CN114621299A - Preparation method of ezetimibe intermediate - Google Patents
Preparation method of ezetimibe intermediate Download PDFInfo
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- CN114621299A CN114621299A CN202011471817.9A CN202011471817A CN114621299A CN 114621299 A CN114621299 A CN 114621299A CN 202011471817 A CN202011471817 A CN 202011471817A CN 114621299 A CN114621299 A CN 114621299A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 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 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 75
- 239000003054 catalyst Substances 0.000 claims abstract description 40
- 239000003446 ligand Substances 0.000 claims abstract description 27
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 17
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 11
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052751 metal Inorganic materials 0.000 claims abstract description 10
- 239000002184 metal Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 30
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 13
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 11
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 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 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 6
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical group [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 abstract description 3
- JRHWHSJDIILJAT-UHFFFAOYSA-N 2-hydroxypentanoic acid Chemical compound CCCC(O)C(O)=O JRHWHSJDIILJAT-UHFFFAOYSA-N 0.000 abstract 1
- 230000002862 amidating effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 28
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 150000004696 coordination complex Chemical class 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 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 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 229960000815 ezetimibe Drugs 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 4
- 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 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 239000003524 antilipemic agent Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- -1 ezetimibe intermediate compound Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 235000015816 nutrient absorption Nutrition 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- 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
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic System
-
- 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
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- 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
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
-
- 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
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/827—Iridium
-
- 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
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
- B01J2531/842—Iron
-
- 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
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Materials Engineering (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of an ezetimibe intermediate, which comprises the following steps: the catalyst prepared from a metal iridium (Ir) complex and a chiral tridentate ligand L with a ferrocene structure is adopted to catalyze 4- (4-fluorobenzoyl) butyric acid to carry out asymmetric hydrogenation reaction to obtain S-5- (4-fluorophenyl) -5-hydroxypentanoic acid, and S-5- (4-fluorophenyl) -5-hydroxy valeric acid is prepared by asymmetric hydrogenationProtecting hydroxy valeric acid with TBS, and amidating to obtain high selectivity ezetimibe intermediate. The catalyst of the invention has high activity, low catalyst consumption, high selectivity, yield up to 90% and ee value up to 90% during asymmetric hydrogenation reaction. The preparation method disclosed by the invention is mild in reaction conditions, high in yield and purity, green and environment-friendly, and does not need a complex post-treatment process. Wherein, the structural formula of the chiral ligand L is shown as follows.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of an ezetimibe intermediate.
Background
Ezetimibe (Ezetimibe) is a new hypolipidemic drug developed by Milingbao and Merck corporation, approved by the FDA in the United states and marketed in 2012, and has the chemical name of (3R, 4S) -1-4- (4-fluorophenyl) -3- (3S) -3- [3- (4-fluorophenyl) -3-hydroxyphenylpropyl]-4- (4-hydroxyphenyl) -2-azetidinone of formula C24H21F2NO3Molecular weight 409.4, having the formula:
ezetimibe is the first selective inhibitor for cholesterol absorption approved by the FDA in the United states to be marketed, is used as a novel hypolipidemic drug, has different effects from other hypolipidemic drugs, mainly acts on the small intestine, reduces the intestinal cholesterol transportation to the liver by inhibiting the absorption of cholesterol, and does not influence other nutrient absorption; and the composition can be used together with statins, so that the using amount of the statins is reduced, the defect that the using amount of the statins is increased but the effect is not obvious can be overcome, and the combination of ezetimibe and the statins shows a strong application prospect.
The ezetimibe has good treatment effect on hyperlipidemia no matter single use or combined use, and with the wide use of ezetimibe, the existing preparation method can not meet the requirements, and a new preparation method of an ezetimibe intermediate is urgently needed to be developed.
Disclosure of Invention
The invention aims to provide a preparation method of an ezetimibe intermediate on the basis of the prior art.
