CN105622661A - Molecular sieve catalytic synthesis method of ezetimibe midbody - Google Patents
Molecular sieve catalytic synthesis method of ezetimibe midbody Download PDFInfo
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- CN105622661A CN105622661A CN201511016734.XA CN201511016734A CN105622661A CN 105622661 A CN105622661 A CN 105622661A CN 201511016734 A CN201511016734 A CN 201511016734A CN 105622661 A CN105622661 A CN 105622661A
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- zsm
- molecular sieve
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- sieve catalyst
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- 239000002808 molecular sieve Substances 0.000 title claims abstract description 73
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 238000000034 method Methods 0.000 title claims description 21
- 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 title abstract description 14
- 229960000815 ezetimibe Drugs 0.000 title abstract description 12
- 238000007036 catalytic synthesis reaction Methods 0.000 title 1
- 239000003054 catalyst Substances 0.000 claims abstract description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 239000001301 oxygen Substances 0.000 claims abstract description 9
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 229940126062 Compound A Drugs 0.000 claims description 20
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 20
- 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 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003223 protective agent Substances 0.000 claims description 11
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 239000010941 cobalt Substances 0.000 claims description 8
- 229910017052 cobalt Inorganic materials 0.000 claims description 8
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 229910052710 silicon Inorganic materials 0.000 claims description 5
- 239000010703 silicon Substances 0.000 claims description 5
- UUOOAIRCIZPMJT-UHFFFAOYSA-N CN(C)C.[Si+4] Chemical compound CN(C)C.[Si+4] UUOOAIRCIZPMJT-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000007605 air drying Methods 0.000 claims description 3
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- 238000004458 analytical method Methods 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- 239000007787 solid Substances 0.000 abstract description 16
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000003912 environmental pollution Methods 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 abstract description 4
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 abstract description 4
- 238000011084 recovery Methods 0.000 abstract description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract 1
- 238000010924 continuous production Methods 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 239000008367 deionised water Substances 0.000 description 9
- 229910021641 deionized water Inorganic materials 0.000 description 9
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 8
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 8
- 238000005119 centrifugation Methods 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 8
- 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 6
- 238000005342 ion exchange Methods 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 5
- 229940011182 cobalt acetate Drugs 0.000 description 4
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- GGKNTGJPGZQNID-UHFFFAOYSA-N (1-$l^{1}-oxidanyl-2,2,6,6-tetramethylpiperidin-4-yl)-trimethylazanium Chemical compound CC1(C)CC([N+](C)(C)C)CC(C)(C)N1[O] GGKNTGJPGZQNID-UHFFFAOYSA-N 0.000 description 2
- 101710194905 ARF GTPase-activating protein GIT1 Proteins 0.000 description 2
- 102100035959 Cationic amino acid transporter 2 Human genes 0.000 description 2
- 102100021391 Cationic amino acid transporter 3 Human genes 0.000 description 2
- 102100021392 Cationic amino acid transporter 4 Human genes 0.000 description 2
- 101710195194 Cationic amino acid transporter 4 Proteins 0.000 description 2
- 102100029217 High affinity cationic amino acid transporter 1 Human genes 0.000 description 2
- 101710081758 High affinity cationic amino acid transporter 1 Proteins 0.000 description 2
- 108091006231 SLC7A2 Proteins 0.000 description 2
- 108091006230 SLC7A3 Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical group C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000005554 pickling Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000000563 Hyperlipoproteinemia Type II Diseases 0.000 description 1
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 1
- 206010063985 Phytosterolaemia Diseases 0.000 description 1
- 208000002227 Sitosterolemia Diseases 0.000 description 1
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- UFMZWBIQTDUYBN-UHFFFAOYSA-N cobalt dinitrate Chemical compound [Co+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O UFMZWBIQTDUYBN-UHFFFAOYSA-N 0.000 description 1
- 229910001981 cobalt nitrate Inorganic materials 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000012809 cooling fluid Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 201000001386 familial hypercholesterolemia Diseases 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007172 homogeneous catalysis Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000011949 solid catalyst Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 229940051223 zetia Drugs 0.000 description 1
