CN116283948A - Synthesis method of ezetimibe intermediate - Google Patents
Synthesis method of ezetimibe intermediate Download PDFInfo
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- CN116283948A CN116283948A CN202310163351.3A CN202310163351A CN116283948A CN 116283948 A CN116283948 A CN 116283948A CN 202310163351 A CN202310163351 A CN 202310163351A CN 116283948 A CN116283948 A CN 116283948A
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- XXSSRSVXDNUAQX-QGZVFWFLSA-N 1-(4-fluorophenyl)-5-[(4s)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]pentane-1,5-dione Chemical compound C1=CC(F)=CC=C1C(=O)CCCC(=O)N1C(=O)OC[C@@H]1C1=CC=CC=C1 XXSSRSVXDNUAQX-QGZVFWFLSA-N 0.000 title claims abstract description 20
- 238000001308 synthesis method Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 238000006243 chemical reaction Methods 0.000 claims abstract description 58
- 239000003960 organic solvent Substances 0.000 claims abstract description 21
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims abstract description 11
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims abstract description 10
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 claims abstract description 7
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 72
- 238000000034 method Methods 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 5
- DWUJDNHHQKEOPR-UHFFFAOYSA-N 2-(2-piperidin-4-ylethyl)pyridine Chemical compound C1CNCCC1CCC1=CC=CC=N1 DWUJDNHHQKEOPR-UHFFFAOYSA-N 0.000 claims description 4
- 229910015900 BF3 Inorganic materials 0.000 claims description 4
- QDMNNMIOWVJVLY-MRVPVSSYSA-N (4s)-4-phenyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@H]1C1=CC=CC=C1 QDMNNMIOWVJVLY-MRVPVSSYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 33
- 239000006227 byproduct Substances 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 125000006239 protecting group Chemical group 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 239000012074 organic phase Substances 0.000 description 36
- 239000000243 solution Substances 0.000 description 34
- 239000000203 mixture Substances 0.000 description 19
- 238000001914 filtration Methods 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 15
- 229960000815 ezetimibe Drugs 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 238000001035 drying Methods 0.000 description 14
- 238000000605 extraction Methods 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- 238000010791 quenching Methods 0.000 description 10
- 230000000171 quenching effect Effects 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 238000011010 flushing procedure Methods 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 3
- ZBQROUOOMAMCQW-UHFFFAOYSA-N 5-(4-fluorophenyl)-5-oxopentanoic acid Chemical compound OC(=O)CCCC(=O)C1=CC=C(F)C=C1 ZBQROUOOMAMCQW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- -1 ezetimibe intermediate compound Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical group C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- LIBFVQBAZPYQCJ-UHFFFAOYSA-N 2-oxaspiro[3.4]octane-1,3-dione Chemical compound O=C1OC(=O)C11CCCC1 LIBFVQBAZPYQCJ-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- QDMNNMIOWVJVLY-UHFFFAOYSA-N 4-phenyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)NC1C1=CC=CC=C1 QDMNNMIOWVJVLY-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- QMMLUKRVXWXKSI-UHFFFAOYSA-J dichloromethane;titanium(4+);tetrachloride Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Ti+4].ClCCl QMMLUKRVXWXKSI-UHFFFAOYSA-J 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesis method of ezetimibe intermediate, belonging to the technical field of drug synthesis. In order to solve the problem of improving the product yield, a synthetic method of ezetimibe intermediate is provided, which comprises the steps of carrying out Friedel-crafts acylation reaction on fluorobenzene and glutaric anhydride under the action of a catalyst to generate a compound shown in a formula 5, carrying out reaction on the compound shown in the formula 5 and ethanedithiol under the action of the catalyst in an organic solvent to generate a compound shown in a formula 4, carrying out reaction on the compound shown in the formula 4 and (S) -4-phenyl-2-oxazolidone in an alkaline environment in the organic solvent to generate a compound shown in a formula 3, carrying out reaction on p-fluoroaniline and p-hydroxybenzaldehyde in the organic solvent to generate a compound shown in a formula 2, connecting a hydroxy protecting group, and carrying out reaction on the compound shown in the formula 3 and the compound shown in the formula 2 in the organic solvent to generate a compound shown in a formula 1; the invention has the advantages of high product yield, less byproduct generation and the like.