The technical scheme of the invention is as follows:
a preparation method of an ezetimibe intermediate comprises the following steps:
(1) uniformly mixing a metal iridium complex, a chiral ligand L and a solvent A, and carrying out chemical reaction at 20-40 ℃ under the protection of nitrogen for 1-3 hours to prepare a catalyst solution;
the structural formula of the compound shown by the chiral ligand L is as follows:
wherein R is1Represents methyl, ethyl, tert-butyl, phenyl or adamantyl; r2Selected from hydrogen, methyl or ethyl;
(2) uniformly mixing a compound I, alkali, the catalyst solution prepared in the step (1) and a solvent B, introducing hydrogen, controlling the pressure to be 0.1-10.0MPa, and carrying out asymmetric hydrogenation reaction at 25-100 ℃ to prepare a compound II;
(3) dissolving the compound II prepared in the step (2) in a solvent C, adding imidazole and TBSCl, and after uniformly mixing, carrying out chemical reaction at 20-40 ℃ to prepare a compound III;
(4) dissolving the compound III prepared in the step (3) in a solvent D, adding triethylamine and pivaloyl chloride, uniformly mixing, stirring and reacting for 1-3 hours at-5-10 ℃, adding a compound IV, heating to 20-40 ℃ for chemical reaction, and preparing an intermediate compound V; the specific synthetic route is as follows:
wherein the compound I is 4- (4-fluorobenzoyl) butyric acid, the compound II is S-5- (4-fluorophenyl) -5-hydroxypentanoic acid, and the compound IV is S-4-phenyloxazolidinebutan-2-one.
The method comprises the steps of taking 4- (4-fluorobenzoyl) butyric acid (compound I) as a raw material, carrying out a chemical reaction on a metal iridium (Ir) complex and a chiral tridentate ligand L with a ferrocene structure, carrying out an asymmetric hydrogenation reaction to prepare S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II) under the condition that an obtained reaction solution is used as a catalyst, and carrying out an amidation reaction on the compound II under TBS protection to prepare a high-selectivity ezetimibe intermediate compound V.
When the catalyst is adopted and 4- (4-fluorobenzoyl) butyric acid (compound I) is used as a raw material to prepare S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II), the asymmetric hydrogenation reaction activity is high, the dosage of the catalyst is low, and the advantages of high selectivity and high yield are achieved.
In a preferred embodiment, in step (1), the metallic iridium complex may be, but is not limited to, [ Ir (COD) Cl]2、[Ir(COE)2Cl]2Or [ Ir (COD) OMe]2. The molar ratio of the metallic Ir complex to the chiral ligand L may be adjusted according to actual needs, and the molar ratio of the metallic Ir complex to the chiral ligand L may be set to 1:1.0 to 4.0, for example, but not limited to 1:1, 1:1.5, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.5, 1:3.0, 1:3.5 or 1:4.0, more preferably 1:2.0 to 3.0, and particularly preferably 1:2.2, in order to obtain a high yield and save cost.
In the step (1), the solvent A is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide; preferably, solvent a is isopropanol.
In the step (1), the structural formula of the compound represented by the chiral ligand L provided by the invention is as follows:
wherein R is1Represents methyl, ethyl, tert-butyl, phenyl or adamantyl; r2Selected from hydrogen, methyl or ethyl.
In a preferred embodiment, R1Represents phenyl or adamantyl. R2Selected from hydrogen or methyl.
In a more preferred embodiment, the chiral ligand L is selected from the following compounds:
the chiral ligand L can be prepared according to the following synthetic route, which comprises the following specific steps:
when the chiral ligand is L1, the preparation method comprises the following more detailed steps:
when the chiral ligand is L2, the preparation method comprises the following more detailed steps:
in the step (2), when the compound II is prepared, the adopted base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium methoxide or sodium ethoxide; preferably, the base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide or sodium methoxide.
When the compound II is prepared, the solvent B is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide; preferably, the solvent B is isopropanol, methanol or ethanol.
In a preferred embodiment, the molar ratio of the compound I to the base in the preparation of the compound II can be adjusted according to actual needs, and the molar ratio of the compound I to the base can be set to 40 to 60:1, for example, but not limited to 40:1, 45:1, 50:1, 55:1 or 60:1, and further preferably 45 to 50:1, and particularly preferably 50:1, for higher yield and cost saving.
In a preferred embodiment, the amount of the catalyst used in the preparation of the compound II is determined according to the amount of the metal iridium complex used in the step (1), and the molar ratio of the compound I to the metal iridium complex can be 5-15: 1, for example, but not limited to, 5:1, 8:1, 10:1, 12:1 or 15:1, and further preferably 8-12: 1, and particularly preferably 10:1, for higher yield and cost saving.
