CN117886789A - Synthesis method of chiral alcohol or chiral cyclic ether - Google Patents
Synthesis method of chiral alcohol or chiral cyclic ether Download PDFInfo
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- 150000004292 cyclic ethers Chemical class 0.000 title claims abstract description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000001308 synthesis method Methods 0.000 title claims abstract description 20
- 239000003446 ligand Substances 0.000 claims abstract description 30
- 239000002243 precursor Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims description 53
- 239000003054 catalyst Substances 0.000 claims description 41
- 150000001875 compounds Chemical class 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 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
- 239000011261 inert gas Substances 0.000 claims description 24
- 229910052723 transition metal Inorganic materials 0.000 claims description 22
- 150000003624 transition metals Chemical class 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- -1 nitro, amino Chemical group 0.000 claims description 18
- 239000000010 aprotic solvent Substances 0.000 claims description 15
- 238000003786 synthesis reaction Methods 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 150000007514 bases Chemical class 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- 230000000536 complexating effect Effects 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 239000001307 helium Substances 0.000 claims description 3
- 229910052734 helium Inorganic materials 0.000 claims description 3
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 3
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 3
- 229910052743 krypton Inorganic materials 0.000 claims description 3
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052754 neon Inorganic materials 0.000 claims description 3
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 229910052724 xenon Inorganic materials 0.000 claims description 3
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 abstract description 5
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 229910052741 iridium Inorganic materials 0.000 abstract 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- 239000002904 solvent Substances 0.000 description 13
- 230000000975 bioactive effect Effects 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 150000001298 alcohols Chemical class 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 6
- AQYSYJUIMQTRMV-UHFFFAOYSA-N hypofluorous acid Chemical compound FO AQYSYJUIMQTRMV-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 150000002431 hydrogen Chemical group 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- NYNZQNWKBKUAII-KBXCAEBGSA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 NYNZQNWKBKUAII-KBXCAEBGSA-N 0.000 description 4
- 102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- JQBKWZPHJOEQAO-DVPVEWDBSA-N faropenem medoxil Chemical compound S([C@@H]1[C@H](C(N1C=1C(=O)OCC2=C(OC(=O)O2)C)=O)[C@H](O)C)C=1[C@H]1CCCO1 JQBKWZPHJOEQAO-DVPVEWDBSA-N 0.000 description 4
- 229950009817 faropenem medoxil Drugs 0.000 description 4
- 229950003970 larotrectinib Drugs 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 150000001450 anions Chemical class 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- JGXZVDAPLSTBGZ-IRPSRAIASA-N (+)-Myristinin A Chemical compound CCCCCCCCCCCC(=O)C1=C(O)C=C(O)C([C@H]2C3=CC=C(O)C=C3O[C@@H](C2)C=2C=CC(O)=CC=2)=C1O JGXZVDAPLSTBGZ-IRPSRAIASA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- 229960000379 faropenem Drugs 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- CZSDJYXNNJQXBB-UHFFFAOYSA-N 10-methoxy-2,2,4-trimethyl-5-prop-2-enyl-1,5-dihydrochromeno[3,4-f]quinoline Chemical compound N1C(C)(C)C=C(C)C2=C1C=CC1=C2C(CC=C)OC2=C1C(OC)=CC=C2 CZSDJYXNNJQXBB-UHFFFAOYSA-N 0.000 description 1
- HGGAKXAHAYOLDJ-FHZUQPTBSA-N 6alpha-[(R)-1-hydroxyethyl]-2-[(R)-tetrahydrofuran-2-yl]pen-2-em-3-carboxylic acid Chemical compound S([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1[C@H]1CCCO1 HGGAKXAHAYOLDJ-FHZUQPTBSA-N 0.000 description 1
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N benzofuran Natural products C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 description 1
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 description 1
- 229950011318 cannabidiol Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JGXZVDAPLSTBGZ-UHFFFAOYSA-N myristinin C Natural products CCCCCCCCCCCC(=O)C1=C(O)C=C(O)C(C2C3=CC=C(O)C=C3OC(C2)C=2C=CC(O)=CC=2)=C1O JGXZVDAPLSTBGZ-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 102220079670 rs759826252 Human genes 0.000 description 1
- DJOJDHGQRNZXQQ-AWEZNQCLSA-N sakuranetin Chemical compound C1([C@@H]2CC(=O)C3=C(O)C=C(C=C3O2)OC)=CC=C(O)C=C1 DJOJDHGQRNZXQQ-AWEZNQCLSA-N 0.000 description 1
- RNAPFFYGJWALAQ-UHFFFAOYSA-N sakuranetin Natural products O1C2=CC(C)=CC(O)=C2C(=O)CC1C1=CC=C(O)C=C1 RNAPFFYGJWALAQ-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application discloses a synthesis method of chiral alcohol or chiral cyclic ether. The synthesis method reduces 2-fluoroaryl ketone by using a simple and easy-to-synthesize chiral Ir/f-phamidol complex efficient asymmetric catalytic hydrogenation method, and divergently synthesizes chiral alcohol shown in a structural formula II or chiral cyclic ether shown in a structural formula III through one-step reaction; wherein the chiral Ir/f-phamidol complex is metallic iridium precursor [ Ir (COD) Cl ]] 2 Complexes with f-phamidol structural ligands. The synthesis method has the advantages of simplicity, easiness in operation, high catalytic efficiency, high yield and high enantioselectivity; and, adoptThe used raw materials are cheap and easy to obtain, the cost is low, and a new scheme and a new way are provided for the large-scale production of chiral alcohol or chiral cyclic ether.