Classifications
-
- 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
- B01J29/00—Catalysts comprising molecular sieves
- B01J29/04—Catalysts comprising molecular sieves having base-exchange properties, e.g. crystalline zeolites
- B01J29/06—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof
- B01J29/40—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof of the pentasil type, e.g. types ZSM-5, ZSM-8 or ZSM-11, as exemplified by patent documents US3702886, GB1334243 and US3709979, respectively
-
- 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
- B01J29/00—Catalysts comprising molecular sieves
- B01J29/04—Catalysts comprising molecular sieves having base-exchange properties, e.g. crystalline zeolites
- B01J29/06—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof
- B01J29/40—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof of the pentasil type, e.g. types ZSM-5, ZSM-8 or ZSM-11, as exemplified by patent documents US3702886, GB1334243 and US3709979, respectively
- B01J29/42—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof of the pentasil type, e.g. types ZSM-5, ZSM-8 or ZSM-11, as exemplified by patent documents US3702886, GB1334243 and US3709979, respectively containing iron group metals, noble metals or copper
- B01J29/46—Iron group metals or copper
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- 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
- B01J2229/00—Aspects of molecular sieve catalysts not covered by B01J29/00
- B01J2229/10—After treatment, characterised by the effect to be obtained
- B01J2229/18—After treatment, characterised by the effect to be obtained to introduce other elements into or onto the molecular sieve itself
- B01J2229/186—After treatment, characterised by the effect to be obtained to introduce other elements into or onto the molecular sieve itself not in framework positions
-
- 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
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of an ezetimibe midbody 3-[(2R, 5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl (amino)]][4-R1oxygroup] phenyl] methyl]-1- oxo-5-[(trimethylsilyl) oxygen] phenyl]-4-phenyl-(4S)-2-oxazolidinone.A solid H-ZSM-5 molecular sieve based catalysts and/or a Co-ZSM-5 molecular sieve based catalysts are/is adopted to replace an original titanium tetrachloride and isopropyl titanate catalyst, so that the environmental pollution and the requirement on production equipment are reduced, the separation and recovery problems of the catalyst are solved, and a foundation is laid for large-scale continuous production of ezetimibe.
Description
Technical field
The application relates to a kind of Ezetimibe intermediate 3-[(2R, 5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl (amino)]] [4-R1Oxygen base] phenyl] methyl]-1-oxo-5-[(trimethylammonium silicon) oxygen] phenyl] preparation method of-4-phenyl-(4S)-2-oxazolidone, belong to pharmaceutical synthesis field.
Background technology
Ezetimibe sheet is a novel anticholesteremic agent of class, is a kind of selectivity cholesterol absorption inhibitor, the main external source absorption features blocking cholesterol. It suppresses the absorption of enteron aisle inner cholesterol by acting on cholesterol transport albumen. Further, Ezetimibe f hardlyes pass through cytochrome P 450 enzymes metabolism, and interaction between other drug is few, and security and tolerance are good.
Ezetimibe (Ezetimibe) is called according to ezetimibe, Zetia, jointly develops successfully by Schering Plough (Schering Plough) company and Merck (Merck) company the earliest. U.S. FDA approval listing on October 25th, 2002, commodity are called Ai ZetingAfter in Canada, Japan, European Union, China etc. all list. Commodity in China's listing benefit by name is suitable pureFormulation is tablet, specification: 10mg/ sheet, for the treatment of primary hypercholesterolemia, homozygote familial hypercholesterolemia, homozygote Sitosterolemia.
The synthesis of Ezetimibe and intermediate thereof mainly taking titanium tetrachloride and titanium isopropylate as the homogeneous catalysis methodology of organic synthesis of catalyzer, its exist cost height, environmental pollution, to the requirement height of production unit and feed moisture content, be difficult to successive reaction, catalyzer be difficult to the problems such as recovery.
Summary of the invention
An aspect according to the application, it is provided that a kind of Ezetimibe intermediate 3-[(2R, 5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl (amino)]] [4-R1Oxygen base] phenyl] methyl]-1-oxo-5-[(trimethylammonium silicon) oxygen] phenyl] preparation method of-4-phenyl-(4S)-2-oxazolidone, by adopting solid H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst to instead of original titanium tetrachloride and titanium isopropylate catalyzer, reduce environmental pollution and the requirement to production unit, solve separation and the recovery problem of catalyzer, make the large scale continuous prod of Ezetimibe become possibility.