In the step (2), when the compound II is prepared by asymmetric hydrogenation, the pressure during the reaction is controlled to be 1.0-3.0MPa, preferably 2.0 MPa.
Further, the reaction temperature is controlled to be 40-60 ℃, and preferably 50 ℃.
Further, the reaction time is controlled to be 20-30 hours, preferably 24 hours.
For the present invention, in the step (3), the reaction temperature is controlled to 25 ℃ and the reaction time is controlled to 10 to 20 hours, for example, 12 hours, when preparing the compound III. The molar ratio of the compound II to the imidazole in the reaction process can be adjusted according to actual needs, and the molar ratio of the compound II to the imidazole can be assumed to be 1:2 to 8, for example, but not limited to, 1:2, 1:2.5, 1:3.0, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:7 or 1:8, and further preferably 1:3 to 5, and particularly preferably 1:4.
Further, in the reaction process, the molar ratio of the compound II to the TBSCl is 1: 1.0-2.5, preferably 1: 1.2-1.8, and more preferably 1: 1.5.
In the reaction process, the used solvent C is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide; preferably, solvent C is N, N-dimethylformamide.
In the step (4), the compound III prepared in the step (3) is dissolved in a solvent D, triethylamine and pivaloyl chloride are added, after uniform mixing, the mixture is stirred and reacted for 1 to 3 hours at the temperature of between 5 ℃ below zero and 10 ℃, then the compound IV is added, and the temperature is raised to 20 to 40 ℃ for chemical reaction, so that an intermediate compound V is prepared.
Before the compound IV is added, the molar ratio of triethylamine to pivaloyl chloride is 1: 0.5-1.0, preferably 1: 0.7-0.8, and more preferably 1: 0.75.
In a preferred scheme, the reaction temperature is controlled to be 0 ℃; the reaction time is 1 to 3 hours, preferably 2 hours.
After the addition of compound IV, the reaction time is controlled to 3 to 8 hours, preferably 5 hours.
In the whole reaction process, the solvent D is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide; preferably, the solvent D is N, N-dimethylformamide.
For the purposes of the present invention, the process for the preparation of the ezetimibe intermediate described above comprises the following more detailed steps:
(1) uniformly mixing a metal iridium complex, a chiral ligand L and a solvent A, and carrying out chemical reaction at 20-40 ℃ under the protection of nitrogen for 1-3 hours to prepare a catalyst solution;
(2) uniformly mixing a compound I, alkali, the catalyst solution prepared in the step (1) and a solvent B, introducing hydrogen to control the pressure to be 0.1-10.0MPa (for example, 2MPa), and carrying out asymmetric hydrogenation reaction at 25-100 ℃ (for example, 50 ℃) to prepare a compound II;
(3) dissolving the compound II prepared in the step (2) in a solvent C, adding imidazole and TBSCl, uniformly mixing, carrying out a chemical reaction at 20-40 ℃, adding a saturated ammonium chloride aqueous solution to quench after the reaction is finished, extracting with dichloromethane, concentrating an organic layer under reduced pressure, dissolving the obtained crude product with methyl tert-butyl ether, washing with a saturated NaCl aqueous solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound III, wherein the compound III is directly used in the next step without further purification;
(4) dissolving the compound III prepared in the step (3) in a solvent D, adding triethylamine and pivaloyl chloride, uniformly mixing, stirring and reacting for 1-3 hours under the condition of-5-10 ℃ (for example, 0 ℃), then adding a compound IV, heating to 20-40 ℃ for chemical reaction, adding water and methyl tert-butyl ether for extraction after the reaction is completed, collecting an organic phase, washing with a saturated NaCl aqueous solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain an intermediate compound V.
By adopting the technical scheme of the invention, the advantages are as follows:
(1) the method adopts the catalyst prepared from the iridium (Ir) complex and the chiral tridentate ligand L with the ferrocene structure to catalyze the 4- (4-fluorobenzoyl) butyric acid to carry out asymmetric hydrogenation reaction to obtain the S-5- (4-fluorophenyl) -5-hydroxyvaleric acid, and has the advantages of high catalyst activity, low catalyst consumption, high selectivity, yield of 90 percent and ee value of 90 percent.