Description
Technical Field
The invention relates to a synthesis method of ezetimibe intermediate, belonging to the field of preparation of pharmaceutical intermediates.
Background
Ezetimibe (Ezetimibe Tablets), which is a cholesterol absorption inhibitor, is developed by the company of moesadong and the company of pioneering, is used for treating primary hypercholesterolemia by being combined with statin drugs, is not increased in bile secretion, does not inhibit synthesis of cholesterol in liver, has long duration, is an ideal lipid-lowering drug, occupies an important market position from the beginning of the appearance, and has wide prospects, unlike other lipid-lowering drugs.
The chemical name of the ezetimibe intermediate compound shown in the formula 1 is 1- (4-fluorophenyl) - (3R) - [3- (4-fluorophenyl) - (3S) -hydroxypropyl ] - (4S) - (4-hydroxyphenyl) -2-propiolactam, and the chemical structural formula is shown as follows:
in patent WO2000034240, fluorobenzene is used to react with cyclopentanedioic anhydride to obtain 4- (4-fluorobenzoyl) butyric acid, then 4- (4-fluorobenzoyl) butyric acid is reacted with 4-phenyl-2-oxazolidone to obtain (4S) -3- [5- (4-fluorophenyl) -1, 5-dioxopentyl ] -4-phenyl-2-oxazolidone, one of carbonyl groups in the compound is reduced to hydroxyl by catalytic reduction of oxazoloborane, aldol condensation is carried out with imine derivative to generate ezetimibe ring-opening substance, and then the ezetimibe is generated after the catalytic cyclization of ditrimethyl-silicon acetamide and tetrabutylammonium fluoride, and the method of reducing carbonyl groups is adopted in the reaction route, so that the reaction is easy to generate byproducts and the yield is low. The synthetic route is as follows:
in patent CN104892537B, an ezetimibe intermediate and a synthesis method of ezetimibe are disclosed, wherein a compound 1 and a compound 2 are simultaneously added with a protecting group to obtain a compound of formula 3 and a compound of formula 4 to prepare a feed liquid, and then a catalyst is added to react the compound of formula 3 with the compound of formula 4 to generate a compound of formula 5. The synthetic route is as follows:
from the above documents, it can be seen that the defects in the current ezetimibe intermediate production and preparation process are that byproducts are easy to generate in the reaction process, the reaction yield is low, and the like.
Therefore, there is a need to find a synthetic method with less byproduct generation, high product yield and low production cost.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a synthesis method of ezetimibe intermediate, and solves the problems of how to realize a preparation method for increasing the yield of a product and reducing the generation of byproducts.
The invention aims at realizing the following technical scheme, and discloses a synthesis method of ezetimibe intermediate, which comprises the following steps:
s1: performing Friedel-crafts acylation reaction on fluorobenzene and glutaric anhydride under the action of a catalyst to generate a compound shown in a formula 5;
s2: in an organic solvent, reacting a compound of formula 5 with ethanedithiol under the action of a catalyst to generate a compound of formula 4;
s3: reacting a compound of formula 4 with (S) -4-phenyl-2-oxazolidinone in an organic solvent under a basic environment to produce a compound of formula 3;
s4: in an organic solvent, reacting p-fluoroaniline with p-hydroxybenzaldehyde to generate a compound shown in a formula 2, and connecting a hydroxyl protecting group in parallel;
s5: in an organic solvent, the compound of formula 3 and the compound of formula 2 are combined to form the compound of formula 1.
The synthetic route of the compound of formula 1 is as follows:
in the invention, fluorobenzene and glutaric anhydride are synthesized into a compound 4- (4-fluorobenzoyl) butyric acid in formula 5, then the compound in formula 5 is reacted with ethylene glycol to convert carbonyl into acetal, so that the carbonyl is protected, the accuracy of a reaction condensation position is ensured, then the compound in formula 3 is reacted with 4-phenyl-2-oxazolidinone to generate a compound in formula 3, and then the compound in formula 3 connected with a protecting group is reacted to obtain a final product ezetimibe intermediate, so that whether the dioxolane protecting group is reduced according to requirements is used for synthesizing ezetimibe.