Description
Technical Field
The application relates to the technical field of chemical synthesis, in particular to a synthesis method of chiral alcohol or chiral cyclic ether.
Background
Chiral alcohols and chiral cyclic ether fragments are widely available in bioactive compounds and natural products, are key intermediates of many clinical drug molecules, and have good application value in the field of asymmetric catalysis. In recent years, enantioselective synthesis of chiral cyclic ether compounds has progressed rapidly. However, the existing asymmetric hydrogenation method for synthesizing chiral cyclic ether is limited by the difficulty in substrate synthesis, and the chiral cyclic ether cannot be obtained through one-step reaction, so that the catalytic efficiency is low, and the green economic concept is violated.
Chiral alcohols and chiral cyclic ether fragments are widely found in biologically active compounds and natural products, for example, cannabidiol, candenatin E, sakuranetin, AL-438, myristinin A and the like, each carry chiral cyclic ether fragments in biologically active molecules. In addition, chiral alcohols and chiral cyclic ethers are also useful as intermediates for many drugs, for example, as intermediates for larrotinib (Larotrectinib), faropenem ester (Faropenem medoxomil). Therefore, chiral alcohols and chiral cyclic ethers have important applications in the field of bioactive substances and pharmaceutical synthesis.
In recent years, enantioselective synthesis of chiral cyclic ether compounds has also been rapidly developed, compared to the mature and efficient technique of asymmetric hydrogenation of unsaturated ketone compounds. Methods such as Rawal et al, which utilize palladium-catalyzed etherification of intramolecular phenolic hydroxyl groups to synthesize benzocyclic ether compounds, followed by decarboxylation etherification, have also been developed. Cai Qian et al developed a palladium-catalyzed method of asymmetric carbon-oxygen bond coupling to synthesize chiral benzocyclic ether compounds. Asymmetric hydrogenation of transition metal catalyzed benzofuran derivatives is also an important method for synthesizing benzo ethers. Liu Lei et al developed an oxidative de-racemization reduction strategy that enabled dynamic kinetic asymmetric conversion of racemic cyclic benzocyclic ethers followed by dynamic resolution asymmetric oxidation of racemic cyclic benzocyclic ethers.
Despite the significant advances made in the synthesis of chiral cyclic ethers today, it remains important to develop asymmetric synthetic methods that are more practical, more efficient, and have higher yields and enantioselectivities.
Disclosure of Invention
The object of the present application is to provide a novel synthesis method of chiral alcohols or chiral cyclic ethers.
In order to achieve the above purpose, the present application adopts the following technical scheme:
the application discloses a synthesis method of chiral alcohol or chiral cyclic ether, which comprises the steps of carrying out a first reaction on a compound shown as a structural formula I and hydrogen in the presence of a catalyst to obtain the chiral alcohol shown as a structural formula II; or the chiral alcohol shown in the structural formula II is subjected to a second reaction to obtain the chiral cyclic ether shown in the structural formula III, wherein the reaction formula is as follows:
wherein in structural formula I, structural formula II and structural formula III, R 1 Or R is 2 One selected from aryl, alkyl, halogen, nitro, amino and fluoro alkane, n is 0,1 or 2;
the catalyst is obtained by complexing a transition metal precursor and a ligand, wherein the transition metal precursor is [ Ir (COD) Cl ]] 2 The ligand comprises the following structural formula:
in the transition metal precursor, COD represents 1, 5-cyclooctadiene; in the structural formula of the ligand, tBu represents tertiary butyl, ar represents aryl or heterocyclic aryl, and the structure of the ligand also comprises diastereoisomers thereof.