(2) The S-5- (4-fluorophenyl) -5-hydroxyvaleric acid prepared by asymmetric hydrogenation is protected by TBS and subjected to amidation reaction to prepare the high-selectivity ezetimibe intermediate, the reaction condition is mild, a complex post-treatment process is not required, the yield and the purity are high, and the method is green and environment-friendly.
Detailed Description
The preparation of the ezetimibe intermediate of the present invention is further illustrated by the following examples, which are not intended to limit the invention in any way.
Example 1: synthesis of chiral ligand L1
(1) Adding the compound 1(46.6mmol, 12g) into a three-neck flask, adding 80mL of anhydrous ether as a solvent under the protection of nitrogen, stirring the obtained mixed solution at-40 ℃, slowly dropwise adding sec-butyl lithium (35mL, 1.6M) into the mixed solution while stirring, and continuing to stir for 20-30 min. After the dropwise addition, the obtained reaction solution is transferred to a temperature of 25 ℃ and stirred for 2 hours. Then, dissolving diphenyl phosphorus chloride (20.5g, 93mmol) in 40mL of diethyl ether, slowly dropwise adding the solution into the obtained reaction solution, transferring the obtained reaction solution into an oil bath after dropwise adding is finished, and heating and refluxing for 4 hours; quenching the reaction by using a saturated aqueous solution of sodium bicarbonate, washing the reaction solution by using saturated sodium chloride, taking an organic phase, drying the organic phase by using anhydrous sodium, removing the solvent by reducing pressure, and purifying the mixture by using a column chromatography to obtain a yellow solid 2 with the yield of 53 percent.1H NMR(400MHz，Chloroform-d)δ7.59(dq，J＝7.6，3.1，2.3Hz，2H)，7.44-7.29(m，3H)，7.23-7.10(m，5H)，4.36(q，J＝1.9Hz，1H)，4.24(d，J＝2.5Hz，1H)，4.15(qd，J＝6.8，2.6Hz，1H)，3.94(s，5H)，3.88-3.82(m，1H)，1.76(s，6H)，1.25(d，J＝6.7Hz，3H)。
(2) The compound 2(3g) obtained in the step (1) is dissolved in 6mL of acetic anhydride and reacted overnight at 60 ℃ under the protection of nitrogen. After the reaction is finished, most of acetic anhydride is removed by reduced pressure distillation to obtain a crude product 3, and the crude product is directly used for the next step without purification and stored at low temperature.
(3) In N2Under protection, the compound 3(5g, 11mmol) obtained in step (2) was added to a mixed solution of 40mL of THF and 40mL of methanol, 40mL of aqueous ammonia was added, and the mixture was reacted at 60 ℃ for 4 hours. TLC detection reaction is complete, decompression distillation is carried out to remove redundant solvent, EA and water are added for layering treatment, organic phases are combined, anhydrous sodium sulfate is dried, and column chromatography is carried out to obtain a yellow product 4 with the yield of 64%.1H NMR(400MHz，Chloroform-d)δ7.68-7.49(m，1H)，7.47-7.30(m，2H)，7.25(d，J＝3.5Hz，4H)，4.44(dt，J＝3.0，1.7Hz，1H)，4.27(t，J＝2.5Hz，1H)，4.21(qd，J＝6.6，2.4Hz，1H)，4.01(s，3H)，3.80-3.74(m，1H)，1.44(d，J＝6.7Hz，2H)。