In the above-mentioned ezetimibe synthesis method, preferably, in the step S1, the catalyst is one of aluminum chloride, ferric chloride and boron trifluoride. Most preferably, aluminum chloride is used as the catalyst for the reaction, and the reaction yield is the largest.
In the above-mentioned ezetimibe synthesis method, preferably, in the step S2, the organic solvent is selected from toluene or dichloromethane. Most preferably, toluene is used as the reaction solvent to stabilize the reaction.
In the above-mentioned ezetimibe synthesis method, preferably, in the step S2, the catalyst is selected from one of p-toluenesulfonic acid and trifluoromethanesulfonic acid. Most preferably, the reaction rate is maximized when p-toluenesulfonic acid is used as a catalyst.
In the above-mentioned ezetimibe synthesis method, preferably, trimethyl orthoformate is added in the step S2 to remove water in the reaction system.
In the above synthesis method of ezetimibe, preferably, in step S3, the organic solvent is selected from one of tetrahydrofuran, dichloromethane and ethyl acetate. Most preferably, tetrahydrofuran is used as the reaction solvent, and the reaction rate is maximized.
In the above synthesis method of ezetimibe, preferably, the base added in step S3 is selected from one of pyridine, sodium methoxide and triethylamine. Most preferably, the use of pyridine to adjust the reaction environment can reduce the formation of byproducts.
In the above-mentioned ezetimibe synthesis method, preferably, in the step S3, the catalyst is one of 3, 3-dimethylbutyryl chloride and pivaloyl chloride. Most preferably, the use of 3, 3-dimethylbutyryl chloride as the catalyst reduces environmental pollution.
In the above synthesis method of ezetimibe, preferably, in step S4, the organic solvent is selected from one of ethanol and diethyl ether. Most preferably, ethanol is used as the reaction solvent with the highest yield.
In the above-mentioned ezetimibe synthesis method, preferably, in step S5, the organic solvent is selected from one of dichloromethane, tetrahydrofuran and ethyl acetate. Most preferably, the reaction is stable when methylene chloride is used as the reaction solvent.
In summary, compared with the prior art, the invention has the following advantages:
1. in the invention, the carbonyl of the compound shown in the formula 5 is protected and then reacts with 4-phenyl-2-oxazolidone, so that the accuracy of a condensation position in the reaction can be ensured, the generation of byproducts in the reaction process can be reduced, and the reaction yield can be improved;
2. the invention adopts the mode of converting carbonyl into acetal for protection, the protection effect is not easy to fall off in the reaction process, and byproducts are produced at the same time, the acetal can adapt to more reaction environments, and the stable and accurate reaction is ensured.
Drawings
FIG. 1 is a general synthetic route of the present invention.
Detailed Description
The technical scheme of the present invention will be further specifically described by means of specific examples, but the present invention is not limited to these examples.
Example 1
Into a three-necked flask, 96.1ml of fluorobenzene was charged66.67gAlCl 3 144.15mL of fluorobenzene suspension solution containing 72g of glutaric anhydride is added into a flask at the temperature of 0-5 ℃ and stirred for reaction until the raw materials are exhausted, the temperature is raised to 10 ℃, 500mL of 4% HCl aqueous solution is slowly added into the mixture, and the residual AlCl in the reaction system is removed 3 Quenching with sodium hydroxide solution after the reaction, pouring the mixture into ice water, standing for layering, adding dichloromethane into the water layer for extraction, combining organic phases, washing the organic phases with saturated saline solution, adding 200ml of NaHCO 3 Saturated aqueous solution, steam heating for 1h, filtering, cooling filtrate to room temperature, dropwise adding HCl into the filtrate to regulate the pH of the solution to 1-2 for crystallization, removing the solution, flushing with ice water, filtering, and vacuum drying for 1h to obtain 91.17g of the compound of formula 5, wherein the product yield is 86.8%, and the product purity is 98.9%.
