, the mol ratio of compound A and compound B is 1:2��3.
Also containing organic amine, hydroxy-protecting agent and organic solvent in described raw material. The technician of this area, it is possible to according to the needs of the needs of actual production and concrete technique, select the add-on of suitable organic amine, hydroxy-protecting agent and organic solvent. Preferably, in raw material, the part by weight of organic amine and compound A is 0.2��1:1; Hydroxy-protecting agent: the molar ratio of (compound A+ compound B) is 1��2:1; The part by weight of organic solvent and compound A is 4��10:1. Further preferably, in raw material, the part by weight of organic amine and compound A is 0.5��0.8:1; Hydroxy-protecting agent: the molar ratio of (compound A+ compound B) is 1.2��1.6:1; The mass ratio of organic solvent and compound A is 5��8:1.
Preferably, at least one that described organic amine is selected from triethylamine, N, N-diisopropylethylamine, pyridine, piperidines, morpholine.
Preferably, at least one that described organic solvent is selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF), toluene.
Preferably, at least one that described hydroxy-protecting agent is selected from the compound with structural formula shown in formula V:
Wherein, R11, R12, R13Separately it is selected from the alkyl that carbonatoms is no more than 10; X is selected from least one in haloid element. Further preferably, described hydroxy-protecting agent is trimethylchlorosilane.
Preferably, the temperature of reaction of described raw material and H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts is-30 DEG C��-20 DEG C. Further preferably, the temperature of reaction of described raw material and H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts is-30 DEG C��-25 DEG C.
As one preferred embodiment, the preparation method of described Ezetimibe intermediate, at least comprises following step:
A) being dissolved in organic solvent by compound A and compound B, system temperature is down to less than-20 DEG C, adds organic amine and hydroxy-protecting agent, obtains raw material;
B), at-30 DEG C��-20 DEG C, after step a) gained raw material and H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts, acid solution termination reaction is added;
C) add the two front three silicon yl acetamide of N, O-, after extracting and concentrating, add crystallization solvent, crystallize out drying, obtain described Ezetimibe intermediate.
Preferably, step b) in the acid solution at least one that is selected from formic acid, acetic acid, hydrochloric acid, sulfuric acid, perchloric acid.
Preferably, step c) described crystallization solvent is made up of normal heptane and ethyl acetate, and the volume ratio of normal heptane and ethyl acetate is 2��3:1.
Preferably, step c) in 30��40 DEG C add N, the two front three silicon yl acetamide of O-, reflux after 1��3 hour, crystallization solvent is added in 40��50 DEG C, stirring is cooled to 10��20 DEG C of analysis after being no less than 1 hour brilliant, and gained crystal, through 40��50 DEG C of forced air dryings, can obtain described Ezetimibe intermediate.
The useful effect of the application includes but not limited to:
(1) method that the application provides, by adopting solid H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst to instead of original titanium tetrachloride and titanium isopropylate catalyzer, reduces environmental pollution and the requirement to production unit.
(2) method that the application provides, catalyzer is convenient to separation, it is possible to reclaims and uses.
(3) method that the application provides, adopts solid catalyst, makes the large scale continuous prod of Ezetimibe become possibility.
Embodiment
Below in conjunction with embodiment in detail the application is described in detail, but the application is not limited to these embodiments.
The preparation of embodiment 1H-ZSM-5 catalyzer
The preparation of CAT-1:
The ZSM-5 molecular sieve (silica alumina ratio Si/Al=25) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 2mol/L, and 80 DEG C of stirred in water bath 2 hours, carry out ion-exchange. After repeatedly exchanging three times, the solid sample that centrifugation obtains, after dry at deionized water wash 3 times, 100 DEG C, roasting 4 hours at 550 DEG C, gained H-ZSM-5 sieve sample, is designated as CAT-1.
The preparation of CAT-2:
The ZSM-5 molecular sieve (silica alumina ratio Si/Al=30) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 2mol/L, and 80 DEG C of stirred in water bath 2 hours, carry out ion-exchange. After repeatedly exchanging three times, after dry at deionized water wash 3 times, 100 DEG C, roasting 4 hours at 550 DEG C, gained H-ZSM-5 sieve sample, is designated as CAT-2.
The preparation of CAT-3:
The ZSM-5 molecular sieve (silica alumina ratio Si/Al=50) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 2mol/L, and 80 DEG C of stirred in water bath 2 hours, carry out ion-exchange. After repeatedly exchanging three times, the solid sample that centrifugation obtains, after dry at deionized water wash 3 times, 100 DEG C, roasting 4 hours at 550 DEG C, gained H-ZSM-5 sieve sample, is designated as CAT-3.