(4) Compound 5(1.08g, 4.4mmol) was dissolved in anhydrous dichloromethane at-78 deg.C under nitrogen and Tf was added slowly2O (1.47g, 5.2mmol), 2, 6-lutidine (0.68mL, 5.2mmol) are added after reacting for 30min, a dichloromethane solution of the compound 4(1.65g, 4mmol) obtained in the step (3) and triethylamine (1.1mL, 8mmol) are added, the reaction is raised to 25 ℃ for reaction, the reaction is monitored, after the reaction is completed, water is added for quenching reaction, dichloromethane is used for extraction, an organic phase is collected, a saturated sodium chloride aqueous solution is washed, anhydrous sodium sulfate is dried, reduced pressure distillation is carried out to obtain a crude product, and column chromatography is carried out to obtain 1.08g of the target product L1, wherein the yield is 42%.1H NMR(400MHz，Chloroform-d)δ7.60-7.48(m，2H)，7.43-7.33(m，3H)，7.25-7.18(m，5H)，4.48(s，1H)，4.29(d，J＝2.6Hz，1H)，4.10-4.01(m，2H)，3.98(s，5H)，3.82-3.75(m，1H)，3.29(td，J＝9.0，5.3Hz，1H)，2.71(dd，J＝11.3，5.3Hz，1H)，2.38(dd，J＝11.3，9.1Hz，1H)，1.97(s，3H)，1.84-1.74(m，6H)，1.74-1.66(m，6H)，1.50(d，J＝6.6Hz，3H)，0.82(d，J＝6.4Hz，3H)。
Example 2: synthesis of ligand L2
Preparation of Compound 4 As in example 1
Compound 5(0.78g, 4.4mmol) was dissolved in anhydrous dichloromethane at-78 deg.C under nitrogen and Tf was added slowly2O (1.47g, 5.2mmol) and 2, 6-lutidine (0.68mL, 5.2mmol) are added after reaction for 30min, a dichloromethane solution of a compound 4(1.65g, 4mmol) and triethylamine (1.1mL, 8mmol) are added, the temperature is raised to 25 ℃ for reaction, the reaction is monitored, after the reaction is completed, water quenching is added for reaction, dichloromethane is used for extraction, an organic phase is collected, saturated sodium chloride aqueous solution is used for washing, anhydrous sodium sulfate is used for drying, reduced pressure distillation is carried out to obtain a crude product, and column chromatography is carried out to obtain 1.03g of a target product L2, wherein the yield is 45%.1H NMR(400MHz，Chloroform-d)δ8.02-7.67(m，2H)，7.57-7.48(m，2H)，7.48-7.42(m，1H)，7.40-7.34(m，5H)，7.27(d，J＝4.0Hz，5H)，4.63-4.35(m，1H)，4.29(t，J＝2.5Hz，1H)，4.11(dd，J＝6.6，2.9Hz，1H)，3.99(s，5H)，3.85(dd，J＝9.4，8.0Hz，1H)，3.81-3.68(m，2H)，3.51(t，J＝7.7Hz，1H)，2.79(dd，J＝11.1，4.5Hz，1H)，2.34(dd，J＝11.2，8.5Hz，1H)，1.47(d，J＝6.5Hz，3H)。
Example 3: preparation of catalyst and asymmetric hydrogenation reaction of catalyzing 4- (4-fluorobenzoyl) butyric acid by catalyst
(1) Metal complex [ Ir (COD) Cl]2(0.10mmol, 70mg) and ligand L1(0.22mmol, 141mg) were charged into a reaction tube, air was replaced, 10mL of isopropanol was added under a nitrogen atmosphere, and the reaction was carried out at 25 ℃ for 2 hours to obtain a catalyst solution.
(2) 4- (4-fluorobenzoyl) butyric acid (compound I, 210g, 1mol), 1L isopropanol, potassium tert-butoxide (2.24g, 20mmol), and the catalyst solution prepared in step (1) above were added to a hydrogen reaction vessel and stirred uniformly.And (3) replacing the reaction kettle with hydrogen for three times, finally filling hydrogen (controlling the pressure in the hydrogen reaction kettle to be 2.0MPa), reacting at 50 ℃ for 24 hours, concentrating under reduced pressure, and recovering isopropanol to obtain the S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II), wherein the yield is 92% and the ee value is 94%.1H NMR(400MHz，Chloroform-d)δ7.30-7.06(m，4H)，5.40(d,J＝4.9Hz,2H),4.89(dt,J＝5.1,1.1Hz,1H)，2.32-2.28(m,2H),1.81-1.64(m,3H),1.61-1.51(m,1H)。
Example 4: preparation of catalyst and asymmetric hydrogenation reaction of catalyzing 4- (4-fluorobenzoyl) butyric acid by catalyst
(1) Reacting a metal complex [ Ir (COD) Cl]2(0.10mmol, 70mg) and ligand L2(0.22mmol, 126mg) were charged into a reaction tube, air was replaced, 10mL of isopropyl alcohol was added under nitrogen atmosphere, and reaction was carried out at 25 ℃ for 2 hours to obtain a catalyst solution.