Example 2
To the flask was added 300ml of toluene, 34.44g of p-toluenesulfonic acid and 14ml of HCl, 53.06ml of trimethyl orthoformate, 42.01g of the compound of formula 5 and 31.02g of ethylene glycol, and the mixture was heated to 110℃and reacted under reflux for 6 hours, 10g of pyridine was added, and the reaction was quenched. Standing for layering, adding 200ml of ethyl acetate for extraction, combining organic phases, washing the organic phases with saturated saline, removing solution, recrystallizing, filtering, adding 10g of anhydrous sodium sulfate for drying to obtain 48.27g of a compound of formula 4, wherein the yield of the product is 95%, and the purity of the product is 97.4%.
Example 3
50.82g of the compound of formula 4 is added into a sealed container, 300ml of tetrahydrofuran is added, 50ml of pyridine is added, the temperature is controlled between minus 20 ℃ and minus 10 ℃,30 ml of a mixture of 3, 3-dimethylbutyryl chloride and 50ml of tetrahydrofuran is added dropwise, and the reaction is carried out for 2 hours. 6.5g of anhydrous lithium chloride is added, the mixture is stirred and reacted for 2 hours, 32.63g of 4-phenyl-2-oxazolidone is added, the mixture is stirred and reacted for 6 hours, the reduced pressure desolventizing is carried out, 200ml of ethyl acetate is added for extraction, the organic phases are combined, the organic phases are washed by saturated saline water, the desolventizing is carried out, recrystallization and filtration are carried out, 10g of anhydrous magnesium sulfate is added for drying, 76.16g of compound of the formula 3 is obtained, the product yield is 95.4%, and the product purity is 98.5%.
Example 4
24.42g of parahydroxyben-zaldehyde is added into a beaker, 200ml of ethanol is added, the temperature is raised to 85 ℃, stirring is carried out for 30min, after the solution is clarified, parafluoroaniline is slowly added into the solution, the reaction is continued for 2h, the reaction is carried out for 1h under the condition of heat preservation and stirring, and the solution is cooled to room temperature and is stirred for 2h. Quenching the reaction by adding HCl aqueous solution, decompressing and desolventizing, adding 200ml of ethyl acetate for extraction, combining organic phases, washing the organic phases by using saturated saline, removing the solution, recrystallizing, filtering, and drying in vacuum for 3 hours to obtain the compound of the formula 2 with the yield of 41.94, the purity of the product of 98.2 percent.
200ml of dichloromethane is added into a three-neck flask, 43.04g of a compound of formula 2 is added, the temperature is controlled to be-5 ℃, 28.72ml of DIPEA is dripped, dripping is completed for 30min, 24ml of trimethylchlorosilane is continuously dripped, dripping is completed for 30min, stirring is continued for 3h after heating to 45 ℃, HCl aqueous solution is added for quenching reaction, standing and layering are carried out, 200ml of ethyl acetate is added for extraction, organic phases are combined, saturated saline solution is used for washing the organic phases, solution is removed, recrystallization and filtration are carried out, 10g of anhydrous magnesium sulfate is added for drying, 54.83g of intermediate compound is obtained, the product yield is 95.5%, and the product purity is 97.3%.
Example 5
300ml of dichloromethane and 79.83g of compound of formula 3 and 30ml of diisopropylethylamine are added into a beaker, the temperature is reduced to-5 to 0 ℃,50ml of dichloromethane solution containing 18.97g of titanium tetrachloride is added dropwise, the temperature is raised to 20 to 25 ℃ for reaction for 1h after the completion of the dripping, the temperature is reduced to-40 to-30 ℃, 57.42g of compound of formula 2 is added, the reaction is kept for 1h, 30ml of isopropanol is added, the mixture is stirred for 30min, HCl aqueous solution is added for quenching reaction, 200ml of ethyl acetate is added for extraction, the organic phases are combined, saturated saline is used for flushing the organic phases, ethanol is used for recrystallization, filtration and drying are carried out, 119.27g of compound of formula 1 is obtained, the product yield is 86.9%, and the product purity is 99.2%.