Ezetimibe intermediate described in the application is the intermediate being produced Ezetimibe technique by following step:
The first step: condensation reaction
2nd step: ring-closure reaction
3rd step: hydrolysis reaction
4th step: recrystallization is purified
By organic dissolution to the crude product after hydrolysis reaction, carry out recrystallization purification, obtain the Ezetimibe of high purity.
The preparation method of Ezetimibe intermediate described in the application, the first step being in above-mentioned steps, it is characterised in that, by containing the raw material of compound A and compound B, with H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts, prepare described Ezetimibe intermediate;
Described compound A is (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl base]-4-phenyl-1,3-oxazolidine-2-ketone, and structural formula is such as formula shown in I:
Described compound B is 4-(4-fluorophenyl imines) methylphenol, and structural formula is such as formula shown in II:
Described Ezetimibe intermediate is 3-[(2R, 5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl (amino)]] [4-R1Oxygen base] phenyl] methyl]-1-oxo-5-[(trimethylammonium silicon) oxygen] phenyl]-4-phenyl-(4S)-2-oxazolidone, structural formula is as shown in formula III:
Wherein, R1At least one being selected from the group with structural formula shown in formula IV:
Wherein, R11, R12, R13Separately it is selected from the alkyl that carbonatoms is no more than 10.
Preferably, the R in formula IV11, R12, R13In have at least one to be methyl. Further preferably, the R in formula IV11, R12, R13It it is all methyl.
Preferably, in described H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst, the weight percentage of H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is not less than 30%. Further preferably, in described H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst, the weight percentage of H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is 50%��100%.
Preferably, the sial atomic ratio Si/Al in described H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is no more than 50.
Further preferably, the sial atomic ratio Si/Al in described H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is 25��50.
Described Co-ZSM-5 molecular sieve is obtained by ion exchange method or pickling process.
Preferably, in described Co-ZSM-5 molecular sieve, the weight percentage of cobalt element in Co-ZSM-5 molecular sieve is 0.1��5wt%. Further preferably, in described Co-ZSM-5 molecular sieve, the weight percentage of cobalt element in Co-ZSM-5 molecular sieve is 0.5��2wt%.
Preferably, the sial atomic ratio Si/Al in described Co-ZSM-5 molecular sieve is no more than 50. Further preferably, the sial atomic ratio Si/Al in described Co-ZSM-5 molecular sieve is 25��50.
The technician of this area, it is possible to according to the needs of the needs of actual production and concrete technique, select the ratio of H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst and raw material. Preferably, weight ratio 1:1��100 of compound A in H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst and raw material. Further preferred, weight ratio 1:3��30 of compound A in H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst and raw material.
Preferably, in described raw material, the mol ratio of compound A and compound B is 1:1��3. Further preferably, in described raw material, the mol ratio of compound A and compound B is 1:2��3.
Also containing organic amine, hydroxy-protecting agent and organic solvent in described raw material. The technician of this area, it is possible to according to the needs of the needs of actual production and concrete technique, select the add-on of suitable organic amine, hydroxy-protecting agent and organic solvent. Preferably, in raw material, the part by weight of organic amine and compound A is 0.2��1:1; Hydroxy-protecting agent: the molar ratio of (compound A+ compound B) is 1��2:1; The part by weight of organic solvent and compound A is 4��10:1. Further preferably, in raw material, the part by weight of organic amine and compound A is 0.5��0.8:1; Hydroxy-protecting agent: the molar ratio of (compound A+ compound B) is 1.2��1.6:1; The mass ratio of organic solvent and compound A is 5��8:1.
Preferably, at least one that described organic amine is selected from triethylamine, N, N-diisopropylethylamine, pyridine, piperidines, morpholine.
Preferably, at least one that described organic solvent is selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF), toluene.
Preferably, at least one that described hydroxy-protecting agent is selected from the compound with structural formula shown in formula V:
Wherein, R11, R12, R13Separately it is selected from the alkyl that carbonatoms is no more than 10; X is selected from least one in haloid element. Further preferably, described hydroxy-protecting agent is trimethylchlorosilane.
Preferably, the temperature of reaction of described raw material and H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts is-30 DEG C��-20 DEG C. Further preferably, the temperature of reaction of described raw material and H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts is-30 DEG C��-25 DEG C.
