CN116283901A - 一种不对称制备巴洛沙韦重要中间体的方法 - Google Patents
一种不对称制备巴洛沙韦重要中间体的方法 Download PDFInfo
- Publication number
- CN116283901A CN116283901A CN202310139506.XA CN202310139506A CN116283901A CN 116283901 A CN116283901 A CN 116283901A CN 202310139506 A CN202310139506 A CN 202310139506A CN 116283901 A CN116283901 A CN 116283901A
- Authority
- CN
- China
- Prior art keywords
- asymmetric
- important intermediate
- ligand
- baluo
- sha
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims description 10
- -1 alcohol compound Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 8
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003446 ligand Substances 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 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
- 239000002243 precursor Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 2
- 229910020366 ClO 4 Inorganic materials 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910018286 SbF 6 Inorganic materials 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 1
- 230000009467 reduction Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 15
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 4
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 description 4
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 4
- 238000005750 Corey-Bakshi-Shibata reduction reaction Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 206010022000 influenza Diseases 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- 241000712461 unidentified influenza virus Species 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 102000004533 Endonucleases Human genes 0.000 description 2
- 108010042407 Endonucleases Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 2
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- RZVPBGBYGMDSBG-GGAORHGYSA-N baloxavir marboxil Chemical compound COC(=O)OCOc1c2C(=O)N3CCOC[C@H]3N([C@H]3c4ccc(F)c(F)c4CSc4ccccc34)n2ccc1=O RZVPBGBYGMDSBG-GGAORHGYSA-N 0.000 description 1
- 229940008411 baloxavir marboxil Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D337/12—[b,e]-condensed
-
- 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
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/249—Spiro-condensed ring systems