(2) To a hydrogen reaction vessel were added 4- (4-fluorobenzoyl) butyric acid (compound I, 210g, 1mol), 1L isopropanol, potassium tert-butoxide (2.24g, 20mmol), and the catalyst solution prepared in step (1) above. After stirring evenly, replacing the reaction kettle with hydrogen for three times, finally filling hydrogen (controlling the pressure in the hydrogen reaction kettle to be 2.0MPa), reacting for 24h at 50 ℃, concentrating under reduced pressure, and recovering isopropanol to obtain S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II), wherein the yield is 92% and the ee value is 94%.
Example 5: preparation of catalyst and asymmetric hydrogenation reaction of catalyzing 4- (4-fluorobenzoyl) butyric acid by catalyst
(1) Reacting a metal complex [ Ir (COD) Cl]2(0.10mmol, 70mg) and ligand L2(0.22mmol, 126mg) were charged into a reaction tube, air was replaced, 10mL of isopropyl alcohol was added under nitrogen atmosphere, and reaction was carried out at 25 ℃ for 2 hours to obtain a catalyst solution.
(2) To a hydrogen reaction vessel was added 4- (4-fluorobenzoyl) butyric acid (compound I, 210g, 1mol), 1L isopropanol, sodium tert-butoxide (1.92g, 20mmol), and the catalyst solution prepared in step (1) above. After stirring uniformly, replacing the reaction kettle with hydrogen for three times, finally filling hydrogen (controlling the pressure in the hydrogen reaction kettle to be 2.0MPa), reacting for 24 hours at 50 ℃, concentrating under reduced pressure, and recovering isopropanol to obtain the S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II), wherein the yield is 93 percent, and the ee value is 91 percent.
Example 6: preparation of catalyst and asymmetric hydrogenation reaction of catalyzing 4- (4-fluorobenzoyl) butyric acid by catalyst
(1) Reacting a metal complex [ Ir (COD) Cl]2(0.10mmol, 70mg) and ligand L2(0.22mmol, 126mg) were charged into a reaction tube, air was replaced, 10mL of isopropyl alcohol was added under nitrogen atmosphere, and reaction was carried out at 25 ℃ for 2 hours to obtain a catalyst solution.
(2) To a hydrogen reaction kettle was added 4- (4-fluorobenzoyl) butyric acid (compound I, 210g, 1mol), 1L of isopropanol, sodium methoxide (1.08g, 20mmol), and the catalyst solution prepared in step (1) above. The reaction kettle is replaced by hydrogen for three times, finally hydrogen (2.0MPa) is filled, the reaction is carried out for 24 hours at the temperature of 50 ℃, the reduced pressure concentration is carried out, the isopropanol is recovered, and the S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II) is obtained, the yield is 93 percent, and the ee value is 91 percent.
Example 7: preparation of catalyst and asymmetric hydrogenation reaction of catalyzing 4- (4-fluorobenzoyl) butyric acid by catalyst
(1) Reacting a metal complex [ Ir (COD) Cl]2(0.10mmol, 70mg) and ligand L2(0.22mmol, 126mg) were charged into a reaction tube, air was replaced, 10mL of isopropyl alcohol was added under nitrogen atmosphere, and reaction was carried out at 25 ℃ for 2 hours to obtain a catalyst solution.
(2) To a hydrogen reaction vessel were added 4- (4-fluorobenzoyl) butyric acid (compound I, 210g, 1mol), 1L methanol, sodium methoxide (1.08g, 22mmol), and the catalyst solution prepared in the above step (1). After stirring evenly, replacing the reaction kettle with hydrogen for three times, finally filling hydrogen (controlling the pressure in the hydrogen reaction kettle to be 2.0MPa), reacting for 24h at 50 ℃, concentrating under reduced pressure, and recovering isopropanol to obtain the S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II), wherein the yield is 94% and the ee value is 94%.
Example 8: preparation of catalyst and asymmetric hydrogenation reaction of catalyzing 4- (4-fluorobenzoyl) butyric acid by catalyst
(1) Reacting a metal complex [ Ir (COD) Cl]2(0.10mmol, 70mg) and ligand L2(0.22mmol, 126mg) were added to the reaction tube, air was replaced, 10mL of isopropanol was added under a nitrogen atmosphere, 25 deg.CReacting for 2h to obtain a catalyst solution.