In the present application, the tetradentate ligand Ir/f-phamidol anion catalyst is a catalyst obtained by complexing a ligand with a transition metal precursor. According to the synthesis method, a simple and easy-to-synthesize tetradentate ligand Ir/f-phamidol anion catalyst is used, a cheap and easy-to-obtain 2-fluoroaryl ketone compound (namely a compound shown as a structural formula I) is used as a substrate, hydrogen is used as a hydrogen source, chiral alcohol or chiral cyclic ether compound is synthesized in a chemical and selective divergent manner, and the chiral alcohol or chiral cyclic ether can be synthesized through one-step reaction, so that the synthesis steps are simple and easy to operate, and the large-scale production of the chiral alcohol or chiral cyclic ether can be better satisfied; in addition, the synthesis method has high catalytic efficiency, high yield and high enantioselectivity (in one embodiment of the application, the reaction yield is up to 99 percent, and the enantioselectivity is up to 99 percent), and is favorable for leading the synthesized chiral alcohol or chiral cyclic ether to have higher purity, thereby being capable of better further synthesizing bioactive substances such as medicine molecules and improving the efficiency and quality of synthesizing the bioactive substances such as medicine molecules.
It can be understood that the key point of the application is that the chiral Ir/f-phamidol complex is used for efficiently catalyzing asymmetric hydrogenation to reduce the 2-fluoroaryl ketone derivative, and the chiral alcohol shown in the structural formula II or the chiral cyclic ether shown in the structural formula III is synthesized in a divergent manner; for the use of the synthesized chiral alcohol and chiral cyclic ether, reference may be made to the prior art, for example, as an intermediate for various drug molecules, and in one implementation of the present application, larrotinib (Larotrectinib) may be synthesized by chiral alcohol as shown in II-o, and AMPK agonist may be synthesized by chiral cyclic ether as shown in III-2 e. Therefore, the synthetic method of the application has important practical significance in utilizing asymmetric hydrogenation means to efficiently develop omega-ketone divergent synthetic chiral alcohol or chiral cyclic ether. The chiral alcohol shown in the structural formula II or the chiral cyclic ether shown in the structural formula III synthesized in the example can be used for synthesizing drug molecules such as an AMPK agonist, faropenem medoxomil (faropenem), larricericinol and larrotecinib or constructing a core skeleton of an important bioactive compound.
In one implementation of the present application, the first reaction or the second reaction is performed in an aprotic solvent.
Preferably, the aprotic solvent in the first reaction is selected from at least one of tetrahydrofuran, dichloromethane, dichloroethane, toluene, ethylene glycol dimethyl ether.
Preferably, the aprotic solvent in the second reaction is selected from at least one of toluene, dichloromethane, dichloroethane, dioxane, tetrahydrofuran, and n-hexane.
In one implementation of the present application, the chiral alcohol of formula II is produced under weak base conditions, and the intramolecular cyclization reaction further occurs under strong base conditions to produce the chiral cyclic ether of formula III, wherein the weak base conditions are formed by adding a first basic compound to the aprotic solvent, and the strong base conditions are formed by adding a second basic compound to the aprotic solvent.
In one implementation of the present application, the first basic compound or the second basic compound is added in an amount of 1.0 to 3.0 molar equivalents of the compound represented by structural formula I.
Preferably, the first alkaline compound is at least one of cesium carbonate and potassium carbonate.
Preferably, the second alkaline compound is at least one of sodium hydroxide, potassium hydroxide and potassium tert-butoxide. It is understood that other alkaline compounds forming strong alkaline conditions may also be employed under the inventive concepts of the present application.
In one implementation of the present application, the compound of structural formula I is at least one of I-1a to I-1o and I-2a to I-2 d:
in one implementation of the present application, the chiral cyclic ether represented by structural formula II is at least one of II-1a to II-1 s:
in one implementation of the present application, the chiral cyclic ether of formula III is at least one of III-2a to III-2o and III-4a to III-4 d:
in one implementation of the present application, the pressure of hydrogen in the first reaction is 40-80atm. .
In one embodiment of the present application, the catalyst is used in an amount of 0.001 to 0.01 molar equivalents of the compound of formula I.
Preferably, the catalyst is used in an amount of 0.001 molar equivalent to the compound of formula I.
In one implementation of the present application, the reaction temperature of the first reaction or the second reaction is 20-200 ℃ and the reaction time is 5-48 hours.
In one implementation of the present application, the first reaction or the second reaction is performed in an oxygen-free environment.
Preferably, the oxygen-free environment is an inert gas atmosphere.
Preferably, the inert gas is at least one of nitrogen, helium, neon, argon, krypton, and xenon.
Preferably, the inert gas is nitrogen.
In one implementation manner of the present application, the preparation method of the catalyst includes: mixing the transition metal precursor and the ligand in a solvent to obtain the catalyst.
In one implementation manner of the application, in the preparation method of the catalyst, the solvent is at least one of isopropanol and tetrahydrofuran.
In one implementation of the present application, in the preparation method of the catalyst, the transition metal precursor and the ligand may be stirred for 2 to 10 hours to mix the transition metal precursor and the ligand and obtain the catalyst.