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种不对称制备巴洛沙韦重要中间体[(R/S)‑7,8‑二氟‑6,11‑二氢‑二苯并[B,E]噻吩并‑11‑醇]的方法。该方法以廉价易得的氢气为氢源,通过手性铱催化剂催化7,8‑二氟二苯并[B,E]噻吩‑11(6H)‑酮的不对称氢化还原,以高选择性和高产率得到手性醇化合物。该方法成本低廉,催化剂用量低、操作简便、易于大规模工业化应用。
Description
技术领域
本发明属于医药合成技术领域,具体涉及一种不对称巴洛沙韦重要中间体[(R/S)-7,8-二氟-6,11-二氢-二苯并[B,E]噻吩并-11-醇]的方法。
背景技术
巴洛沙韦(Baloxavir marboxil)属第三代抗流感化学药物,由日本盐野义制药首创并与罗氏进行全球开发,该药于2018年在日本上市。该药是一种单剂量口服药物,具有全新的抗流感作用机制,通过抑制流感病毒中的cap-依赖型核酸内切酶(cap-dependentendonuclease)起到直接抑制病毒复制的作用,使流感病毒基因组无法正常复制,从而在流感病毒刚进入细胞就阻断了病毒的增殖,其抗流感病毒的能力大大提高。
巴洛沙韦的化学结构如下所示:
专利JP6212678B1报道了巴洛沙韦的原研路线工艺,将消旋化合物式(II)[7,8-二氟-6,11-二氢-二苯并[B,E]噻吩并-11-醇]和化合物式(III)通过Mitsunobu反应制备化合物式(IV),再经脱保护和酯化合成巴洛沙韦,其反应工艺路线如下:
在该路线工艺中,将消旋化合物式(II)[7,8-二氟-6,11-二氢-二苯并[B,E]噻吩并-11-醇]用于巴洛沙韦的合成,不可避免地会产生立体异构体,增加分离难度,降低巴洛沙韦的合成效率,增加“三废”排放,产率低,生产成本高。
选择结构如下单一手性的中间体式(VI)[(R)-7,8-二氟-6,11-二氢-二苯并[B,E]噻吩并-11-醇]来合成巴洛沙韦可以提高合成效率,降低成本。
目前并没有很多的方法合成该芳基醇,除了用硼氢化钠还原成消旋体,再利用手性试剂进行拆分的传统方法外,直接得到手性醇的方法主要包括酶催化、CBS还原以及不对称转移氢化。
2018年,专利CN109504721A报道了酶催化手性还原方法,氢源选自乙醇、异丙醇或葡萄糖,使手性芳基醇的收率达91%,ee值最高可达99%。2019年,专利CN110143944A报道了CBS还原反应应用于巴洛沙韦中间体的手性合成,在CBS-噁唑硼烷的催化作用下,以BH3为还原剂,将羰基还原为手性醇,其ee值高达96%。2021年,专利CN112812095A报道了的钌金属催化剂RuCl(p-cymene)[(S,S)-Ts-DPEN]对巴洛沙韦潜手性中间体实现了过渡金属催化的不对称转移氢化,手性产物的ee值高达98%。2022年,专利CN 114874183A报道了的铑金属催化剂对巴洛沙韦潜手性中间体实现了过渡金属催化的不对称转移氢化,手性产物的ee值高达99%。
尽管上面所介绍的现有专利技术中都取得了不错的产率以及非常高的ee值,但酶催化反应的温度、pH、离子浓度等因素要保持在很适宜且窄的范围内,否则容易导致酶失活;CBS还原反应中硼烷的用量相当大,极易造成环境问题;钌金属催化的不对称转移氢化有着催化剂负载高,且反应温度需达到60-70℃等问题;铑金属催化虽然其对映体选择性好,但其相应的催化剂价格昂贵,工业化面临不少困难。
发明内容
定义
为便于对本发明的理解,除非另外说明的,对本文使用的一些术语、缩写或其它缩略语定义如下。
“烷基”,单用或与其它基团合用时,代表含1~8个碳原子的饱和直链或支链基团,例如:甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、正戊基、正己基、异己基、正庚基、正辛基和正癸基等。
“芳基”,单用或与其它基团合用时,指含有1、2或3个环的任选取代的芳香碳环基团,所述环之间以键连或稠合方式连接,例如:苯基、联苯基、萘基、四氢化萘、二氢化茚,其可进一步被其它芳基或含芳基的取代基取代。
“杂芳基”,单用或与其它基团合用时,指含有1或2个环的任选取代的芳香杂环基团,所述杂环上的杂原子为1~3个,相同或不同,选自O、N、S,例如:苯基、联苯基、萘基、四氢化萘、二氢化茚,其可进一步被其它芳基或含芳基的取代基取代。
COD表示1,5-环辛二烯。
NBD表示降冰片二烯。
发明详述
针对以上问题,本发明提供了一种不对称制备巴洛沙韦重要中间体[(R/S)-7,8-二氟-6,11-二氢-二苯并[B,E]噻吩并-11-醇]的方法。该方法具有成本低廉,催化剂用量低、选择性好、操作简便、易于大规模工业化应用的优点。
本发明的技术方案如下:
上述所用过渡金属铱催化剂由铱金属盐前体和手性配体混合后生成,氢源为氢气。
作为本发明的一种优选方案,合适的铱金属前体包括[Ir(NBD)Cl]2;[Ir(NBD)2]X;[Ir(COD)Cl]2;[Ir(COD)2]X;X为负阴离子,如Cl-,Br-,I-,BF4 -,ClO4 -,SbF6 -,PF6 -,TfO-,RCOO-,优选[Ir(COD)Cl]2。
