CN114621126B - Improved ezetimibe preparation method - Google Patents

Improved ezetimibe preparation method Download PDF

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CN114621126B
CN114621126B CN202011453660.7A CN202011453660A CN114621126B CN 114621126 B CN114621126 B CN 114621126B CN 202011453660 A CN202011453660 A CN 202011453660A CN 114621126 B CN114621126 B CN 114621126B
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reaction
ezetimibe
catalyst
titanium tetrachloride
triethylamine
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CN114621126A (en
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和国栋
马小艳
陈丽娟
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Chongqing Changjie Pharmaceutical Co ltd
Chongqing Shenghuaxi Pharmaceutical Co Ltd
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Chongqing Changjie Pharmaceutical Co ltd
Chongqing Shenghuaxi 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
    • B01J31/0275—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 also containing elements or functional groups covered by B01J31/0201 - B01J31/0269
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
    • B01J31/38—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of titanium, zirconium or hafnium
    • 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 Table
    • 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
    • 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 Table
    • 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
    • C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
    • 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 Table
    • 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
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
    • B01J2231/341—1,2-additions, e.g. aldol or Knoevenagel condensations
    • B01J2231/346—Mannich type reactions, i.e. nucleophilic addition of C-H acidic compounds, their R3Si- or metal complex analogues to aldimines or ketimines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Inorganic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention solves the technical problem of providing the ezetimibe preparation method which has higher yield, fewer optical isomers and can be used for industrial production. Aiming at the problems existing in ezetimibe synthesis, the invention improves the yield and purity of the intermediate a-2 and the intermediate a-4 by using a novel catalyst, and reduces the content of optical isomer impurities.