The preparation of embodiment 2Co-ZSM-5 catalyzer
The preparation (ion exchange method) of CAT-4:
The sodium form ZSM-5 molecular sieve (silica alumina ratio Si/Al=25) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 1mol/L, 80 DEG C of stirred in water bath 2 hours, repeatedly exchanges three times. The solid sample that centrifugation obtains, after dry at deionized water wash 3 times, 100 DEG C, adds in the cobalt nitrate solution that 500mL concentration is 1mol/L by gained solid sample, and 80 DEG C of stirred in water bath 2 hours, carry out ion-exchange, repeatedly exchange three times. The solid sample that centrifugation obtains, after dry at deionized water wash 3 times, 100 DEG C, roasting 4 hours at 550 DEG C, gained Co-ZSM-5 sieve sample, is designated as CAT-4.
The preparation (pickling process) of CAT-5:
The sodium form ZSM-5 molecular sieve (silica alumina ratio Si/Al=30) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 1mol/L, 80 DEG C of stirred in water bath 2 hours, repeatedly exchange three times, the solid sample that centrifugation obtains, at deionized water wash 3 times, 100 DEG C after drying, gained solid sample is adopted equi-volume impregnating, 4h is flooded in cobalt acetate solution, 16h is dried through 110 DEG C, roasting 4 hours at 550 DEG C, the weight percentage preparing cobalt element is the Co-ZSM-5 sieve sample of 0.1wt%, is designated as CAT-5.
The preparation of CAT-6:
The sodium form ZSM-5 molecular sieve (silica alumina ratio Si/Al=50) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 1mol/L, 80 DEG C of stirred in water bath 2 hours, repeatedly exchange three times, the solid sample that centrifugation obtains, at deionized water wash 3 times, 100 DEG C after drying, gained solid sample is adopted equi-volume impregnating, 4h is flooded in cobalt acetate solution, 16h is dried through 110 DEG C, roasting 4 hours at 550 DEG C, the weight percentage preparing cobalt element is the Co-ZSM-5 sieve sample of 0.5wt%, is designated as CAT-6.
The preparation of CAT-7:
The sodium form ZSM-5 molecular sieve (silica alumina ratio Si/Al=30) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 1mol/L, 80 DEG C of stirred in water bath 2 hours, repeatedly exchange three times, the solid sample that centrifugation obtains, at deionized water wash 3 times, 100 DEG C after drying, gained solid sample is adopted equi-volume impregnating, 4h is flooded in cobalt acetate solution, 16h is dried through 110 DEG C, roasting 4 hours at 550 DEG C, the weight percentage preparing cobalt element is the Co-ZSM-5 sieve sample of 2wt%, is designated as CAT-7.
The preparation of CAT-8:
The sodium form ZSM-5 molecular sieve (silica alumina ratio Si/Al=30) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 1mol/L, 80 DEG C of stirred in water bath 2 hours, repeatedly exchange three times, the solid sample that centrifugation obtains, at deionized water wash 3 times, 100 DEG C after drying, gained solid sample is adopted equi-volume impregnating, 4h is flooded in cobalt acetate solution, 16h is dried through 110 DEG C, roasting 4 hours at 550 DEG C, the weight percentage preparing cobalt element is the Co-ZSM-5 sieve sample of 5wt%, is designated as CAT-8.
Embodiment 3 is reacted
Reaction raw materials
According to the proportioning of table 1, being dissolved in organic solvent by compound A and compound B respectively, system temperature is down to-20 DEG C, adds organic amine and hydroxy-protecting agent, and the reaction raw materials obtained is as shown in table 1.
Table 1 reaction raw materials
Note*: A is compound A; B is compound B.
Tank reactor
300g reaction raw materials is added in 1L tank reactor, then according to table 2, catalyzer is joined in tank reactor. Containing cooling tube in tank reactor, cooling tube leads to into cooling fluid, the temperature in tank reactor is controlled the temperature shown in table 2, everywhere all without thermograde in reactor.
Reaction 1#��reaction 8#Reaction conditions be shown in Table 2.
Table 2
Note*: mass space velocity WHSV
Reaction
Reaction 1#��reaction 8#Under the reaction conditions of table 2 correspondence, leading in reactor by raw material, with catalyzer contact reacts, after reaction terminates, collect material in reactor, after filtering separation reclaims catalyzer, filtrate adds the acid solution in table 3 with termination reaction. Adding the two front three silicon yl acetamide of N, O-again, after extracting and concentrating, add the crystallization solvent in table 3, crystallize out, through 45 DEG C of forced air dryings, obtains described Ezetimibe intermediate.