As one preferred embodiment, the preparation method of described Ezetimibe intermediate, at least comprises following step:
A) being dissolved in organic solvent by compound A and compound B, system temperature is down to less than-20 DEG C, adds organic amine and hydroxy-protecting agent, obtains raw material;
B), at-30 DEG C��-20 DEG C, after step a) gained raw material and H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts, acid solution termination reaction is added;
C) add the two front three silicon yl acetamide of N, O-, after extracting and concentrating, add crystallization solvent, crystallize out drying, obtain described Ezetimibe intermediate.
Preferably, step b) in the acid solution at least one that is selected from formic acid, acetic acid, hydrochloric acid, sulfuric acid, perchloric acid.
Preferably, step c) described crystallization solvent is made up of normal heptane and ethyl acetate, and the volume ratio of normal heptane and ethyl acetate is 2��3:1.
Preferably, step c) in 30��40 DEG C add N, the two front three silicon yl acetamide of O-, reflux after 1��3 hour, crystallization solvent is added in 40��50 DEG C, stirring is cooled to 10��20 DEG C of analysis after being no less than 1 hour brilliant, and gained crystal, through 40��50 DEG C of forced air dryings, can obtain described Ezetimibe intermediate.
The useful effect of the application includes but not limited to:
(1) method that the application provides, by adopting solid H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst to instead of original titanium tetrachloride and titanium isopropylate catalyzer, reduces environmental pollution and the requirement to production unit.
(2) method that the application provides, catalyzer is convenient to separation, it is possible to reclaims and uses.
(3) method that the application provides, adopts solid catalyst, makes the large scale continuous prod of Ezetimibe become possibility.
Embodiment
Below in conjunction with embodiment in detail the application is described in detail, but the application is not limited to these embodiments.
The preparation of embodiment 1H-ZSM-5 catalyzer
The preparation of CAT-1:
The ZSM-5 molecular sieve (silica alumina ratio Si/Al=25) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 2mol/L, and 80 DEG C of stirred in water bath 2 hours, carry out ion-exchange. After repeatedly exchanging three times, the solid sample that centrifugation obtains, after dry at deionized water wash 3 times, 100 DEG C, roasting 4 hours at 550 DEG C, gained H-ZSM-5 sieve sample, is designated as CAT-1.
The preparation of CAT-2:
The ZSM-5 molecular sieve (silica alumina ratio Si/Al=30) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 2mol/L, and 80 DEG C of stirred in water bath 2 hours, carry out ion-exchange. After repeatedly exchanging three times, after dry at deionized water wash 3 times, 100 DEG C, roasting 4 hours at 550 DEG C, gained H-ZSM-5 sieve sample, is designated as CAT-2.
The preparation of CAT-3:
The ZSM-5 molecular sieve (silica alumina ratio Si/Al=50) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 2mol/L, and 80 DEG C of stirred in water bath 2 hours, carry out ion-exchange. After repeatedly exchanging three times, the solid sample that centrifugation obtains, after dry at deionized water wash 3 times, 100 DEG C, roasting 4 hours at 550 DEG C, gained H-ZSM-5 sieve sample, is designated as CAT-3.
The preparation of embodiment 2Co-ZSM-5 catalyzer
The preparation (ion exchange method) of CAT-4:
The sodium form ZSM-5 molecular sieve (silica alumina ratio Si/Al=25) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 1mol/L, 80 DEG C of stirred in water bath 2 hours, repeatedly exchanges three times. The solid sample that centrifugation obtains, after dry at deionized water wash 3 times, 100 DEG C, adds in the cobalt nitrate solution that 500mL concentration is 1mol/L by gained solid sample, and 80 DEG C of stirred in water bath 2 hours, carry out ion-exchange, repeatedly exchange three times. The solid sample that centrifugation obtains, after dry at deionized water wash 3 times, 100 DEG C, roasting 4 hours at 550 DEG C, gained Co-ZSM-5 sieve sample, is designated as CAT-4.
The preparation (pickling process) of CAT-5:
The sodium form ZSM-5 molecular sieve (silica alumina ratio Si/Al=30) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 1mol/L, 80 DEG C of stirred in water bath 2 hours, repeatedly exchange three times, the solid sample that centrifugation obtains, at deionized water wash 3 times, 100 DEG C after drying, gained solid sample is adopted equi-volume impregnating, 4h is flooded in cobalt acetate solution, 16h is dried through 110 DEG C, roasting 4 hours at 550 DEG C, the weight percentage preparing cobalt element is the Co-ZSM-5 sieve sample of 0.1wt%, is designated as CAT-5.