In one implementation of the present application, in the preparation method of the catalyst, the molar ratio of the transition metal precursor and the ligand is 1:1 to 1:1.5. Preferably, in the preparation method of the catalyst, the molar ratio of the transition metal precursor to the ligand is 1:1.2.
In one implementation manner of the present application, in the preparation method of the catalyst, the solvent may be volatilized after the transition metal precursor and the ligand are mixed, so as to obtain the catalyst.
The other side of the application discloses chiral alcohol or chiral cyclic ether obtained by the synthesis method.
The other side of the application discloses application of chiral alcohol or chiral cyclic ether obtained by the synthesis method in preparation of bioactive compounds.
In one implementation of the present application, the bioactive compound may include at least one of AMPK agonist, faropenemmedoxomil, laricericinol, and Larotrectinib.
Due to the adoption of the technical scheme, the beneficial effects of the application are that:
according to the synthesis method, a simple and easy-to-synthesize tetradentate ligand Ir/f-phamidol anion catalyst is used, a cheap and easy-to-obtain 2-fluoroaryl ketone compound (namely a compound shown in a structural formula I) is used as a substrate, hydrogen is used as a green energy source, the green development concept is met, chiral alcohol or chiral cyclic ether compound is synthesized in a chemical and selective divergent mode, and the chiral alcohol or chiral cyclic ether can be synthesized through one-step reaction, so that the synthesis steps are simple and easy to operate, and the large-scale production of the chiral alcohol or chiral cyclic ether can be better met; in addition, the synthesis method has high catalytic efficiency, high yield and high enantioselectivity (in one embodiment of the application, the reaction yield is up to 99 percent, and the enantioselectivity is up to 99 percent), and is favorable for leading the synthesized chiral alcohol or chiral cyclic ether to have higher purity, thereby being capable of better further synthesizing bioactive substances such as medicine molecules and improving the efficiency and quality of synthesizing the bioactive substances such as medicine molecules.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a chiral cyclic ether shown in III-2a in the examples of the present application.
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the chiral cyclic ether shown in III-2a in the example of the present application.
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of a chiral cyclic ether shown in III-2p in the examples of the present application.
FIG. 4 is a nuclear magnetic resonance carbon spectrum of a chiral cyclic ether shown in III-2p in the examples of the present application.
Detailed Description
The invention will be described in further detail below with reference to the drawings by means of specific embodiments. In the following embodiments, numerous specific details are set forth in order to provide a better understanding of the present application. However, one skilled in the art will readily recognize that some of the features may be omitted in various situations, or replaced by other materials, methods. In some instances, some operations associated with the present application have not been shown or described in the specification to avoid obscuring the core portions of the present application, and may not be necessary for a person skilled in the art to describe in detail the relevant operations, as will be apparent from the description herein and the general knowledge of one skilled in the art.
Furthermore, the described features, operations, or characteristics of the description may be combined in any suitable manner in various embodiments. Also, various steps or acts in the method descriptions may be interchanged or modified in a manner apparent to those of ordinary skill in the art. Thus, the various orders in the description and drawings are for clarity of description of only certain embodiments, and are not meant to be required orders unless otherwise indicated.
In this application, for example, "structural formula I", "structural formula II", "structural formula III", etc., are used only to distinguish the described objects, and do not have any sequential or technical meaning. In this application, the description of numerical ranges includes endpoints and any number within the range, e.g., "1-10" may include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
Term interpretation:
in the chemical formulas of the present application, ar represents an aryl group or a heterocyclic aryl group, such as an unsubstituted phenyl group, a phenyl group in which at least one hydrogen is substituted, a five-membered heterocyclic ring, or a five-membered or more heterocyclic ring; tBu represents tert-butyl; me represents methyl; ph represents phenyl.
According to a first aspect, the present application discloses a method for synthesizing chiral alcohol or chiral cyclic ether, which may include reacting a compound shown in structural formula I with hydrogen in the presence of a catalyst to obtain the chiral alcohol shown in structural formula II or the chiral cyclic ether shown in structural formula III, where the reaction formula is as follows:
wherein in structural formula I, structural formula II and structural formula III, R 1 Or R is 2 Selected from one of aryl, alkyl, halogen, nitro, amino and fluoro alkane, n is 0,1 or 2.
In one embodiment, the catalyst may be obtained by complexing a transition metal precursor, which may be [ Ir (COD) Cl] 2 The ligand may comprise the following structural formula:
wherein, in the transition metal precursor, COD represents 1, 5-cyclooctadiene; in the structural formula of the ligand, tBu represents tert-butyl, ar represents aryl or heterocyclic aryl, and the structure of the ligand also comprises diastereoisomers thereof.
In one embodiment, the compound of structural formula I may be at least one of I-1a to I-1 s:
in one embodiment, the chiral alcohol of formula II may be at least one of II-1a to II-1 s:
in one embodiment, the chiral cyclic ether of formula III may be at least one of III-2a to III-2 s:
in one embodiment, the ligand may comprise the following structural formula:
in one embodiment, the method of preparing the catalyst may include: the transition metal precursor and the ligand are mixed in a solvent to obtain a catalyst.
In one embodiment, the solvent may be at least one of isopropanol and tetrahydrofuran.
In one embodiment, in the method of preparing the catalyst, the transition metal precursor and the ligand may be stirred for 2 to 10 hours to mix the transition metal precursor and the ligand and obtain the catalyst.
In one embodiment, the catalyst may be prepared by a molar ratio of transition metal precursor to ligand of 1:1 to 1:1.5. Preferably, in the preparation method of the catalyst, the molar ratio of the transition metal precursor and the ligand is 1:1.2.
In one embodiment, the catalyst may be prepared by mixing a transition metal precursor and a ligand and then volatilizing the solvent to obtain the catalyst.
In one embodiment, the asymmetric hydrogenation reaction may be carried out in an aprotic solvent.
In one embodiment, the aprotic solvent that generates the chiral alcohol of formula II is selected from at least one of tetrahydrofuran, dichloromethane, dichloroethane, toluene, ethylene glycol dimethyl ether.
In one embodiment, the aprotic solvent that generates the chiral cyclic ether of formula III is selected from at least one of toluene, methylene chloride, ethylene dichloride, dioxane, tetrahydrofuran, and n-hexane.
In one embodiment, the compound of formula I may form chiral alcohols of formula II under weak alkaline conditions, and may undergo further intramolecular cyclization under strong alkaline conditions to form chiral cyclic ethers of formula III.
In one embodiment, weak or strong base conditions may be formed by adding basic compounds.
In one embodiment, the basic compound is added in an amount of 1.0 to 3.0 molar equivalents of the compound of formula I.
In one embodiment, the weak base condition may be formed by adding at least one of cesium carbonate and potassium carbonate to the aprotic solvent.
In one embodiment, the strong base condition may be formed by adding at least one of sodium hydroxide, potassium hydroxide and potassium tert-butoxide to the aprotic solvent.
In one embodiment, the pressure of hydrogen at the time of the reaction may be 40-80atm.
In one embodiment, the catalyst may be used in an amount of 0.001 to 0.01 molar equivalents of the compound of formula I. Preferably, the catalyst is used in an amount of 0.001 molar equivalents of the compound of formula I.
In one embodiment, the reaction temperature may be 20-200deg.C and the reaction time may be 5-48 hours.
In one embodiment, the reaction is carried out in an oxygen-free environment.
In one embodiment, the oxygen-free environment is an inert gas atmosphere.
In one embodiment, the inert gas is at least one of nitrogen, helium, neon, argon, krypton, and xenon. Preferably, the inert gas is nitrogen.
In the present application, inert gas is introduced into the reaction system, mainly to form an anaerobic environment, and if the anaerobic environment can be ensured, the inert gas may not be used; in one implementation of the present application, even though inert gas is used, a majority of the overall reaction environment is hydrogen, e.g., more than 99% is hydrogen, and the remainder is inert gas.
According to a second aspect, the present application discloses a chiral alcohol or chiral cyclic ether obtained according to the synthetic method of the first aspect.
According to a second aspect, the present application discloses the use of a chiral alcohol or chiral cyclic ether obtained according to the synthesis method of the first aspect for the preparation of a biologically active compound.
The application uses a chiral Ir/f-phamidol complex efficient asymmetric catalytic hydrogenation method to reduce 2-fluoroaryl ketone compounds, divergently synthesizes chiral alcohol derivatives shown in a structural formula II and chiral cyclic ether derivatives shown in a structural formula III, and the obtained products have high optical purity and can be used as intermediates of various bioactive compounds.
In one embodiment, the bioactive compound may refer to a drug molecule.
In one embodiment, the drug molecule comprises at least one of AMPK agonist, faropenem medoxomil, larricirimol, and Larotrectinib.
The present application is described in further detail below by way of specific examples. The following examples are merely illustrative of the present application and should not be construed as limiting the present application.
Examples
(1) Preparation of the catalyst
In a glass bottle, a metal precursor [ Ir (COD) Cl ] is added] 2 (6.7 mg,0.01 mmol), ligand f-phamidol (11.6 mg,0.012 mmol) and solvent anhydrous tetrahydrofuran (1.0 mL). The concentration of the mixed system is 0.01mmol/mL, and the mixture is stirred for 2.0h at room temperature (25 ℃) to obtain a clear orange-red solution, namely the catalyst solution required by the reaction. And (3) performing rotary evaporation on the solvent of the catalyst solution to obtain a crude product, namely the catalyst required by the reaction.
(2) Synthesis of chiral alcohols of formula II
Nitrogen gasIn a hydrogenation flask, 0.2mmol of the 2-fluoroaryl ketone derivative of the compound of formula I was introduced under an atmosphere, followed by 0.76mg (1.0X10) of the Ir/f-phamidol complex as catalyst -3 mmol); alternatively, 0.1mL of catalyst solution is added; 33mg (0.1 mmol) of cesium carbonate and 0.5mL of deoxytetrahydrofuran are added, then the mixture is transferred into an autoclave, inert gas in the reaction chamber is nitrogen, more than 99% of the inert gas is hydrogen in the reaction atmosphere, the hydrogen pressure is set to 60atm, the reaction is carried out at 25 ℃ for 48 hours, then the hydrogen is slowly released, 1.0mL of ethyl acetate is added for dilution, 2.0mL of water is used for quenching, an organic phase is separated, 2.0mL of ethyl acetate is used for washing two times of water phases, the organic phases are combined, anhydrous sodium sulfate is used for drying, and a spin-drying solvent is used for obtaining crude products, and the crude products are separated and purified by column chromatography to obtain clean chiral alcohol shown in a structural formula II.
(3) Synthesizing chiral cyclic ether shown in structural formula III
The substrate (0.2 mmol) was weighed in advance into a 5.0mL hydrogenation flask and Cs was added 2 CO 3 (195.5 mg,0.6mmol,3.0 eq.) Ir/f-phamidol complex as catalyst 0.76mg, 1.0X10) -3 mmol (alternatively, 0.1mL of catalyst solution) 1mL of anhydrous toluene. The inert gas in the reaction chamber is nitrogen, more than 99% of the inert gas in the reaction atmosphere is hydrogen, the pressure of the hydrogen is set to be 60atm, and the reaction is carried out for 48 hours at room temperature (25 ℃). Then, tBuOK (potassium tert-butoxide, 44.9mg,0.4 mmol) was added by releasing the hydrogen pressure. The reaction system is heated to 110 ℃ for reaction for 12 hours under the protection of argon, cooled to room temperature and diluted with ethyl acetate. The solvent was removed by rotary evaporation under reduced pressure, and the product was purified by column chromatography to give chiral cyclic ether of formula III.
(4) Product structure, yield and enantioselectivity detection
By passing through 1 H NMR 13 The structure of the hydrogenated product was determined by C NMR spectrum, ee value (enantioselectivity) of the product was determined by HPLC (high Performance liquid chromatography), yield (yield) analysis was performed by nuclear magnetic resonance hydrogen spectrum, and the optical rotation value of the product was determined by using a polarimeter.
The present example specifically synthesizes a variety of chiral alcohols and chiral cyclic ethers, and the structure of each product and the yield and enantioselectivity results are as follows:
this example schematically illustrates the specific synthetic steps of a portion of the products and their product structure, yield and enantioselectivity detection analysis data, as follows:
a) Synthesis of chiral alcohols of II-1a
55mg, i.e., 0.2mmol, of the 2-fluoroaryl ketone derivative represented by I-1a is introduced into a hydrogenation flask under an inert gas atmosphere, and then 0.76mg, i.e., 1.0X10 g of chiral Ir/f-phamidol complex is introduced -3 33mg of cesium carbonate, namely 0.1mmol, 0.5mL of deoxytetrahydrofuran is transferred into an autoclave, inert gas in a reaction chamber is nitrogen, more than 99% of the inert gas is hydrogen in the reaction atmosphere, the pressure of the hydrogen is set to 60atm, the reaction is carried out for 48 hours at 25 ℃, the hydrogen is slowly released, 1.0mL of ethyl acetate is added for dilution, 2.0mL of water is used for quenching, an organic phase is separated, 2.0mL of ethyl acetate is used for washing two times of water phases, the organic phase is combined, anhydrous sodium sulfate is used for drying, and a spin-drying solvent is used for obtaining chiral fluoroalcohol shown as a crude product II-1a, and the chiral fluoroalcohol shown as a clean II-1a is obtained through separation and purification by column chromatography. Nuclear magnetic resonance analysis shows that Colorless liquid,55.5mg,99% yield,94% ee; the nuclear magnetic data of the product II-1a is 1 H NMR(400MHz,CDCl 3 )δ7.76–7.72(m,2H),7.39–7.30(m,6H),7.23–7.18(m,2H),7.04–6.98(m,2H),6.83(d,J＝7.6Hz,1H),6.15(s,1H)； 13 C NMR(100MHz,CDCl3)δ143.8(J＝324.9Hz),139.6,129.5,129.4(J＝1.87Hz),128.52,128.5(J＝22.0Hz),128.2,127.8,127.6,127.2(J＝7.08Hz),126.6,126.4,98.7,79.0,72.8； 19 F NMR(376MHz,CDCl 3 )δ-114.9；HPLC(Chiralpak OJ-H column,n-hexane/i-PrOH＝95/5；flow rate＝0.7mL/min；UV detection at 220nm；t1＝26.3min(major)，t2＝30.2min(minor)
b) Synthesis of chiral cyclic ether-benzopyran represented by III-2a
55mg, i.e., 0.2mmol, of the 2-fluoroaryl ketone derivative represented by I-1a is charged into a hydrogenation flask under an inert gas atmosphere, and then is charged with a handSex Ir/f-phamidol complex 0.76mg, i.e. 1.0X10 -3 33mg of cesium carbonate, namely 0.1mmol, 0.5mL of deoxytetrahydrofuran is transferred into an autoclave, inert gas in the reaction chamber is nitrogen, more than 99% of the inert gas in the reaction atmosphere is hydrogen, the pressure of the hydrogen is set to 60atm, the reaction is carried out for 5 hours at 25 ℃, and then the temperature is raised to 80 ℃ for 4 hours. Slowly releasing hydrogen. Then adding 1.0mL of ethyl acetate for dilution, quenching with 2.0mL of water, separating an organic phase, washing the aqueous phase twice with 2.0mL of ethyl acetate, combining the organic phases, drying the organic phase with anhydrous sodium sulfate, spin-drying the solvent to obtain a chiral fluoroalcohol shown as a crude product II-1a, dissolving the chiral fluoroalcohol with deoxygenated toluene, adding potassium tert-butoxide, heating to 110 ℃ under the protection of argon for reaction for 12 hours, recovering the room temperature, and separating and purifying the chiral fluoroalcohol shown as a clean III-2a (benzopyran compound) through column chromatography.
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a chiral cyclic ether shown in III-2a in the examples of the present application, and FIG. 2 is a nuclear magnetic resonance carbon spectrum of a chiral cyclic ether shown in III-2a in the examples of the present application. 51.0mg of chiral cyclic ether shown in III-2a obtained is Colorless oil, and nuclear magnetic resonance analysis results show that the chiral liquid is 51mg,99% yield and 94% ee; [ alpha ]]20D＝+30.6(c＝0.5，CHCl 3 )；HPLC(ChiralpakOD-3column，hexane/isopropanol＝95/5；flow rate＝1.0mL/min；UV detection at 220nm；t1＝8.7min(minor)，t2＝9.6min(major)； 1 H NMR(600MHz，Chloroform-d)δ7.76(t，J＝8.2Hz，2H)，7.42–7.31(m，6H)，7.26–7.19(m，2H)，7.07–6.97(m，2H)，6.85(d，J＝7.6Hz，1H)，6.16(s，1H)； 13 C NMR(151MHz，Chloroform-d)δ153.6，139.6，134.0，130.1，129.6，128.5，128.5，128.4，128.2，127.6，126.3，123.1，122.8，122.1，117.9，79.7。
c) Synthesis of chiral cyclic ether-benzofuran shown in III-2p
In a hydrogenation flask under inert gas atmosphere, 18.2mg,0.2mmol of the 2-fluoroaryl ketone derivative shown by I-1p was added, followed by 0.76mg, 1.0X10 of chiral Ir/f-phamidol complex -3 mmol, 33mg of cesium carbonate, 0.1mmol, 0.5mL of deoxytoluene, and then transferred to an autoclave, inert in the reaction chamberThe method comprises the steps of (1) setting the pressure of hydrogen to 60atm, reacting at 25 ℃ for 48 hours, slowly releasing hydrogen, adding 1.0mL of ethyl acetate for dilution, quenching with 2.0mL of water, separating an organic phase, washing two times of water phases with 2.0mL of ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, spin-drying the solvent to obtain chiral fluoroalcohol shown as crude II-1p, dissolving with deoxytoluene, adding potassium tert-butoxide, heating to 110 ℃ under the protection of argon, reacting for 12 hours, recovering room temperature, and separating and purifying by column chromatography to obtain the chiral benzofuran compound shown as III-2 p.
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of a chiral cyclic ether shown in III-2p in the examples of the present application, and FIG. 4 is a nuclear magnetic resonance carbon spectrum of a chiral cyclic ether shown in III-2p in the examples of the present application. The chiral cyclic ether shown in III-2p was obtained as a Colorless oil,40.3mg, and nuclear magnetic resonance analysis showed that Colorless oil,40.3mg,94% yield,99% ee [ alpha ]]D20＝+3.80(c＝0.50，CHCl3).HPLC:The ee was determined by chiral HPLC(ChiralpakOD-3，n-hexane/isopropanol98:2v/v，flow rate 1.0mL/min，λ＝254nm，25℃).Retentiontimes:tR＝6.094min(major)，tR＝9.415min(minor). 1 HNMR(400MHz，CDCl3)δ(ppm)7.41-7.36(m，4H)，7.36-7.29(m，1H)，7.16-7.07(m，1H)，6.66(d，J＝8.0Hz，1H)，6.59(t，J＝8.4Hz，1H)，5.80(dd，J＝9.3，8.2Hz，1H)，3.66(dd，J＝15.8，9.5Hz，1H)，3.22(dd，J＝15.8，8.0Hz，1H). 13 CNMR(100MHz，CDCl3)δ(ppm)161.9(d，J＝8.7Hz)，159.3(d，J＝247.1Hz)，141.3，129.6(d，J＝8.8Hz)，128.7，128.2，125.7，112.9(d，J＝21.5Hz)，107.7(d，J＝20.3Hz)，105.3(d，J＝4.5Hz)，84.9，35.0.19FNMR(376MHz，CDCl3)δ(ppm)-116.80.HRMS(ESI)m/z:calcd for C14H10FO-[M-H]-:213.0721，found:213.0714。
In conclusion, the synthesis method of chiral alcohol or chiral cyclic ether has the advantages of low-cost and easily-obtained raw materials, simple operation steps, high catalytic efficiency, high yield, high enantioselectivity of products and the like.
The foregoing is a further detailed description of the present application in connection with the specific embodiments, and it is not intended that the practice of the present application be limited to such descriptions. It will be apparent to those skilled in the art to which the present application pertains that several simple deductions or substitutions may be made without departing from the spirit of the present application.
Claims (10)
1. A method for synthesizing chiral alcohol or chiral cyclic ether is characterized in that: the method comprises the steps of carrying out a first reaction on a compound shown as a structural formula I and hydrogen in the presence of a catalyst to obtain chiral alcohol shown as a structural formula II; or the chiral alcohol shown in the structural formula II is subjected to a second reaction to obtain the chiral cyclic ether shown in the structural formula III, wherein the reaction formula is as follows:
wherein in structural formula I, structural formula II and structural formula III, R 1 Or R is 2 One selected from aryl, alkyl, halogen, nitro, amino and fluoro alkane, n is 0,1 or 2;
the catalyst is obtained by complexing a transition metal precursor and a ligand, wherein the transition metal precursor is [ Ir (COD) Cl ]] 2 The ligand comprises the following structural formula:
in the transition metal precursor, COD represents 1, 5-cyclooctadiene; in the structural formula of the ligand, tBu represents tertiary butyl, ar represents aryl or heterocyclic aryl, and the structure of the ligand also comprises diastereoisomers thereof.
2. The synthesis method according to claim 1, wherein: the first reaction or the second reaction is carried out in an aprotic solvent;
preferably, the aprotic solvent in the first reaction is selected from at least one of tetrahydrofuran, dichloromethane, dichloroethane, toluene, ethylene glycol dimethyl ether;
preferably, the aprotic solvent in the second reaction is selected from at least one of toluene, dichloromethane, dichloroethane, dioxane, tetrahydrofuran, and n-hexane.
3. The synthesis method according to claim 2, characterized in that: generating chiral alcohol shown in a structural formula II under a weak base condition, and further generating intramolecular cyclization reaction under the strong base condition to generate chiral cyclic ether shown in a structural formula III, wherein the weak base condition is formed by adding a first basic compound into the aprotic solvent, and the strong base condition is formed by adding a second basic compound into the aprotic solvent.
4. A synthetic method according to claim 3, characterized in that: the addition amount of the first alkaline compound or the second alkaline compound is 1.0-3.0 molar equivalent of the compound shown in the structural formula I;
preferably, the first alkaline compound is at least one of cesium carbonate and potassium carbonate;
preferably, the second alkaline compound is at least one of sodium hydroxide, potassium hydroxide and potassium tert-butoxide.
5. The synthesis method according to claim 1, wherein: the compound of the structural formula I is at least one of I-1a to I-1 s:
6. the method of synthesis according to claim 5, wherein:
the chiral cyclic ether shown in the structural formula II is at least one of II-1a to II-1 s:
the chiral cyclic ether shown in the structural formula III is at least one of III-2a to III-2 s:
7. the synthetic method according to any one of claims 1 to 6, wherein: the pressure of hydrogen in the first reaction is 40-80atm.
8. The method of synthesis according to claim 7, wherein: the catalyst is used in an amount of 0.001-0.01 molar equivalent of the compound shown in the structural formula I;
preferably, the catalyst is used in an amount of 0.001 molar equivalent to the compound of formula I.
9. The synthesis method according to claim 1, wherein: the reaction temperature of the first reaction or the second reaction is 20-200 ℃ and the reaction time is 5-48 hours.
10. The method of synthesis according to claim 7, wherein: the first reaction or the second reaction is performed in an oxygen-free environment;
preferably, the oxygen-free environment is an inert gas atmosphere;
preferably, the inert gas is at least one of nitrogen, helium, neon, argon, krypton and xenon;
preferably, the inert gas is nitrogen.
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