作为本发明的一种优选方案,本发明提出的手性配体的结构通式(L)如下:
其中,R表示烷基、芳基、取代芳基或者杂环;
X具有以下结构中的任一种:
其中,R1-R5表示C1-C6的烷基、C1-C6的烷氧基、卤素原子、氢原子,R6表示C1-C6的烷基、氢原子或者氮保护基,氮保护基选自苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏甲氧基羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲(或乙)氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Ts)、三氟乙酰基(Tfa)、硝基苯磺酰基(Ns)、特戊酰基、苯甲酰基、三苯甲基(Trt)、2,4-二甲氧基苄基(Dmb)、对甲氧基苄基(PMB)、苄基(Bn)。
进一步地,X具有以下结构中的任一种:
优选地,所述配体的结构包括下述配体,以及每一个配体对应的对映异构体:
更优选,所述配体结构如下:
作为本发明的一种优选方案,不对称氢化所使用的溶剂为甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、乙酸乙酯、正己烷、二氯甲烷、1,2-二氯乙烷、甲苯、二甲苯、1,4-二氧六环、甲基叔丁基醚的一种或者任意比例的混合物。
作为本发明的一种优选方案,不对称氢化反应所用的碱为叔丁醇钾、叔丁醇钠、叔丁醇锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯、甲醇钠、甲醇钾的一种或任意比例的混合物。
作为本发明的一种优选方案,所述中间体(VII)与催化剂的摩尔比为1,000-50,000:1,优选5,000-10,000:1。
作为本发明的一种优选方案,不对称氢化的反应温度为10-80摄氏度;氢气压力为1-10Mpa。
本发明相对于现有技术具有以下有益效果:
(1)本发明提供了一种不对称制备巴洛沙韦重要中间体(R)-7,8-二氟-6,11-二氢-二苯并[B,E]噻吩并-11-醇的方法。反应具有高度的稳定性,实现了优异的立体控制,可以得到大于98%ee的对映选择性的手性醇中间体。
(2)通过大量的实验研究发现,使用优选的催化剂体系Ir/L12,催化剂用量低,反应活性高,催化剂转化数(TON,turnover number)高达5,000。
(3)本发明操作简便、成本低廉、环境友好,有利于大规模工业化应用,具有较高的商业价值。
附图说明
图1,式(VI)的X射线单晶衍射图。
具体实施方式
为了使本发明易于理解,结合具体实施例对本发明做进一步的说明。
实施例中未注明具体条件的实验方法,通常按照常规条件以及手册中所述的条件,或按照制造厂商所建议的条件;所用材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1配体L1的合成
在惰性气氛下,向S1(127.0mg,0.3mmol)的1,2-二氯乙烷溶液中加入醛Q1(43.6mg,0.36mmol),于20-30℃下搅拌均匀,加入醋酸硼氢化钠(212mg,1.0mmol),继续在该温度下反应,TLC监测,至原料S1转化完全。硅藻土过滤,收集滤液,减压浓缩,柱层析纯化得到配体L1(127.0mg,83%yield)。
L1表征数据:1H NMR(600MHz,CDCl3)δ7.93(d,J=3.9Hz,1H),7.37(d,J=6.6Hz,
1H),7.25(d,J=7.8Hz,1H),7.22–7.17(m,3H),7.09(td,J=7.3,1.2Hz,1H),7.02–6.97(m,5H),6.81(td,J=8.0,1.4Hz,2H),6.77–6.72(m,2H),6.60(dd,J=7.1,3.8Hz,1H),6.31(d,J=8.0Hz,1H),5.76(d,J=8.0Hz,1H),5.42(d,J=3.6Hz,1H),5.20(dd,J=9.0,2.8Hz,1H),4.78(dd,J=19.0,9.2Hz,2H),4.62(d,J=9.4Hz,1H),3.92(dd,J=15.9,5.6Hz,1H),3.20(d,J=15.9Hz,1H),2.15(s,3H).13C NMR(151MHz,CDCl3)δ161.15,160.99,160.92,153.93,145.44,144.52,138.07,137.99,136.86,135.55,135.41,134.87,134.80,134.09,133.95,133.24,133.11,132.78,132.61,130.64,129.77,129.50,128.16,128.12,128.01,127.52,127.47,121.43,112.74,112.72,110.87,103.51,98.91,84.49,84.45,81.04,56.38,56.36,44.80,17.17.31P NMR(243MHz,CDCl3)δ-23.34.