The preparation of CAT-6:
The sodium form ZSM-5 molecular sieve (silica alumina ratio Si/Al=50) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 1mol/L, 80 DEG C of stirred in water bath 2 hours, repeatedly exchange three times, the solid sample that centrifugation obtains, at deionized water wash 3 times, 100 DEG C after drying, gained solid sample is adopted equi-volume impregnating, 4h is flooded in cobalt acetate solution, 16h is dried through 110 DEG C, roasting 4 hours at 550 DEG C, the weight percentage preparing cobalt element is the Co-ZSM-5 sieve sample of 0.5wt%, is designated as CAT-6.
The preparation of CAT-7:
The sodium form ZSM-5 molecular sieve (silica alumina ratio Si/Al=30) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 1mol/L, 80 DEG C of stirred in water bath 2 hours, repeatedly exchange three times, the solid sample that centrifugation obtains, at deionized water wash 3 times, 100 DEG C after drying, gained solid sample is adopted equi-volume impregnating, 4h is flooded in cobalt acetate solution, 16h is dried through 110 DEG C, roasting 4 hours at 550 DEG C, the weight percentage preparing cobalt element is the Co-ZSM-5 sieve sample of 2wt%, is designated as CAT-7.
The preparation of CAT-8:
The sodium form ZSM-5 molecular sieve (silica alumina ratio Si/Al=30) taking 10g adds in the ammonium nitrate solution that 500mL concentration is 1mol/L, 80 DEG C of stirred in water bath 2 hours, repeatedly exchange three times, the solid sample that centrifugation obtains, at deionized water wash 3 times, 100 DEG C after drying, gained solid sample is adopted equi-volume impregnating, 4h is flooded in cobalt acetate solution, 16h is dried through 110 DEG C, roasting 4 hours at 550 DEG C, the weight percentage preparing cobalt element is the Co-ZSM-5 sieve sample of 5wt%, is designated as CAT-8.
Embodiment 3 is reacted
Reaction raw materials
According to the proportioning of table 1, being dissolved in organic solvent by compound A and compound B respectively, system temperature is down to-20 DEG C, adds organic amine and hydroxy-protecting agent, and the reaction raw materials obtained is as shown in table 1.
Table 1 reaction raw materials
Note*: A is compound A; B is compound B.
Tank reactor
300g reaction raw materials is added in 1L tank reactor, then according to table 2, catalyzer is joined in tank reactor. Containing cooling tube in tank reactor, cooling tube leads to into cooling fluid, the temperature in tank reactor is controlled the temperature shown in table 2, everywhere all without thermograde in reactor.
Reaction 1#��reaction 8#Reaction conditions be shown in Table 2.
Table 2
Note*: mass space velocity WHSV
Reaction
Reaction 1#��reaction 8#Under the reaction conditions of table 2 correspondence, leading in reactor by raw material, with catalyzer contact reacts, after reaction terminates, collect material in reactor, after filtering separation reclaims catalyzer, filtrate adds the acid solution in table 3 with termination reaction. Adding the two front three silicon yl acetamide of N, O-again, after extracting and concentrating, add the crystallization solvent in table 3, crystallize out, through 45 DEG C of forced air dryings, obtains described Ezetimibe intermediate.
Reclaim catalyzer reaction repeated again, until inactivation, obtain catalyst life and be shown in Table 3.
Table 3
Note*: mass space velocity WHSV
The above, it is only several embodiments of the application, not the application is done any type of restriction, although the application discloses as above with better embodiment, but and be not used to restriction the application, any those skilled in the art, in the scope not departing from technical scheme, utilize the technology contents of above-mentioned announcement to make a little variation or modify and all it is equal to equivalence case study on implementation, all belong within the scope of technical scheme.
Claims (10)
1. the preparation method of an Ezetimibe intermediate, it is characterised in that, containing the raw material of compound A and compound B, with H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts, described Ezetimibe intermediate will be prepared;
Described compound A is (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl base]-4-phenyl-1,3-oxazolidine-2-ketone, and structural formula is such as formula shown in I:
Described compound B is 4-(4-fluorophenyl imines) methylphenol, and structural formula is such as formula shown in II:
Described Ezetimibe intermediate is 3-[(2R, 5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl (amino)]] [4-R1Oxygen base] phenyl] methyl]-1-oxo-5-[(trimethylammonium silicon) oxygen] phenyl]-4-phenyl-(4S)-2-oxazolidone, structural formula is as shown in formula III:
Wherein, R1At least one being selected from the group with structural formula shown in formula IV:
Wherein, R11, R12, R13Separately it is selected from the alkyl that carbonatoms is no more than 10.
2. method according to claim 1, it is characterised in that, the R in formula IV11, R12, R13In have at least one to be methyl; Preferably, the R in formula IV11, R12, R13It it is all methyl.
3. method according to claim 1, it is characterised in that, in described H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst, the weight percentage of H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is not less than 30%;
Preferably, in described H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst, the weight percentage of H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is 50%��100%.
4. method according to claim 1, it is characterised in that, the sial atomic ratio Si/Al in described H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is no more than 50;
Preferably, the sial atomic ratio Si/Al in described H-ZSM-5 molecular sieve and/or Co-ZSM-5 molecular sieve is 25��50;
In described Co-ZSM-5 molecular sieve, the weight percentage of cobalt element in Co-ZSM-5 molecular sieve is 0.1��5wt%;
Preferably, in described Co-ZSM-5 molecular sieve, the weight percentage of cobalt element in Co-ZSM-5 molecular sieve is 0.5��2wt%.
5. method according to claim 1, it is characterised in that, in described raw material, the mol ratio of compound A and compound B is 1:1��3; Preferably, in described raw material, the mol ratio of compound A and compound B is 1:2��3.
6. method according to claim 1, it is characterised in that, containing organic amine, hydroxy-protecting agent and organic solvent in described raw material; At least one that described organic amine is selected from triethylamine, N, N-diisopropylethylamine, pyridine, piperidines, morpholine;
At least one that described organic solvent is selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF), toluene;
At least one that described hydroxy-protecting agent is selected from the compound with structural formula shown in formula V:
Wherein, R11, R12, R13Separately it is selected from the alkyl that carbonatoms is no more than 10; X is selected from least one in haloid element.
7. method according to claim 1, it is characterised in that, the temperature of reaction of described raw material and H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts is-30 DEG C��-20 DEG C; Preferably, the temperature of reaction of described raw material and H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts is-30 DEG C��-25 DEG C.
8. method according to claim 1 or 6, it is characterised in that, at least comprise following step:
A) being dissolved in organic solvent by compound A and compound B, system temperature is down to less than-20 DEG C, adds organic amine and hydroxy-protecting agent, obtains raw material;
B), at-30 DEG C��-20 DEG C, after step a) gained raw material and H-ZSM-5 molecular sieve catalyst and/or Co-ZSM-5 molecular sieve catalyst contact reacts, acid solution termination reaction is added;
C) add the two front three silicon yl acetamide of N, O-, after extracting and concentrating, add crystallization solvent, crystallize out drying, obtain described Ezetimibe intermediate.
9. method according to claim 8, it is characterised in that, step b) in the acid solution at least one that is selected from formic acid, acetic acid, hydrochloric acid, sulfuric acid, perchloric acid; Step c) described crystallization solvent is made up of normal heptane and ethyl acetate, and the volume ratio of normal heptane and ethyl acetate is 2��3:1.
10. method according to claim 8, it is characterized in that, step c) in 30��40 DEG C add N, the two front three silicon yl acetamide of O-, reflux after 1��3 hour, add crystallization solvent in 40��50 DEG C, stir and after being no less than 1 hour, be cooled to 10��20 DEG C of analysis crystalline substances, gained crystal, through 40��50 DEG C of forced air dryings, can obtain described Ezetimibe intermediate.
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| US6207822B1 (en) * | 1998-12-07 | 2001-03-27 | Schering Corporation | Process for the synthesis of azetidinones |
| CN103864708A (en) * | 2012-12-12 | 2014-06-18 | 天津市医药集团技术发展有限公司 | Preparation method of ezetimibe intermediate |
| CN104402790A (en) * | 2014-12-28 | 2015-03-11 | 严白双 | Improved method for preparing ezetimibe |
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