Example 6
In a three-necked flask, 96.1ml of fluorobenzene was charged with 81.1g of FeCl 3 144.15mL of fluorobenzene suspension solution containing 72g of glutaric anhydride is added into a flask at the temperature of 0-5 ℃ and stirred for reaction until the raw materials are exhausted, the temperature is raised to 10 ℃, 500mL of HCI water solution with the concentration of 4% is slowly added into the mixture, and the rest FeCI in the reaction system is removed 3 Quenching the mixture by adding sodium hydroxide solution after the reaction is completedPouring into ice water, standing for layering, adding dichloromethane into the water layer for extraction, combining organic phases, washing the organic phases with saturated saline solution, adding 200ml of NaHCO 3 Saturated aqueous solution, steam heating for 1h, filtering, cooling filtrate to room temperature, dropwise adding HCl into the filtrate to regulate the pH of the solution to 1-2 for crystallization, removing the solution, flushing with ice water, filtering, and vacuum drying for 1h to obtain 87.18g of the compound of formula 5, wherein the product yield is 83%, and the product purity is 98.5%.
Example 7
96.1mL of fluorobenzene is put into a three-necked flask, 33.9g of boron trifluoride is added, the temperature is controlled to be 0-5 ℃, 144.15mL of fluorobenzene suspension solution containing 72g of glutaric anhydride is added into the flask, stirring reaction is carried out until the raw material is exhausted, the temperature is increased to 10 ℃, 500mL of HCI aqueous solution with the concentration of 4% is slowly added into the mixture, the residual boron trifluoride in the reaction system is removed, sodium hydroxide solution is added for quenching after the reaction is finished, the mixture is poured into ice water for standing and layering, the aqueous layer is added with dichloromethane for extraction, the organic phase is combined, saturated saline water is used for washing the organic phase, 200mL of NaHCO3 saturated aqueous solution is added, steam is used for heating for 1h, filtration is carried out, the filtrate is cooled to room temperature, HCl is added dropwise into the filtrate for regulating the pH of the solution to be 1-2 for crystallization, the solution is removed, the ice water is used for washing, filtration is carried out, vacuum drying is carried out for 1h, 88.86g of compound with the formula 5, the product yield is 84.6%, and the product purity is 98.4%.
Example 8
Into the flask, 300ml of methylene chloride was added, 30.01g of trifluoromethanesulfonic acid and 14ml of HCl were added, 53.06ml of trimethyl orthoformate was added, 42.01g of the compound of formula 5 and 31.02g of ethylene glycol were added, the temperature was raised to 110℃and the reaction was refluxed for 6 hours, 10g of pyridine was added, and the reaction was quenched. Standing for layering, adding 200ml of ethyl acetate for extraction, combining organic phases, washing the organic phases with saturated saline, removing solution, recrystallizing, filtering, adding 10g of anhydrous sodium sulfate for drying to obtain 46.4g of a compound of formula 4, wherein the yield of the product is 94.3%, and the purity of the product is 97.7%.
Example 9
50.82g of the compound of formula 4 are introduced into a sealed vessel, 300ml of methylene chloride is added, 35g of sodium methoxide is added, the temperature is controlled between-20 ℃ and-10 ℃, and a mixture of 27ml of pivaloyl chloride and 50ml of methylene chloride is dropwise added for reaction for 2 hours. 6.5g of anhydrous lithium chloride is added, the mixture is stirred and reacted for 2 hours, 32.63g of 4-phenyl-2-oxazolidone is added, the mixture is stirred and reacted for 6 hours, the reduced pressure desolventizing is carried out, 200ml of ethyl acetate is added for extraction, the organic phases are combined, the organic phases are washed by saturated saline water, the desolventizing is carried out, recrystallization and filtration are carried out, 10g of anhydrous magnesium sulfate is added for drying, 70.81g of the compound of the formula 3 is obtained, the product yield is 88.7%, and the product purity is 97.9%.
Example 10
50.82g of the compound of formula 4 is added into a sealed container, 300ml of ethyl acetate is added, 80ml of triethylamine is added, the temperature is controlled between minus 20 ℃ and minus 10 ℃, and a mixture of 27ml of pivaloyl chloride and 50ml of ethyl acetate is dropwise added for reaction for 2 hours. 6.5g of anhydrous lithium chloride is added, the mixture is stirred and reacted for 2 hours, 32.63g of 4-phenyl-2-oxazolidone is added, the mixture is stirred and reacted for 6 hours, the reduced pressure desolventizing is carried out, 200ml of ethyl acetate is added for extraction, the organic phases are combined, the organic phases are washed by saturated saline water, the desolventizing is carried out, recrystallization and filtration are carried out, 10g of anhydrous magnesium sulfate is added for drying, 68.97g of the compound of the formula 3 is obtained, the product yield is 86.4%, and the product purity is 98.1%.
Example 11
24.42g of parahydroxyben-zaldehyde is added into a beaker, 200ml of diethyl ether is added, the temperature is raised to 85 ℃, stirring is carried out for 30min, after the solution is clarified, parafluoroaniline is slowly added into the solution, the reaction is continued for 2h, the reaction is carried out for 1h under heat preservation and stirring, and the solution is cooled to room temperature and is stirred for 2h. Quenching the reaction by adding HCl aqueous solution, decompressing and desolventizing, adding 200ml of ethyl acetate for extraction, combining organic phases, washing the organic phases by using saturated saline, removing the solution, recrystallizing, filtering, and drying in vacuum for 3 hours to obtain 40g of the compound of the formula 2, wherein the yield of the product is 93%, and the purity of the product is 97.5%.
200ml of dichloromethane is added into a three-neck flask, 43.04g of a compound of formula 2 is added, the temperature is controlled to be-5 ℃, 28.72ml of DIPEA is dripped, dripping is completed for 30min, 24ml of trimethylchlorosilane is continuously dripped, dripping is completed for 30min, stirring is continued for 3h after heating to 45 ℃, HCl aqueous solution is added for quenching reaction, standing and layering are carried out, 200ml of ethyl acetate is added for extraction, organic phases are combined, saturated saline solution is used for washing the organic phases, solution is removed, recrystallization and filtration are carried out, 10g of anhydrous magnesium sulfate is added for drying, 54.83g of intermediate compound is obtained, the product yield is 95.5%, and the product purity is 97.3%.
Example 12
300ml of tetrahydrofuran and 79.83g of compound of formula 3 and 30ml of diisopropylethylamine are added into a beaker, the temperature is reduced to-5 to 0 ℃,50ml of tetrahydrofuran solution containing 18.97g of titanium tetrachloride is dripped, the temperature is raised to 20 to 25 ℃ for reaction for 1h after the dripping is completed, the temperature is reduced to-40 to-30 ℃, 57.42g of compound of formula 2 is added, the reaction is kept for 1h, 30ml of isopropanol is added, the stirring is carried out for 30min, the quenching reaction is carried out by adding into HCl aqueous solution, the solution is extracted by adding 200ml of ethyl acetate, the organic phases are combined, the saturated saline is used for flushing the organic phases, ethanol is used for recrystallization, the filtration and drying are carried out, 117.62g of compound of formula 1 is obtained, the product yield is 84.7%, and the product purity is 98.6%.
Example 13
Adding 300ml of ethyl acetate, 79.83g of compound of formula 3 and 30ml of diisopropylethylamine into a beaker, cooling to-5-0 ℃, dropwise adding 50ml of ethyl acetate solution containing 18.97g of titanium tetrachloride, heating to 20-25 ℃ for reaction for 1h, cooling to-40-30 ℃, adding 57.42g of compound of formula 2, reacting for 1h while maintaining the temperature, adding 30ml of isopropanol, stirring for 30min, adding HCl aqueous solution for quenching reaction, pumping solution, adding 200ml of ethyl acetate for extraction, combining organic phases, flushing the organic phases with saturated saline, recrystallizing with ethanol, filtering, drying to obtain 115.57g of compound of formula 1, wherein the product yield is 84.2%, and the product purity is 97.8%
Comparative example
This embodiment is an embodiment of the disclosed patent CN104513187B
Compound (1) (10 g,81.90 mmol) and p-fluoroaniline (9 g,81.00 mmol) were dissolved in isopropanol (75 ml), heated to 50 ℃, stirred for 1h, cooled to room temperature, suction filtered, and rinsed with isopropanol (10 ml) to give compound (2) (14.2 g,80% yield) as a pale yellow solid.
Compound (2) (6 g,27.88 mmol), TBDMSCl (5.04 g,33.44 mmol) and imidazole (3.8 g,55.80 mmol) were dissolved in DMF (12 ml), heated to 60℃and stirred for 4h, cooled to room temperature, added water (60 ml), extracted with ethyl acetate (20 ml. Times.3), the organic phases combined, washed with water (20 ml. Times.2) and MgSO was added to the organic phase 4 Drying, concentrating to obtain pale yellow solidThe compound (3 a) (9.0 g,97.5% yield).
Compound (4) (30 g,142.72 mmol), triethylamine (26 g,256.91 mmol) were dissolved in dichloromethane (150 ml), cooled to 5 to 10 ℃, pivaloyl chloride (17.3 g,142.62 mmol) was added dropwise, the system was exothermic, the reaction was continued for 2h at 5 to 10 ℃, (S) -4-phenyl-2-oxazolidinone (23.3 g,142.76 mmol), DMAP (2.4 g,19.63 mmol), DMF (15 ml) was added to the reaction system, the exotherm was raised to 15 ℃, the temperature was raised to 45 ℃ for 3h, cooled to room temperature, dichloromethane (150 ml) was added, the organic phase was washed successively with water (60 ml), 1N hydrochloric acid (120 ml), water (60 ml), 2.5% aqueous solution (180 ml), water (50 ml) was added, the organic phase was concentrated to dryness, isopropanol (60 ml) was added, stirring was carried out for 24h, and isopropanol (10 ml) was added to obtain a white solid (34.4% yield, 34% sodium hydroxide) by suction filtration.
Example 4-1: borane dimethyl sulfide (34 ml,10M,34 mmol) is dissolved in dichloromethane (40 ml), cooled to-10 to-5 ℃, added dropwise (R) -2-methyl-CBS-oxazoloborane (14 ml,1M,14 mmol) at-10 to-5 ℃ for 15min, cooled to-15 to-10 ℃, added dropwise with dichloromethane (20 ml) solution of compound (5) (10 g,28 mmol) at-20 min, reacted for 20min at-10 to-5 ℃, added dropwise with methanol (50 ml) at-10 to 0 ℃, released heat, added dropwise with hydrogen peroxide (30% 40 ml) at-10 to 0 ℃, released heat, added dropwise with diluted hydrochloric acid (1M, 50 ml) at-10 ℃, released heat vigorously, concentrated organic solvent in the system, extracted with ethyl acetate (100 ml), washed with water (10 ml) in turn, 5% NaHSO 3 Aqueous (20 ml) was washed and concentrated to give compound (6) (9.0 g,90% yield) as a pale yellow oil.
Example 5-1: compound (6) (5.2 g,14.5 mmol), t-butyldimethylsilyl chloride (2.6 g,17.5 mmol) and imidazole (1.9 g,29.0 mmol) were dissolved in DMF (10.5 ml), the system was warmed to 60℃and reacted for 1 to 2 hours, cooled to room temperature, water (20 ml) was added, ethyl acetate (40 ml) was extracted, the ethyl acetate layer was washed with water (10 ml. Times.2) and MgSO was added thereto 4 Drying and concentration gave colorless transparent liquid 7 (4.2 g,61% yield).
Compound (7) (800 mg,1.7 mmol) and diisopropylethylamine (1534 mg,11.8 mmol) are dissolved in dichloromethane (19 ml), cooled to-5 to 0 ℃, titanium tetrachloride dichloromethane solution (6.1 ml,1M,6.1 mmol) is added dropwise, the mixture is heated to 20 to 25 ℃ for reaction for 5 to 10min, cooled to-40 to-30 ℃, dichloromethane (16 ml) solution of compound (3 a) (1340 mg,4.1 mmol) is added dropwise, the mixture is reacted for 20min at-40 to-30 ℃ with heat preservation, water (10 ml) and dichloromethane (10 ml) are added dropwise in sequence, the solution is separated, the organic phase is washed with water (10 ml), the organic phase is filtered with silica gel, concentrated, ethanol (5 ml) is added, stirring is carried out for 1h, and the white solid is obtained after suction filtration, namely compound (8 a) (694 mg,51% yield).
Compared with the preparation method in the invention, the yield is lower in the embodiment, which is unfavorable for mass production.
The embodiments of the present invention are not limited to the examples described above, and those skilled in the art can make various changes and modifications in form and detail without departing from the spirit and scope of the present invention, which are considered to fall within the scope of the present invention.
Claims (10)
1. The synthesis method of ezetimibe intermediate is characterized by comprising the following steps of:
s1: performing Friedel-crafts acylation reaction on fluorobenzene and glutaric anhydride under the action of a catalyst to generate a compound shown in a formula 5;
s2: in an organic solvent, reacting a compound of formula 5 with ethanedithiol under the action of a catalyst to generate a compound of formula 4;
s3: reacting a compound of formula 4 with (S) -4-phenyl-2-oxazolidinone in an organic solvent under a basic environment to produce a compound of formula 3;
s4: in an organic solvent, reacting p-fluoroaniline with p-hydroxybenzaldehyde to generate a compound shown in a formula 2, and connecting a hydroxyl protecting group in parallel;
s5: in an organic solvent, the compound of formula 3 and the compound of formula 2 are combined to form the compound of formula 1.
2. The method for synthesizing ezetimibe intermediate according to claim 1, wherein the method comprises the steps of: in the step S1, the catalyst is selected from one of aluminum chloride, ferric chloride or boron trifluoride.
3. The method for synthesizing ezetimibe intermediate according to claim 1, wherein the method comprises the steps of: in the step S2, the organic solvent is selected from toluene or dichloromethane.
4. The method for synthesizing ezetimibe intermediate according to claim 1, wherein the method comprises the steps of: in the step S2, the catalyst is selected from one of p-toluenesulfonic acid or trifluoromethanesulfonic acid.
5. The method for synthesizing ezetimibe intermediate according to claim 1, wherein the method comprises the steps of: and in the step S2, adding trimethyl orthoformate to remove water in the reaction system.
6. The method for synthesizing ezetimibe intermediate according to claim 1, wherein the method comprises the steps of: in the step S3, the organic solvent is selected from one of tetrahydrofuran, dichloromethane or ethyl acetate.
7. The method for synthesizing ezetimibe intermediate according to claim 1, wherein the method comprises the steps of: the alkali added in the step S3 can be selected from one of pyridine, sodium methoxide or triethylamine.
8. The method for synthesizing ezetimibe intermediate according to claim 1, wherein the method comprises the steps of: in the step S3, the catalyst is selected from one of 3, 3-dimethylbutyryl chloride or pivaloyl chloride.
9. The method for synthesizing ezetimibe intermediate according to claim 1, wherein the method comprises the steps of: in the step S4, the organic solvent is selected from one of ethanol or diethyl ether.
10. The method for synthesizing ezetimibe intermediate according to claim 1, wherein the method comprises the steps of: in the step S5, the organic solvent is selected from one of dichloromethane, tetrahydrofuran or ethyl acetate.
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| WO2000034240A1 (en) * | 1998-12-07 | 2000-06-15 | Schering Corporation | Process for the synthesis of azetidinones |
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| US20090227786A1 (en) * | 2005-12-22 | 2009-09-10 | Ana Gavalda I Escude | Processes for preparing intermediate compounds useful for the preparation of ezetimibe |
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| CN106967106A (en) * | 2017-04-24 | 2017-07-21 | 上海华源医药科技发展有限公司 | A kind of production method of Ezetimibe intermediate |
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| WO2000034240A1 (en) * | 1998-12-07 | 2000-06-15 | Schering Corporation | Process for the synthesis of azetidinones |
| CN101346349A (en) * | 2005-12-20 | 2009-01-14 | 吉瑞工厂 | Process for the production of ezetimibe and intermediates used in this proces |
| US20090227786A1 (en) * | 2005-12-22 | 2009-09-10 | Ana Gavalda I Escude | Processes for preparing intermediate compounds useful for the preparation of ezetimibe |
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