Description

Improved ezetimibe preparation method
Technical Field
The invention relates to a synthesis method of ezetimibe, belonging to the field of pharmaceutical chemistry.
Background
Ezetimibe has the structural formula:is a novel 2-azetidinone cholesterol absorption inhibitor developed by the company of Pierinobility in the 90 th century, and can inhibit the absorption of cholesterol in the intestinal tract by intestinal epithelial cells, thereby reducing the cholesterol content in blood plasma and liver. Ezetimibe has been marketed in germany for the first time in 2002 for the treatment of familial hypercholesterolemia, primary hypercholesterolemia and phytosterol, the first drug in the world that selectively inhibits cholesterol absorption. Ezetimibe is marketed in China in 2007, currently enters a medical insurance catalog of 11 provinces in China, is more and more concerned by people, and has high economic value and good market prospect.
Ezetimibe is known under the chemical name (3R, 4S) -1- (4-fluorophenyl) -3- [ (3S) -3- (4-fluorophenyl) -3-hydroxypropyl ] -4- [ 4-hydroxyphenyl ] -2-azetidinone (compound 1), and is a white crystalline powder which is readily soluble in organic solvents such as ethanol, methanol and acetone and has poor solubility in water.
The synthesis of ezetimibe is very numerous (see WO0034240, CN1131416, WO2009067960, etc.), and has a difficulty in the construction of 3 chiral centers. The current method for industrial production is to take fluorobenzene as a starting material, carry out Friedel-crafts acylation reaction with glutaric anhydride under the catalysis of aluminum trichloride to obtain 4- (4-fluorobenzoyl) butyric acid, form active anhydride with pivaloyl chloride, then carry out acylation with chiral oxazolidinone to obtain an intermediate a-1, then carry out asymmetric reduction carbonyl on CBS to obtain an intermediate a-2, protect hydroxyl groups of the intermediate a-2 and a raw material b by trimethylsilyl groups, and then carry out mannich condensation under the action of titanium tetrachloride and diisopropylethylamine to obtain the intermediate a-4. And (3) cyclizing under the catalysis of tetrabutylammonium fluoride, and hydrolyzing, removing and protecting to obtain the target product ezetimibe.
The existing problem is that the yield of the intermediate a-4 generated by the intermediate a-2 is not high, and is generally 50-60%. The reaction byproducts are mainly optical isomers, desilication group intermediates, unreacted raw materials and chiral auxiliary group removal products.
The catalyst b is mainly prepared through a large amount of experimental researches, and the catalyst and the titanium tetrachloride intermediate a-2 are utilized to generate mannich reaction of the intermediate a-4, so that the reaction has higher reaction selectivity and better yield.
Disclosure of Invention
The technical problem solved by the invention is that the prior art has several defects, and the preparation method of ezetimibe with higher yield, less optical isomer and industrial amplification is provided by synthesizing and using a new catalyst and modifying reaction parameters.
The technology of the invention is as follows:
a method for preparing ezetimibe, comprising the steps of:
raw material (4S) -3- [5- (4-fluorophenyl) -1, 5-dioxopentyl ] -4-phenyl-2-oxazolidone (a-1) is reduced into an intermediate a-2 by an asymmetric reducing agent borane dimethyl sulfide under the catalysis of D-CBS.
The titanium tetraisopropoxide and the L-benzyl tartrate are heated up to react under the high vacuum condition of 10mmHg and then react with titanium tetrachloride to prepare the catalyst b.
After the intermediate a-2 and the raw material a-3 are mixed, trimethyl chlorosilane and diisopropylethylamine are firstly used for reaction to protect hydroxyl, then a catalyst b is added, and the condensation reaction is carried out to obtain the intermediate a-4
Intermediate a-4 is reacted with BSA and triethylamine-tri-hydrofluoric acid to form ezetimibe.
The catalyst D-CBS used in step A, which is known as (R) -2-methyl-CBS-oxazolylborane, is used in an amount of 3% to 5%;
the dosage of the borane dimethyl sulfide in the step A is 1.1 to 1.4 times;
the optimal reaction temperature of the step A is 10-20 ℃;
and (3) quenching the substrate a-1 in the step A with hydrogen peroxide, wherein the consumption of the hydrogen peroxide is 3 times that of borane dimethyl sulfide.
In the step B, the optimal molar ratio of titanium tetraisopropoxide to benzyl L-tartrate to titanium tetrachloride is 1:2:1, a step of;
the vacuum degree of the reaction system in the step B is more than 10 mmHg;
in the step B, the reaction temperature is controlled to be optimal at 70-80 ℃;
the reaction time in step B is greater than 5 hours.
In the step C, the reaction solvent is chlorinated hydrocarbon, wherein the chlorinated hydrocarbon is the most optimal chloromethane;
the dosage of the catalyst b in the step C is 1.1-1.2 times of that of the substrate a-2 optimally;
in the step C, the reaction temperature is controlled to be optimally within-10 to-5 ℃;
the crystallization solvent of intermediate a-4 in step C is isopropyl ether.
The full name of BSA used in step D is N, O-bis-trimethylsilyl acetamide;
the dosage of the triethylamine trihydrofluoride salt in the step D is 0.3 times of that of the substrate a-4 optimally;
in the step D, the reaction temperature is controlled to be optimal at 40-50 ℃;
the amount of triethylamine in step D is 3 times the amount of triethylamine trihydrofluoride.
Specific examples:
5g of D-CBS catalyst is added into a reaction bottle, the mixture is cooled to 10-20 ℃, 25ml of borane dimethyl sulfide complex is added into the bottle, the temperature is controlled to 10-20 ℃, and a mixed solution of 100g of starting material a-1 and 200ml of dichloromethane is dripped into the reaction bottle (about 1.5 hours after dripping), and the reaction is monitored by a spot plate. (developing agent: n-hexane: ethyl acetate=2:1), dropwise adding 25ml of 30% hydrogen peroxide into a bottle at the temperature of 10-30 ℃ after the reaction is finished, stirring the dropwise adding hydrogen peroxide for 5-10 hours, pouring the reaction liquid into a separating funnel, adding 200ml of methylene dichloride for dilution, washing 3 times with 5% hydrochloric acid water, washing 1 time with 5% NaHCO3 water, washing 1 time with clear water, discarding the washing water, drying and suction filtering an organic layer, concentrating the filtrate at the temperature of 35-40 ℃ under reduced pressure to obtain 103g of intermediate a-2 oily substance.
28g of titanium tetraisopropoxide and 45g of dibenzyl D-tartrate are added into a 250ml three-necked flask, and the temperature is raised to 60-70 ℃. Vacuum pumping is carried out by a mechanical pump, and the reaction is carried out under reduced pressure, heat preservation and stirring for 5 hours at the pressure of 10 mmHg. And then cooling the reaction liquid to 10-15 ℃, dropwise adding 22g of titanium tetrachloride, and stirring at room temperature for 30 minutes to obtain 84g of catalyst b oily matter.
Sequentially adding raw materials of a-3.6 g, a-2 oily matter of 100g, dichloromethane of 500ml and N, N-diisopropylethylamine of 221ml into a reaction bottle, cooling to-5-10 ℃, dropwise adding trimethylchlorosilane of 108ml (dropwise adding for about 1.5 hours) for carrying out heat preservation reaction for 1 hour, dropwise adding catalyst of b 144g for carrying out heat preservation reaction for 3 hours. Pouring the reaction solution into 750ml of ice water, stirring for 10 minutes, carrying out suction filtration, washing a filter cake with 500ml of dichloromethane, pouring the filtrate into a separating funnel to separate an organic layer, discarding a water layer, washing the organic layer with water for 3 times, drying and suction-filtering the organic layer, concentrating the filtrate under reduced pressure at 40-45 ℃ to obtain a dry solid, steaming the solid with 250ml of isopropyl ether, adding 400ml of isopropyl ether, heating to 60 ℃ and boiling for half an hour, cooling to 0-10 ℃ and stirring for 3-5 hours, carrying out suction-filtering, washing a filter cake with 100ml of isopropyl ether, drying at 45 ℃ to obtain an intermediate a-4 163.5g, and obtaining the yield: 83.5%.
Sequentially adding 100g of the intermediate a-4, 750ml of toluene, 100ml of BSA, 30g of triethylamine-tricofluoride salt and 110ml of triethylamine into a reaction bottle, stirring at room temperature to dissolve, and heating to 40-45 ℃ for reaction after dissolving. About 5 hours of reaction, pour the reaction solution into a separating funnel, wash 1 time with 2% acetic acid water (acetic acid 10ml + water 500 ml), wash 1 time with 500ml of water, combine the wash layers and extract 1 time with 200ml of toluene, dry the organic layer, concentrate the dry oil at 55℃under reduced pressure. Adding 300ml of isopropanol into the oily matter, stirring and dissolving, adding 100ml of water, ice-bathing to 5-10 ℃, and using 2% H 2 SO 4 The pH value of the aqueous solution is adjusted to 3-4. About 2 hours of hydrolysis reaction, 600ml of water is added into the reaction liquid after the hydrolysis reaction, the mixture is stirred for 1 to 2 hours and filtered by suction, 55g of ezetimibe is obtained after drying at 50 ℃, and the yield is 88.9 percent and the HPLC purity is 99.7 percent.