实施例2配体L12的合成
在惰性气氛下,向S2(194.4mg,0.3mmol)的1,2-二氯乙烷溶液中加入醛Q2(74.6mg,0.36mmol),于20-30℃下搅拌均匀,加入醋酸硼氢化钠(212mg,1.0mmol),继续在该温度下反应,TLC监测,至原料S1转化完全。硅藻土过滤,收集滤液,减压浓缩,柱层析纯化得到配体L12(188.9mg,75%yield)。
L12表征数据:1H NMR(400MHz,CDCl3)δ9.01(d,J=8.1Hz,1H),7.98(d,J=8.2Hz,
1H),7.88(d,J=7.0Hz,1H),7.78–7.66(m,3H),7.61(d,J=8.8Hz,1H),7.34–7.27(m,3H),7.19(t,J=7.8Hz,1H),7.05(t,J=8.0Hz,1H),6.95(ddd,J=7.7,6.2,1.4Hz,3H),6.85(dd,J=8.0,1.9Hz,2H),6.77(ddd,J=7.6,4.0,1.0Hz,1H),6.35(d,J=7.9Hz,1H),6.01(d,J=8.1Hz,1H),4.88(d,J=9.3Hz,1H),4.70–4.61(m,3H),4.55(t,J=5.2Hz,1H),4.28(dd,J=16.4,5.9Hz,1H),4.06(dd,J=16.4,4.3Hz,1H),1.18(s,18H),1.09(s,18H).13C NMR(101MHz,CDCl3)δ161.65,160.39,160.29,157.24,150.27,150.20,145.73,145.14,145.12,137.24,137.02,136.64,136.54,136.22,134.94,134.83,133.67,132.33,132.06,131.27,130.75,129.55,128.07,128.05,128.00,127.85,127.81,127.58,127.14,126.88,125.11,125.04,124.84,122.82,121.98,119.68,111.52,111.49,110.89,104.36,99.98,82.98,82.93,79.59,56.74,56.71,49.33,34.78,34.74,31.33,31.30.31P NMR(162MHz,CDCl3)δ-20.04.
实施例3(R)-7,8-二氟-6,11-二氢-二苯并[B,E]噻吩并-11-醇[式(VI)]的不对称合成
催化剂的制备:氩气氛围下,将[Ir(COD)Cl]2(3.4mg,5μmol)和手性配体L1(5.6mg,10.5μmol)溶于甲醇(1mL)中,在室温条件下搅拌2小时,得到淡黄色澄清溶液催化剂。
称取中间体酮式(VII)(52.5mg,0.20mmol)溶于甲醇(1mL),加入碳酸铯(6.5mg,0.02mmol)至该溶液中,取上述催化剂溶液20μL(S/C=1000)加入上述反应液。将反应体系置于高压釜中,用氢气置换高压釜中的气体三次,最后充入60atm氢气,在30℃下反应24小时。反应结束后,缓慢释放高压釜中的气体,用硅胶抽滤滤掉碱,用DCM冲洗,减压浓缩得到白色固体,经HPLC分析,转化率88%,测得ee值为93%,过柱分离纯化得到氢化产物式(VI),产率为85%。
I-7,8-二氟-6,11-二氢-二苯并[B,E]噻吩并-11-醇[式(IV)]表征数据:1H NMR(400MHz,CDCl3)δ7.46(dd,J=5.6,3.5Hz,1H),7.23–7.08(m,4H),7.06–6.97(m,1H),6.07(s,1H),4.66(dd,J=14.5,1.4Hz,1H),4.19(dd,J=14.5,1.4Hz,1H),2.85(s,1H).13C NMR(101MHz,CDCl3)δ151.61,151.47,149.13,149.00,148.60,148.47,146.15,146.01,138.61,137.65,137.62,133.35,129.51,128.47,127.39,126.08,123.15,123.03,121.21,121.17,121.15,121.10,115.70,115.53,74.64,74.62,25.14,25.12,25.09,25.06.19F NMR(376MHz,CDCl3)δ-137.69(ddd,J=21.2,9.9,4.8Hz),-142.48(dd,J=20.8,7.6Hz).