Reclaim catalyzer reaction repeated again, until inactivation, obtain catalyst life and be shown in Table 3.
Table 3
Note*: mass space velocity WHSV
The above, it is only several embodiments of the application, not the application is done any type of restriction, although the application discloses as above with better embodiment, but and be not used to restriction the application, any those skilled in the art, in the scope not departing from technical scheme, utilize the technology contents of above-mentioned announcement to make a little variation or modify and all it is equal to equivalence case study on implementation, all belong within the scope of technical scheme.

Claims (10)

1. the preparation method of an Ezetimibe intermediate, it is characterised in that, containing the raw material of compound A and compound B, with H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts, described Ezetimibe intermediate will be prepared;
Described compound A is (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl base]-4-phenyl-1,3-oxazolidine-2-ketone, and structural formula is such as formula shown in I:
Described compound B is 4-(4-fluorophenyl imines) methylphenol, and structural formula is such as formula shown in II:
Described Ezetimibe intermediate is 3-[(2R, 5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl (amino)]] [4-R1Oxygen base] phenyl] methyl]-1-oxo-5-[(trimethylammonium silicon) oxygen] phenyl]-4-phenyl-(4S)-2-oxazolidone, structural formula is as shown in formula III:
Wherein, R1At least one being selected from the group with structural formula shown in formula IV:
Wherein, R11, R12, R13Separately it is selected from the alkyl that carbonatoms is no more than 10.
2. method according to claim 1, it is characterised in that, the R in formula IV11, R12, R13In have at least one to be methyl; Preferably, the R in formula IV11, R12, R13It it is all methyl.
3. method according to claim 1, it is characterised in that, in described H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst, the weight percentage of H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is not less than 30%;
Preferably, in described H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst, the weight percentage of H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is 50%��100%.
4. method according to claim 1, it is characterised in that, the sial atomic ratio Si/Al in described H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is no more than 50;
Preferably, the sial atomic ratio Si/Al in described H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is 25��50;
In described Co-ZSM-5 molecular sieve, the weight percentage of cobalt element in Co-ZSM-5 molecular sieve is 0.1��5wt%;
Preferably, in described Co-ZSM-5 molecular sieve, the weight percentage of cobalt element in Co-ZSM-5 molecular sieve is 0.5��2wt%.
5. method according to claim 1, it is characterised in that, in described raw material, the mol ratio of compound A and compound B is 1:1��3; Preferably, in described raw material, the mol ratio of compound A and compound B is 1:2��3.
6. method according to claim 1, it is characterised in that, containing organic amine, hydroxy-protecting agent and organic solvent in described raw material; At least one that described organic amine is selected from triethylamine, N, N-diisopropylethylamine, pyridine, piperidines, morpholine;
At least one that described organic solvent is selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF), toluene;
At least one that described hydroxy-protecting agent is selected from the compound with structural formula shown in formula V:
Wherein, R11, R12, R13Separately it is selected from the alkyl that carbonatoms is no more than 10; X is selected from least one in haloid element.
7. method according to claim 1, it is characterised in that, the temperature of reaction of described raw material and H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts is-30 DEG C��-20 DEG C; Preferably, the temperature of reaction of described raw material and H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts is-30 DEG C��-25 DEG C.
8. method according to claim 1 or 6, it is characterised in that, at least comprise following step:
A) being dissolved in organic solvent by compound A and compound B, system temperature is down to less than-20 DEG C, adds organic amine and hydroxy-protecting agent, obtains raw material;
B), at-30 DEG C��-20 DEG C, after step a) gained raw material and H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts, acid solution termination reaction is added;
C) add the two front three silicon yl acetamide of N, O-, after extracting and concentrating, add crystallization solvent, crystallize out drying, obtain described Ezetimibe intermediate.
9. method according to claim 8, it is characterised in that, step b) in the acid solution at least one that is selected from formic acid, acetic acid, hydrochloric acid, sulfuric acid, perchloric acid; Step c) described crystallization solvent is made up of normal heptane and ethyl acetate, and the volume ratio of normal heptane and ethyl acetate is 2��3:1.
10. method according to claim 8, it is characterized in that, step c) in 30��40 DEG C add N, the two front three silicon yl acetamide of O-, reflux after 1��3 hour, add crystallization solvent in 40��50 DEG C, stir and after being no less than 1 hour, be cooled to 10��20 DEG C of analysis crystalline substances, gained crystal, through 40��50 DEG C of forced air dryings, can obtain described Ezetimibe intermediate.
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