Claims (4)

1. A method for preparing ezetimibe comprises the following synthetic route:
the method is characterized by comprising the following steps of:
A. raw material (4S) -3- [5- (4-fluorophenyl) -1, 5-dioxopentyl ] -4-phenyl-2-oxazolidone (a-1) is reduced into an intermediate a-2 by using an asymmetric reducing agent borane dimethyl sulfide under the catalysis of D-CBS, and the structural formula is as follows:
B. the titanium tetraisopropoxide and L-benzyl tartrate react at a high vacuum of 10mmHg at a temperature rise, and then react with titanium tetrachloride to prepare the catalyst b, wherein the structural formula is as follows:
C. after the intermediate a-2 and the raw material a-3 are mixed, trimethyl chlorosilane and diisopropylethylamine are firstly used for reaction to protect hydroxyl, then a catalyst b is added, and the intermediate a-4 is obtained through condensation reaction, wherein the structural formula is as follows:
D. intermediate a-4 is reacted with N, O-bis (trimethylsilyl) acetamide (BSA) and triethylamine-tricofluoric acid to produce ezetimibe.
2. The method according to claim 1, wherein in the step B, titanium tetraisopropoxide and L-benzyl tartrate are mixed and then reacted at 70-80 ℃ under the high vacuum condition of more than 10mmHg, and then reacted with titanium tetrachloride to obtain the catalyst B; titanium tetraisopropoxide and L-benzyl tartrate, wherein the molar ratio of titanium tetrachloride to titanium tetrachloride is 1:2:1.
3. the method of claim 1, wherein in step C, the raw material a-3 and the intermediate a-2 are mixed, and then trimethyl chlorosilane and diisopropylethylamine are used for reaction to protect hydroxyl groups, and then a catalyst b is added for condensation reaction to obtain the intermediate a-4.
4. The process according to claim 1, wherein in step D, intermediate a-4 is added with triethylamine trihydrofluoride salt in methylene chloride, BSA and triethylamine are cyclized to obtain ezetimibe, and the amount of triethylamine trihydrofluoride salt is 0.3 times the weight of intermediate a-4.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007030721A2 (en) * 2005-09-08 2007-03-15 Teva Pharmaceutical Industries Ltd. Processes for the preparation of (3r,4s)-4-((4-benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((s)-3-(4-fluorophenyl)-3-hydroxypropyl)-2-azetidinone, an intermediate for the synthesis of ezetimibe
WO2009067960A2 (en) * 2007-11-30 2009-06-04 Zentiva, A.S. A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates
CN103739537A (en) * 2013-12-24 2014-04-23 连云港恒运医药科技有限公司 New synthesis method of ezetimibe
CN103864708A (en) * 2012-12-12 2014-06-18 天津市医药集团技术发展有限公司 Preparation method of ezetimibe intermediate
CN104892537A (en) * 2015-05-15 2015-09-09 江西施美制药有限公司 Ezetimibe intermediate and synthesis method of ezetimibe
WO2015158191A1 (en) * 2014-04-18 2015-10-22 上海方楠生物科技有限公司 Method for stereoselectively synthesizing hypolipidemic drug ezetimibe

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007030721A2 (en) * 2005-09-08 2007-03-15 Teva Pharmaceutical Industries Ltd. Processes for the preparation of (3r,4s)-4-((4-benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((s)-3-(4-fluorophenyl)-3-hydroxypropyl)-2-azetidinone, an intermediate for the synthesis of ezetimibe
WO2009067960A2 (en) * 2007-11-30 2009-06-04 Zentiva, A.S. A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates
CN103864708A (en) * 2012-12-12 2014-06-18 天津市医药集团技术发展有限公司 Preparation method of ezetimibe intermediate
CN103739537A (en) * 2013-12-24 2014-04-23 连云港恒运医药科技有限公司 New synthesis method of ezetimibe
WO2015158191A1 (en) * 2014-04-18 2015-10-22 上海方楠生物科技有限公司 Method for stereoselectively synthesizing hypolipidemic drug ezetimibe
CN104892537A (en) * 2015-05-15 2015-09-09 江西施美制药有限公司 Ezetimibe intermediate and synthesis method of ezetimibe

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