实施例4不对称氢化配体筛选
为进一步提高产物的转化率和对映体选择性,参考实施例3的操作,将配体进行改变和修饰,得到的结果如表1所示。综合转化率和对映体选择性结果来看,L10和L12取得了最好的结果,其转化率>99%,ee分别达到了97%和98%。
表1巴洛沙韦中间体不对称氢化配体筛选
实施例5不对称氢化条件优化
参考实施例3的操作,以L12作为配体,对巴洛沙韦中间体式(VII)的不对称氢化反应条件如溶剂、碱、催化剂用量等进行优化,得到的结果如表2所示。结果表明,反应溶剂在甲醇中活性最高,该反应中添加剂碱的种类选择较多,碳酸铯、碳酸钠、碳酸钾、氢氧化钾、甲醇钾、叔丁醇钾等都有较好的转化率和ee值,催化剂用量也进行了优化和筛选,S/C=2000时,其反应均能完全转化成产物;S/C=5000时,在不同碱的存在下,其转化率有细微差别,同时其ee值会下降1-2个点。当使用L12的对映异构体ent-L12作为配体时,可以得到立体构型为“S”反应产物手性醇式(VI)。
表2巴洛沙韦中间体不对称氢化条件优化
实施例6底物拓展
在以上实施例4-5的结果基础上,以[Ir(COD)Cl]2/L12为催化剂体系,甲醇作为反应溶剂,碳酸钠(10mol%)作为碱,S/C=1 000,对相关酮的底物进行拓展研究,得到的结果如表3所示。
表3巴洛沙韦中间体不对称氢化体系底物拓展
以上所述实施例仅代表了本发明的优选实施方式,需要指出的是,对于本技术工艺领域的技术人员,在利用本发明的构思与方法所作出的改进与润饰,同样应当视为在本发明的保护范围之内。
Claims (10)
2.根据权利要求1所述不对称制备巴洛沙韦重要中间体的方法,其特征在于,铱金属前体选自[Ir(NBD)Cl]2;[Ir(NBD)2]X;[Ir(COD)Cl]2;[Ir(COD)2]X;
其中,X为负阴离子,如Cl-,Br-,I-,BF4 -,ClO4 -,SbF6 -,PF6 -,TfO-,RCOO-。
3.根据权利要求1所述不对称制备巴洛沙韦重要中间体的方法,其特征在于,所用的配体具有如下结构:
其中,R表示烷基、芳基、取代芳基或者杂环;
X具有以下结构中的任一种:
其中,R1-R5表示C1-C6的烷基、C1-C6的烷氧基、卤素原子、氢原子,R6表示C1-C6的烷基、氢原子或者氮保护基,氮保护基选自苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏甲氧基羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲(或乙)氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Ts)、三氟乙酰基(Tfa)、硝基苯磺酰基(Ns)、特戊酰基、苯甲酰基、三苯甲基(Trt)、2,4-二甲氧基苄基(Dmb)、对甲氧基苄基(PMB)、苄基(Bn)。
7.根据权利要求1所述不对称制备巴洛沙韦重要中间体的方法,其特征在于,不对称氢化所使用的溶剂为甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、乙酸乙酯、正己烷、二氯甲烷、1,2-二氯乙烷、甲苯、二甲苯、1,4-二氧六环、甲基叔丁基醚的一种或者任意比例的混合物。
8.根据权利要求1所述不对称制备巴洛沙韦重要中间体的方法,其特征在于,不对称氢化反应所用的碱为叔丁醇钾、叔丁醇钠、叔丁醇锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯、甲醇钠、甲醇钾的一种或任意比例的混合物。
9.根据权利要求1所述不对称制备巴洛沙韦重要中间体的方法,其特征在于,所述中间体(VII)与催化剂的摩尔比为1,000-50,000:1;不对称氢化的反应温度为10-80摄氏度;氢气压力为1-10Mpa。
10.由权利要求1至9任一项所述制备方法制得巴洛沙韦重要中间体。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310139506.XA CN116283901A (zh) | 2023-02-13 | 2023-02-13 | 一种不对称制备巴洛沙韦重要中间体的方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310139506.XA CN116283901A (zh) | 2023-02-13 | 2023-02-13 | 一种不对称制备巴洛沙韦重要中间体的方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116283901A true CN116283901A (zh) | 2023-06-23 |
Family
ID=86795276
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310139506.XA Pending CN116283901A (zh) | 2023-02-13 | 2023-02-13 | 一种不对称制备巴洛沙韦重要中间体的方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116283901A (zh) |