(2) To a hydrogen reaction vessel were added 4- (4-fluorobenzoyl) butyric acid (compound I, 210g, 1mol), 1L ethanol, lithium tert-butoxide (1.60g, 20mmol), and the catalyst solution prepared in step (1) above. After uniformly stirring, replacing the reaction kettle with hydrogen for three times, finally filling hydrogen (controlling the pressure in the hydrogen reaction kettle to be 2.0MPa), reacting at 50 ℃ for 24 hours, concentrating under reduced pressure, and recovering isopropanol to obtain the S-5- (4-fluorophenyl) -5-hydroxyvaleric acid (compound II), wherein the yield is 87%, and the ee value is 94%.
Example 9: preparation of ezetimibe intermediate IV from S-5- (4-fluorophenyl) -5-hydroxyvaleric acid
(1) S-5- (4-fluorophenyl) -5-hydroxypentanoic acid (compound II, 170g, 0.8mol) prepared in example 8 was added to 1.5L of DMF at 25 ℃ and imidazole (217g, 3.2mol) was added thereto, followed by stirring uniformly, and TBSCl (180g, 1.2mol) was added in portions, followed by controlling the reaction temperature at 25 ℃ and the reaction time at 12 h. After the reaction is finished, adding saturated ammonium chloride aqueous solution for quenching, extracting by dichloromethane, concentrating the organic layer under reduced pressure, dissolving the obtained crude product by using methyl tert-butyl ether, washing by saturated NaCl aqueous solution, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound III which is directly used in the next step without further purification.
(2) Compound III prepared in step (1) was dissolved in 3L THF at 0 deg.C, triethylamine (222mL, 1.6mol) and pivaloyl chloride (148mL, 1.2mol) were added, the temperature was maintained constant, stirring was carried out for 2 hours, S-4-phenyloxazolidine butan-2-one (compound IV, 130g, 0.8mol) was added in portions, the temperature was raised to 25 deg.C, and the reaction time was 5 hours. Water and methyl tert-butyl ether were added for extraction, the organic phase was collected, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the target intermediate compound V335 g in 89% yield.1H NMR(400MHz，Chloroform-d)δ7.47-7.40(m,2H),7.38-7.29(m,2H),7.26-7.03(m,5H),5.82(t,J＝0.9Hz,1H),4.65(t,J＝0.9Hz,2H),3.57(d,J＝13.5Hz,1H),3.02(t,J＝8.0Hz,2H),1.73-1.59(m,4H),0.86(s,9H),0.15(s,6H)。
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and these modifications or substitutions do not depart from the spirit of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. The preparation method of the ezetimibe intermediate is characterized by comprising the following steps of:
(1) uniformly mixing a metal iridium complex, a chiral ligand L and a solvent A, and carrying out chemical reaction at 20-40 ℃ under the protection of nitrogen for 1-3 hours to prepare a catalyst solution;
the structural formula of the compound shown by the chiral ligand L is as follows:
wherein R is1Represents methyl, ethyl, tert-butyl, phenyl or adamantyl; r2Selected from hydrogen, methyl or ethyl;
(2) uniformly mixing a compound I, alkali, the catalyst solution prepared in the step (1) and a solvent B, introducing hydrogen, controlling the pressure to be 0.1-10.0MPa, and carrying out asymmetric hydrogenation reaction at 25-100 ℃ to prepare a compound II;
(3) dissolving the compound II prepared in the step (2) in a solvent C, adding imidazole and TBSCl, and after uniformly mixing, carrying out chemical reaction at 20-40 ℃ to prepare a compound III;
(4) dissolving the compound III prepared in the step (3) in a solvent D, adding triethylamine and pivaloyl chloride, uniformly mixing, stirring and reacting for 1-3 hours at-5-10 ℃, adding a compound IV, heating to 20-40 ℃ for chemical reaction, and preparing an intermediate compound V; the specific synthetic route is as follows:
2. the process for preparing an ezetimibe intermediate according to claim 1, wherein in step (1), the metal iridium complex is [ ir (cod) Cl [, (ir-cod) Cl ]]2、[Ir(COE)2Cl]2Or [ Ir (COD) OMe]2(ii) a The molar ratio of the metal Ir complex to the chiral ligand L is 1: 1.0-4.0, preferably 1: 2.0-3.0, and more preferably 1: 2.2; the solvent A is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide; preferably, the solvent a is isopropanol.
3. The preparation method of ezetimibe intermediate according to claim 2, wherein in step (1), the chiral ligand L is synthesized by the following route:
4. the process for the preparation of ezetimibe intermediate according to claim 3, wherein in step (1), R is1Represents phenyl or adamantyl; r2Selected from hydrogen or methyl; preferably, the chiral ligand L is selected from the following compounds:
5. the process for preparing an ezetimibe intermediate according to claim 1, wherein in step (2), the base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium methoxide or sodium ethoxide; preferably, the base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide or sodium methoxide; the solvent B is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide; preferably, the solvent B is isopropanol, methanol or ethanol.
6. The preparation method of ezetimibe intermediate as claimed in claim 5, wherein in step (2), the molar ratio of compound I to base is 40-60: 1, preferably 45-50: 1, more preferably 50: 1; the molar ratio of the compound I to the metal iridium complex is 5-15: 1, preferably 8-12: 1, and more preferably 10: 1.
7. The process for the preparation of an ezetimibe intermediate according to claim 6, wherein in step (2), the asymmetric hydrogenation is carried out at a pressure of 1.0 to 3.0MPa, preferably 2.0 MPa; the reaction temperature is 40-60 ℃, and preferably 50 ℃; the reaction time is 20 to 30 hours, preferably 24 hours.
8. The process for the preparation of an ezetimibe intermediate according to claim 1, wherein in step (3), the reaction temperature is 25 ℃; the reaction time is 10-20 hours, preferably 12 hours; the molar ratio of the compound II to the imidazole is 1: 2-8, preferably 1: 3-5, and more preferably 1: 4; the molar ratio of the compound II to the TBSCl is 1: 1.0-2.5, preferably 1: 1.2-1.8, and more preferably 1: 1.5; the solvent C is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide; preferably, the solvent C is N, N-dimethylformamide.
9. The preparation method of the ezetimibe intermediate according to claim 1, wherein in the step (4), the molar ratio of triethylamine to pivaloyl chloride is 1: 0.5-1.0, preferably 1: 0.7-0.8, and more preferably 1: 0.75; the reaction temperature was 0 ℃ before the addition of compound IV; the reaction time is 1 to 3 hours, preferably 2 hours.
10. The process for the preparation of an ezetimibe intermediate according to claim 9, wherein in step (4), after addition of compound IV, the reaction time is 3-8 hours, preferably 5 hours; the solvent D is one or more of N-hexane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, N-butanol or N, N-dimethylformamide; preferably, the solvent D is N, N-dimethylformamide.
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| JP2010083880A (en) * | 2008-09-05 | 2010-04-15 | Teijin Pharma Ltd | 1-biaryl azetidinone derivative |
| CN104513187A (en) * | 2015-01-09 | 2015-04-15 | 安润医药科技（苏州）有限公司 | Ezetimibe synthesis method and Ezetimibe intermediate synthesis method |
| CN109293547A (en) * | 2018-12-10 | 2019-02-01 | 无锡福祈制药有限公司 | A new class of Ezetimibe derivative and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2010083880A (en) * | 2008-09-05 | 2010-04-15 | Teijin Pharma Ltd | 1-biaryl azetidinone derivative |
| CN104513187A (en) * | 2015-01-09 | 2015-04-15 | 安润医药科技（苏州）有限公司 | Ezetimibe synthesis method and Ezetimibe intermediate synthesis method |
| CN109293547A (en) * | 2018-12-10 | 2019-02-01 | 无锡福祈制药有限公司 | A new class of Ezetimibe derivative and preparation method thereof |
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| Title |
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| HUA, YUN-YU ET AL.: "Iridium-Catalyzed Asymmetric Hydrogenation of γ- and δ-Ketoacids for Enantioselective Synthesis of γ- and δ-Lactones", ORGANIC LETTERS, vol. 22, no. 3, pages 818 - 822 * |
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