-
2023
- 2023-02-13 CN CN202310139506.XA patent/CN116283901A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Hansen et al. | Scalable, efficient process for the synthesis of (R)-3, 5-bistrifluoromethylphenyl ethanol via catalytic asymmetric transfer hydrogenation and isolation as a DABCO inclusion complex | |
Burk et al. | Catalytic asymmetric hydrogenation of β-substituted α, β, γ, δ-unsaturated amino acids | |
CA2353375C (en) | Process for producing optically active alcohol | |
Willems et al. | Asymmetric ketone reduction using chiral oxazaborolidines derived from aziridine carbinols | |
Gladiali et al. | Optically active phenanthrolines in asymmetric catalysis. III. Highly efficient enantioselective transfer hydrogenation of acetophenone by chiral rhodium/3-alkyl phenanthroline catalysts. | |
CN111484459A (zh) | 一种钯催化不对称氢化合成手性3-三氟甲基-3,4-二氢喹喔啉酮的方法 | |
CN115073251A (zh) | 一种不对称催化合成尼古丁的方法 | |
CN114230553A (zh) | 一种左旋烟碱的不对称合成方法 | |
JPWO2008111371A1 (ja) | ホスホロアミド化合物及びその製造方法、配位子、錯体、触媒、及び光学活性アルコールの製造方法 | |
CN116283901A (zh) | 一种不对称制备巴洛沙韦重要中间体的方法 | |
US6620954B1 (en) | Phosphinometallocenylamides as novel ligands for asymmetric catalysis | |
CN112675920B (zh) | 一类单手性中心催化剂及其制备和催化合成手性醇类化合物和手性α-烯丙醇的方法 | |
JP3159661B2 (ja) | 光学活性アルコール類の製造方法 | |
US20090227805A1 (en) | Axially Asymmetric Phosphorus Compound and Production Method Thereof | |
CN107686460B (zh) | 一种3-取代-3-羟基-2-吲哚酮类化合物的制备方法 | |
EP2275427B1 (en) | Ruthenium-diamine complex and methods for producing optically active compounds | |
CN115160162B (zh) | 一种α氨基β酮酸酯的不对称氢化方法 | |
KR100340760B1 (ko) | (알)-(-)-무스콘의 입체선택적 제조 방법 | |
CN110790708B (zh) | 一种艾利西平中间体的制备方法 | |
CN117720537B (zh) | 一种轴手性吲哚-呋喃类催化剂及其制备方法与应用 | |
CN115232086B (zh) | 一种4-苄基-2(3h)-噁唑酮的制备方法 | |
CN117142917A (zh) | 一种钯催化不对称氢化合成手性4-取代3-烷氧羰基丁内酯类衍生物的方法 | |
JP2005306804A (ja) | 光学活性3−キヌクリジノールの製造方法 | |
Wei et al. | Synthesis of chiral diamine ligands derived from cinchona alkaloids and their catalytic performance for asymmetric transfer hydrogenation | |
CN116947580A (zh) | 一种铑催化的蒽的氢化去对称化构建轴手性化合物的方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |