CN112538095A - 一种手性四齿配体、手性钌络合物,及制备(r)-(-)-1,3-丁二醇的方法 - Google Patents
一种手性四齿配体、手性钌络合物,及制备(r)-(-)-1,3-丁二醇的方法 Download PDFInfo
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- CN112538095A CN112538095A CN202011469441.8A CN202011469441A CN112538095A CN 112538095 A CN112538095 A CN 112538095A CN 202011469441 A CN202011469441 A CN 202011469441A CN 112538095 A CN112538095 A CN 112538095A
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- Prior art keywords
- chiral
- butanediol
- ligand
- naphthol
- tetradentate
- Prior art date
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- 239000003446 ligand Substances 0.000 title claims abstract description 53
- PUPZLCDOIYMWBV-SCSAIBSYSA-N (R)-butane-1,3-diol Chemical compound C[C@@H](O)CCO PUPZLCDOIYMWBV-SCSAIBSYSA-N 0.000 title claims abstract description 42
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (1R)-1,3-butanediol Natural products CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 38
- 239000012327 Ruthenium complex Substances 0.000 title claims abstract description 16
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000003054 catalyst Substances 0.000 claims abstract description 24
- 239000000758 substrate Substances 0.000 claims abstract description 11
- -1 5-trifluoromethylphenyl Chemical group 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 230000008569 process Effects 0.000 claims abstract description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 61
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 16
- 239000002243 precursor Substances 0.000 claims description 16
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 13
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 claims description 11
- 239000007848 Bronsted acid Substances 0.000 claims description 11
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 9
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 7
- ASMQGLCHMVWBQR-UHFFFAOYSA-M diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)([O-])OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-M 0.000 claims description 7
- 229910019891 RuCl3 Inorganic materials 0.000 claims description 5
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 claims description 3
- HDFFVHSMHLDSLO-UHFFFAOYSA-M dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-M 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 229910021603 Ruthenium iodide Inorganic materials 0.000 claims description 2
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 51
- 238000000926 separation method Methods 0.000 abstract description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 4
- 125000004185 ester group Chemical group 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 2
- 238000005516 engineering process Methods 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 19
- KUXDQQMEFBFTGX-UHFFFAOYSA-N [N].P Chemical compound [N].P KUXDQQMEFBFTGX-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000012300 argon atmosphere Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 239000002994 raw material Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000003197 catalytic effect Effects 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000004679 31P NMR spectroscopy Methods 0.000 description 5
- LVSQXDHWDCMMRJ-UHFFFAOYSA-N 4-hydroxybutan-2-one Chemical compound CC(=O)CCO LVSQXDHWDCMMRJ-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 238000004817 gas chromatography Methods 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- IYRMWMYZSQPJKC-UHFFFAOYSA-N kaempferol Chemical compound C1=CC(O)=CC=C1C1=C(O)C(=O)C2=C(O)C=C(O)C=C2O1 IYRMWMYZSQPJKC-UHFFFAOYSA-N 0.000 description 4
- 229910052707 ruthenium Inorganic materials 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000005086 pumping Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- PONXTPCRRASWKW-ZIAGYGMSSA-N (1r,2r)-1,2-diphenylethane-1,2-diamine Chemical compound C1([C@@H](N)[C@H](N)C=2C=CC=CC=2)=CC=CC=C1 PONXTPCRRASWKW-ZIAGYGMSSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- UBSCDKPKWHYZNX-UHFFFAOYSA-N Demethoxycapillarisin Natural products C1=CC(O)=CC=C1OC1=CC(=O)C2=C(O)C=C(O)C=C2O1 UBSCDKPKWHYZNX-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 2
- 235000008777 kaempferol Nutrition 0.000 description 2
- 238000013048 microbiological method Methods 0.000 description 2
- UXOUKMQIEVGVLY-UHFFFAOYSA-N morin Natural products OC1=CC(O)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UXOUKMQIEVGVLY-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- PUPZLCDOIYMWBV-BYPYZUCNSA-N (S)-butane-1,3-diol Chemical compound C[C@H](O)CCO PUPZLCDOIYMWBV-BYPYZUCNSA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 description 1
- 102000005751 Alcohol Oxidoreductases Human genes 0.000 description 1
- 108010031132 Alcohol Oxidoreductases Proteins 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- MPAGVACEWQNVQO-ZCFIWIBFSA-N [(3r)-3-acetyloxybutyl] acetate Chemical compound CC(=O)O[C@H](C)CCOC(C)=O MPAGVACEWQNVQO-ZCFIWIBFSA-N 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 230000007073 chemical hydrolysis Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- LDLDJEAVRNAEBW-SCSAIBSYSA-N methyl (3r)-3-hydroxybutanoate Chemical compound COC(=O)C[C@@H](C)O LDLDJEAVRNAEBW-SCSAIBSYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000003016 pheromone Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
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- 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
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/189—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms containing both nitrogen and phosphorus as complexing atoms, including e.g. phosphino moieties, in one at least bidentate or bridging ligand
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- 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
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- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
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- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2213—At least two complexing oxygen atoms present in an at least bidentate or bridging ligand
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- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
- C07C29/149—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof with hydrogen or hydrogen-containing gases
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- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
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- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
- C07F15/0053—Ruthenium compounds without a metal-carbon linkage
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
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Abstract
Description
技术领域
本发明属于催化剂领域及有机合成领域,具体涉及不对称氢化的手性配体及制备(R)-(-)-1,3-丁二醇的方法。
背景技术
(R)-(-)-1,3-丁二醇是一种重要的手性砌块,广泛用于碳青霉烯类抗生素母核氮杂环丁酮、香料、信息激素和杀虫剂的合成。其中碳青霉烯类抗生素能够有效地缓解青霉素的抗药性,因此(R)-(-)-1,3-丁二醇的合成受到了国内外的广泛关注,合成方法包括化学法和微生物法。
化学法合成(R)-(-)-1,3-丁二醇可通过直接拆分消旋的1,3-丁二醇得到,例如日本Daicel化工报道了采用乙醛为原料,经过羟醛缩合反应和加氢反应制备消旋的1,3-丁二醇,然后用手性拆分剂拆分得到(R)-(-)-1,3-丁二醇和(S)-(-)-1,3-丁二醇,该方法会损失50%的1,3-丁二醇,经济性较差。文献Synth.Commun.1991,21(22):2295-2300报道了采用L-苏氨酸为原料,经过脱氨、甲酯化、氢解脱溴和还原等4步反应制得(R)-(-)-1,3-丁二醇,该工艺物料成本高,三废多,四步反应收率仅有64%。另外一种化学合成法制备(R)-(-)-1,3-丁二醇是以4-羟基-2-丁酮为原料,经过不对称氢化制得。有关酮羰基的不对称氢化反应已有诸多文献和专利报道,例如Noyori报道的Ru-BINAP催化体系(J.Am.Chem.Soc.1995,117:7562-7563),在酮的不对称催化领域取得了广泛的应用,目标醇的ee值最高可达99%,但是这些报道均采用金属Ru催化体系,催化剂不能回收且用量较大,成本高;此外工业上合成4-羟基-2-丁酮是以甲醛和丙酮缩合反应制备,反应收率仅有70~80%,并且4-羟基-2-丁酮分离纯化比较困难,因此采用4-羟基-2-丁酮不对称氢化制备(R)-(-)-1,3-丁二醇整体成本偏高,不适用工业化生产。
微生物法合成(R)-(-)-1,3-丁二醇一条路线是以消旋的1,3-丁二醇为原料,例如文献Biotechnol.Lett.,1993,15(9):955-960采用脂肪酶SP382(Candida sp.)将外消旋的1,3-丁二醇的两个羟基酰基化,得到(R)-1,3-二乙酰氧基丁烷,然后用化学水解法得到(R)-(-)-1,3-丁二醇,ee值最高能达98%,但是步骤长,整体收率偏低。另外一条路线是用羰基还原酶将4-羟基-2-丁酮不对称还原为(R)-(-)-1,3-丁二醇,例如专利CN101899495A和专利CN109749968A都分别报道了不同的菌株,用于催化-羟基-2-丁酮不对称还原为(R)-(-)-1,3-丁二醇,都能够取得99%以上的ee值。但是微生物法合成-R)-(-)-1,3-丁二醇的缺点也是显而易见的,反应时间长、底物浓度底导致时空收率偏低,产物分离纯化也比较困难,工业化应用困难较大。
综上所述,目前现有技术报道的化学法和微生物法制备(R)-(-)-1,3-丁二醇,都存在经济效果差、产物分离困难的缺点,因此开发新的合成(R)-(-)-1,3-丁二醇的方法,具有十分重要的意义。
发明内容
针对现有技术存在的问题,本发明提供一种手性四齿P,P,P,N配体、手性钌络合物,及制备(R)-(-)-1,3-丁二醇的方法。解决了现有制备(R)-(-)-1,3-丁二醇技术存在的成本高、催化剂用量大、产物分离困难等缺点,能够以低成本、用量少的催化剂,将底物乙酰乙酸甲酯的羰基不对称氢化,同时将酯基还原,得到(R)-(-)-1,3-丁二醇。反应操作简单,催化剂制备简单,目标产物收率和ee值都在98%以上。同时催化剂可套用五次,极大的降低了成本,具有工业化应用的潜力。
为了达到其目的,本发明采用以下技术方案:
一种手性四齿P,P,P,N配体,其结构式为
其中R1、R2相互独立的为H、卤原子、C1~C4的烷基、苯基、取代苯基;优选的,R1、R2相互独立的为H、Br、叔丁基、苯基、3,5-三氟甲基苯基。
作为优选的方案,本发明所述的手性四齿P,P,P,N配体选自式L1-L5中的一种或多种,
一种制备本发明所述的手性四齿P,P,P,N配体的方法,包括以下步骤:手性联萘酚、三氯化磷、三乙醇胺在催化剂和碱作用下,反应制备。
本发明所述制备手性四齿P,P,P,N配体的方法中,手性联萘酚和三氯化磷的摩尔比为1:1.0~1.5,优选1:1.1~1.2。
本发明所述制备手性四齿P,P,P,N配体的方法中,手性联萘酚和三乙醇胺的摩尔比为3:0.8~1.2,优选3:0.9~1。
本发明所述制备手性四齿P,P,P,N配体的方法中,所述手性联奈酚选自(R)-1,1’-联-2-萘酚、(R)-6,6’-二溴-1,1’-联-2-萘酚、(R)-3,3’-二叔丁基-1,1’-联-2-萘酚、(R)-3,3’-二苯基-1,1’-联-2-萘酚和(R)-3,3’-二(3,5-三氟甲基苯基)-1,1’-联-2-萘酚中的一种或多种,优选(R)-6,6’-二苯基-1,1’-联-2-萘酚。
本发明所述制备手性四齿P,P,P,N配体的方法中,所述催化剂选自1-羟基-苯并三唑(HOBT)、N,N’-羰基二咪唑(CDI)、4-二甲氨基吡啶(DMAP)、二环己基碳二亚胺(DCC)中的一种或多种,优选4-二甲氨基吡啶。
本发明所述制备手性四齿P,P,P,N配体的方法中,所述催化剂用量为手性联萘酚摩尔量的0.5~2%,优选1.0~1.2%。
本发明所述制备手性四齿P,P,P,N配体的方法中,所述碱选自三乙胺(TEA)、二异丙基乙基胺(DIPEA)、吡啶(Pyridine)中的一种或多种,优选三乙胺。
本发明所述制备手性四齿P,P,P,N配体的方法中,所述碱用量为手性联萘酚质量的20~30倍,优选15~20倍。
本发明所述制备手性四齿P,P,P,N配体的方法中,反应温度为90~130℃。
一种手性钌络合物,包含钌金属前体和本发明所述的手性四齿P,P,P,N配体。
本发明所述的钌金属前体为[Ru(COD)Cl2]、RuI3、RuCl3、Ru(acac)3中的一种或多种,优选RuCl3。
本发明所述的钌金属前体和手性四齿P,P,P,N配体的摩尔比为1:1~2,优选1:1~1.2。
一种制备本发明所述的手性钌络合物的方法,包括以下步骤:钌金属前体和本发明所述的手性四齿P,P,P,N配体原位制备得到。
一种制备(R)-(-)-1,3-丁二醇的方法,包括以下步骤:使用手性钌络合物作为催化剂,布朗斯特酸作为助剂,将乙酰乙酸甲酯不对称氢化得到(R)-(-)-1,3-丁二醇。
反应式如下:
本发明所述的手性钌络合物中的钌金属前体与底物乙酰乙酸甲酯的摩尔比为1:300000~600000,优选1:400000~500000。
本发明所述的制备(R)-(-)-1,3-丁二醇的方法中,布朗斯特酸为磷酸二苯酯、磷酸二苄酯、二(2-乙基己基)磷酸酯中的一种或几种,优选磷酸二苯酯。布朗斯特酸与乙酰乙酸甲酯的摩尔比为0.1%~0.5%:1,优选0.2%~0.3%:1。
本发明所述的制备(R)-(-)-1,3-丁二醇的方法中,所述乙酰乙酸甲酯纯度为99.0~99.9%,氧气含量小于10ppb,水含量小于10ppm。
本发明所述的制备(R)-(-)-1,3-丁二醇的方法中,不对称氢化反应的温度为80~150℃,优选100~120℃
本发明所述的制备(R)-(-)-1,3-丁二醇的方法中,所述不对称氢化反应的氢气压力为6~12MPaG,优选8~10MpaG。
本发明所述的制备(R)-(-)-1,3-丁二醇的方法中,所述不对称氢化反应制备(R)-(-)-1,3-丁二醇的ee值可达到98~99%,产品收率可达到98~99%。
不受限于任何已知理论,本发明公开的钌/手性四齿P,P,P,N配体/布朗斯特酸催化体系,用于催化乙酰乙酸甲酯不对称氢化制备(R)-(-)-1,3-丁二醇,其可能的催化机理如下:首先氢气分子在钌作用下发生异裂,得到Ru-H物种,然后底物分子与Ru中心金属配位,Ru上的H转移到底物分子中的羰基和酯基上,同时通过手性四齿配体控制反应的对映选择性。四齿配体与Ru形成的螯合物稳定性更高,反应活性增加,能够同时实现乙酰乙酸甲酯的羰基和酯基一步氢化,同时布朗斯特酸的加入能够促进加氢反应的进行,提高反应速度。
本发明采用上述技术方案,具有以下积极效果:
(1)本发明采用手性四齿P,P,P,N配体与钌金属前体制备了价格相对低廉钌络合物,该钌络合物与布朗斯特酸形成的催化体系能够将乙酰乙酸甲酯不对称氢化直接得到(R)-(-)-1,3-丁二醇,收率和ee值都在98%以上。
(2)本发明提供的手性四齿P,P,P,N配体,其制备工艺简单,收率高,原料廉价易得;该手性四齿配体与钌前体形成的手性钌络合物催化活性高,手性钌络合物与乙酰乙酸甲酯的摩尔比最高可达1:600000,同时催化体系可实现五次循环套用,极大地降低成本,具有工业化放大的潜力。
具体实施方法
下面通过实施例详述本发明,但本发明并不限于下述的实施例。
一、本发明实施例及对比例的主要试剂来源:
乙酰乙酸甲酯:纯度99%,购自于阿拉丁,使用前进行氢化钙除水、减压蒸馏处理,溶解氧含量小于10ppb,水含量小于100ppm,手套箱中保存;
RuCl3等金属钌前体:纯度98~99%,购自Sigma-aldrich,手套箱中保存;
(R)-1,1’-联-2-萘酚、(R)-6,6’-二溴-1,1’-联-2-萘酚、(R)-3,3’-二叔丁基-1,1’-联-2-萘酚、(R)-3,3’-二苯基-1,1’-联-2-萘酚和(R)-3,3’-二(3,5-三氟甲基苯基)-1,1’-联-2-萘酚,购自于阿拉丁,纯度98~99%,手套箱中备用;
三氯化磷,购自西亚试剂,纯度99%,使用前减压蒸馏处理,手套箱中备用;
三乙醇胺,购自阿拉丁试剂,纯度99%,使用前用分子筛除水;
三乙胺、二异丙基乙基胺、吡啶等,购自阿拉丁试剂,纯度99%,使用前进行氢化钙除水、减压蒸馏处理;
磷酸二苯酯、磷酸二苄酯、二(2-乙基己基)磷酸酯等布朗斯特酸:纯度98~99%,购自于百灵威科技,手套箱中保存;
氢化钙,购自阿拉丁试剂,纯度98.5%。
(R)-BINAP购自于阿拉丁,纯度98%,手套箱中保存;
(1R,2R)-1,2-二苯基-1,2-乙二胺,纯度99%,购自于阿拉丁,手套箱中保存;
叔丁醇钾、异丙醇,纯度99%,购自于阿拉丁。
二、本发明采用的气相色谱测试条件如下:
仪器型号:Agilent 7890 A;
色谱柱:Supelcoβ-DEXTM225;
溶剂:乙腈(HPLC);
进样体积:0.5μL;
进样口温度:280℃;
分流比:30:1
氢气流量:40mL/min;
尾吹流量:25mL/min;
空气流量:400mL/min;
升温程序:初始柱温100℃,保留5min,然后以20℃/min的速度升温至280℃,保留5min。
实施例1:手性四齿膦氮配体L1的合成
手套箱中,50mL的Schlenk瓶中加入(R)-1,1’-联-2-萘酚(1g,3.49mmol)、DMAP(0.004g,0.035mmol)和三乙胺(10g,0.1mol),将其密封;出手套箱,将Schlenk瓶放入水浴锅中,开启搅拌,氩气氛围下向Schlenk瓶中加入三氯化磷(0.48g,3.49mmol),室温下搅拌1h。继续在氩气氛围下,向Schlenk瓶中滴加三乙醇胺,滴加完毕后将Schlenk瓶放入油浴锅中,加热回流2~3h,TLC监测原料联奈酚完全反应后,终止反应。将反应液冷却至室温,减压蒸馏回收碱,得到四齿膦氮配体粗品。将粗品用二氯甲烷和乙醚的混合溶剂结晶,得到纯度大于98%的手性四齿膦氮配体L1,收率89.9%。1H-NMR(400MHz,DMSO-d6):δ8.41(m6H),8.04(m,6H),7.79(m,6H),7.44~7.53(m,12H),7.09(m,6H),3.62(t,J=7.3Hz6H),2.53(t,J=7.2Hz,6H);13C-NMR(100MHz,DMSO-d6):152.1(6C),134.2(6C),129.5(6C),129.0(6C),128.0(6C),126.8(6C),126.6(6C),123.9(6C),118.8(6C),59.3(6C),58.6(6C);31P-NMR(162MHz,DMSO-d6):134;ESI-MS:C66H48NO9P3([M+H+])1092.25,([M+Na+])1114.24。
实施例2:手性四齿膦氮配体L2的合成
手套箱中,25mL的Schlenk瓶中加入(R)-6,6’-二溴-1,1’-联-2-萘酚(0.5g,1.125mmol)、DAMP(1.4mg,0.011mmol)和三乙胺(10g),将其密封;出手套箱,将Schlenk瓶放入水浴锅中,开启搅拌,氩气氛围下向Schlenk瓶中加入三氯化磷(0.17g,1.24mmol),室温下搅拌1h。继续在氩气氛围下,向Schlenk瓶中滴加三乙醇胺(67mg,0.45mmol),滴加完毕后将Schlenk瓶放入油浴锅中,加热回流3h,TLC监测原料联奈酚完全反应后,终止反应。将反应液冷却至室温,减压蒸馏回收碱,得到四齿膦氮配体粗品。将粗品用二氯甲烷和乙醚的混合溶剂结晶,得到纯度大于98%的手性四齿膦氮配体L2,收率86.7%。1H-NMR(400MHz,DMSO-d6):δ8.16(s,6H),7.71~7.85(m,18H),7.11(d,J=7.2Hz,6H),3.68(t,J=7.4Hz6H),2.52(t,J=7.2Hz6H);13C-NMR(100MHz,DMSO-d6):152.4(6C),134.8(6C),130.5(12C),127.8(6C),127.5(6C),125.9(6C),123.6(6C),119.6.6(6C),117.6(6C),59.6(3C),58.9(3C);31P-NMR(162MHz,DMSO-d6):137;ESI-MS:C66H42NO9Br6P3([M+H+])1566.39,([M+Na+])1588.40。
实施例3:手性四齿膦氮配体L3的合成
手套箱中,10mL的Schlenk瓶中加入(R)-3,3’-二叔丁基-1,1’-联-2-萘酚(0.2g,0.50mmol)、DAMP(0.61mg,0.0050mmol)和三乙胺(6g),将其密封;出手套箱,将Schlenk瓶放入水浴锅中,开启搅拌,氩气氛围下向Schlenk瓶中加入三氯化磷(76mg,0.55mmol),室温下搅拌1h。继续在氩气氛围下,向Schlenk瓶中滴加三乙醇胺(30mg,0.20mmol),滴加完毕后将Schlenk瓶放入油浴锅中,加热回流3h,TLC监测原料联奈酚完全反应后,终止反应。将反应液冷却至室温,减压蒸馏回收碱,得到四齿膦氮配体粗品。将粗品用二氯甲烷和乙醚的混合溶剂结晶,得到纯度大于98%的手性四齿膦氮配体L3,收率84.8%。1H-NMR(400MHz,DMSO-d6):δ8.46(m,6H),8.01(m,6H),7.91(s,6H),7.43~7.49(m,12H),3.62(t,J=7.2Hz6H),2.53(t,J=7.2Hz,6H),1.41(s,54H),;13C-NMR(100MHz,DMSO-d6):149.4(6C),140.8(6C),132.5(6C),129.8(6C),127.5(6C),126.6(6C),126.3(6C),126.1(6C),123.7(6C),123.5(6C),59.3(3C),58.8(3C),35.3(6C),31.8(18C);31P-NMR(162MHz,DMSO-d6):135;ESI-MS:C90H96NO9P3([M+H+])1428.63,([M+Na+])1450.64。
实施例4:手性四齿膦氮配体L4的合成
手套箱中,10mL的Schlenk瓶中加入(R)-3,3’-二苯基-1,1’-联-2-萘酚(0.2g,0.46mmol)、DAMP(0.55mg,0.0045mmol)和三乙胺(6g),将其密封;出手套箱,将Schlenk瓶放入水浴锅中,开启搅拌,氩气氛围下向Schlenk瓶中加入三氯化磷(69mg,0.50mmol),室温下搅拌1h。继续在氩气氛围下,向Schlenk瓶中滴加三乙醇胺(27.2mg,0.18mmol),滴加完毕后将Schlenk瓶放入油浴锅中,加热回流3h,TLC监测原料联奈酚完全反应后,终止反应。将反应液冷却至室温,减压蒸馏回收碱,得到四齿膦氮配体粗品。将粗品用二氯甲烷和乙醚的混合溶剂结晶,得到纯度大于98%的手性四齿膦氮配体L4,收率88.7%。1H-NMR(400MHz,DMSO-d6):δ8.41(m,6H),8.04(m,6H),7.80(s,6H),7.41~7.53(m,42H),3.64(t,J=7.2Hz6H),2.52(t,J=7.1Hz6H);13C-NMR(100MHz,DMSO-d6):151.2(6C),138.9(6C),137.9(6C),132.8(6C),130.1(6C),129.2(12C),128.3(6C),128.1(6C),128.0(6C),127.8(6C),127.6(6C),126.8(6C),126.6(6C),124.4(6C),123.8(6C),59.4(3C),58.9(3C);31P-NMR(162MHz,DMSO-d6):135;ESI-MS:C102H72NO9P3([M+H+])1548.43,([M+Na+])1570.43。
实施例5:手性四齿膦氮配体L5的合成
手套箱中,10mL的Schlenk瓶中加入(R)-3,3’-二(3,5-三氟甲基苯基)-1,1’-联-2-萘酚(0.2g,0.28mmol)、DAMP(0.34mg,0.0028mmol)和三乙胺(6g),将其密封;出手套箱,将Schlenk瓶放入水浴锅中,开启搅拌,氩气氛围下向Schlenk瓶中加入三氯化磷(43mg,0.31mmol),室温下搅拌1h。继续在氩气氛围下,向Schlenk瓶中滴加三乙醇胺(16.8mg,0.11mmol),滴加完毕后将Schlenk瓶放入油浴锅中,加热回流3h,TLC监测原料联奈酚完全反应后,终止反应。将反应液冷却至室温,减压蒸馏回收碱,得到四齿膦氮配体粗品。将粗品用二氯甲烷和乙醚的混合溶剂结晶,得到纯度大于98%的手性四齿膦氮配体L4,收率86.8%。1H-NMR(400MHz,DMSO-d6):δ8.43(m,6H),8.33(s,6H),8.18(s,12H),8.02(m,6H),7.82(s,6H),7.44~7.53(m,12H),3.63(t,J=7.2Hz6H),2.53(t,J=7.1Hz6H);13C-NMR(100MHz,DMSO-d6):151.0(6C),138.8(6C),137.1(6C),132.9(6C),131.8(6C),130.3(6C),130.1(6C),129.2(12C),128.3(6C),128.1(6C),128.0(6C),126.8(6C),126.6(6C),124.8(6C),124.6(6C),123.8(6C),122.1(6C),59.3(3C),58.8(3C);31P-NMR(162MHz,DMSO-d6):139;ESI-MS:C114H60F36NO9P3([M+H+])2365.59,([M+Na+])2387.59。
实施例6~15:乙酰乙酸甲酯不对称氢化制备(R)-1,3-丁二醇
手套箱中,将Ru金属前体(0.0033mmol)、手性膦氮四齿配体(0.0037mmol)和底物乙酰乙酸甲酯(116g,1mol)加入到装有磁力搅拌子的单口瓶中,开启搅拌,金属前体和配体溶解、配位30分钟后,得到催化剂溶液,将单口瓶密封,出手套箱,氮气保护下用平流泵打入0.5L的反应釜中,反应釜已提前用氮气置换,并加入布朗斯特酸。催化剂溶液加入完毕,氢气置换反应釜内三次,充入5MPa的氢气,开启反应釜搅拌和伴热。当反应釜内温达到80℃时,打开氢气进气阀门,保持反应釜内压力为6MPa,开始计时,保温反应2~3小时。当流量计显示吸氢速率小于0.1mL/min,终止反应,将反应釜冷却至室温,取样GC分析(R)-1,3-丁二醇的收率和ee值。
各实施例的反应条件和结果如下表1:
表1乙酰乙酸甲酯不对称氢化制备(R)-1,3-丁二醇
实施例16:乙酰乙酸甲酯不对称氢化制备(R)-1,3-丁二醇
手套箱中,将RuCl3(0.35mg,0.0017mmol)、手性膦氮四齿配体L4(5.2mg,0.0033mmol)和底物乙酰乙酸甲酯(116g,1mol)加入到装有磁力搅拌子的单口瓶中,开启搅拌,金属前体和配体溶解、配位30分钟后,得到催化剂溶液,将单口瓶密封,出手套箱,氮气保护下用平流泵打入0.5L的反应釜中,反应釜已提前用氮气置换,并加入磷酸二苯酯(25mg,0.1mmol)。催化剂溶液加入完毕,氢气置换反应釜内三次,充入8MPa的氢气,开启反应釜搅拌和伴热。当反应釜内温达到150℃时,打开氢气进气阀门,保持反应釜内压力为12MPa,开始计时,保温反应6小时,流量计显示吸氢速率小于0.1mL/min,终止反应,将反应釜冷却至室温,取样GC分析,(R)-1,3-丁二醇的收率98.4%,ee值98.8%。
实施例17:乙酰乙酸甲酯不对称氢化制备(R)-1,3-丁二醇
手套箱中,将RuCl3(4.1mg,0.020mmol)、手性膦氮四齿配体L4(37.2mg,0.0024mmol)和底物乙酰乙酸甲酯(116g,1mol)加入到装有磁力搅拌子的单口瓶中,开启搅拌,金属前体和配体溶解、配位30分钟后,得到催化剂溶液,将单口瓶密封,出手套箱,氮气保护下用平流泵打入2L的反应釜中,反应釜已提前用氮气置换,并加入磷酸二苯酯(750.6mg,3mmol)和乙酰乙酸甲酯(1044g,9mol)。催化剂溶液加入完毕,氢气置换反应釜内三次,充入8MPa的氢气,开启反应釜搅拌和伴热。当反应釜内温达到100℃时,打开氢气进气阀门,保持反应釜内压力为10MPa,开始计时,保温反应4h,流量计显示吸氢速率小于0.1mL/min,终止反应,将反应釜冷却至室温,取样GC分析,(R)-1,3-丁二醇的收率99.4%,ee值99.3%。
将反应釜出料阀门用硅胶管与冷凝管相连,冷凝管与三口烧瓶一个支口相连,三口烧瓶的另一个支口与冷肼相连,冷肼与隔膜泵相连。打开反应釜的加热和搅拌,同时调节真空度,通过减压蒸馏将产物(R)-1,3-丁二醇全部蒸出。
向反应釜内充入氮气,氮气氛围下加入乙酰乙酸甲酯(1160g,10mol),进行下一批次反应。各实验条件不变,结果如下表2:
表2批次实验结果
批次 | 反应时间 | 产物收率/% | 产物ee值/% |
1 | 4 | 99.4 | 99.1 |
2 | 4.5 | 99.3 | 98.9 |
3 | 5.0 | 98.8 | 98.7 |
4 | 5.5 | 98.5 | 98.8 |
5 | 5.5 | 98.2 | 98.5 |
对比例1:乙酰乙酸甲酯不对称氢化制备(R)-1,3-丁二醇
手套箱中,将RuCl3(0.69mg,0.0033mmol)、(R)-BINAP(2.3mg,0.0036mmol)、(1R,2R)-1,2-二苯基-1,2-乙二胺(0.78mg,0.0036mmol)和异丙醇(150g)加入到装有磁力搅拌子的单口瓶中,开启搅拌,金属前体和配体溶解、配位30分钟后,得到催化剂溶液,将单口瓶密封,出手套箱,氮气保护下用平流泵打入0.5L的反应釜中,反应釜已提前用氮气置换,并加入底物乙酰乙酸甲酯(116g,1mol)和叔丁醇钾(0.12g)。催化剂溶液加入完毕,氢气置换反应釜内三次,充入8MPa的氢气,开启反应釜搅拌和伴热。当反应釜内温达到100℃时,打开氢气进气阀门,保持反应釜内压力为10MPa,开始计时,保温反应5h,流量计显示吸氢速率小于0.1mL/min,终止反应,将反应釜冷却至室温,取样GC分析,原料乙酰乙酸甲酯转化率99.9%,(R)-1,3-丁二醇的选择性8.8%,ee值99.2%,(R)-3-羟基丁酸甲酯选择性90.9%。
最后应当说明的是,以上实施例仅用以本发明的优选实施方式进行描述,而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,对本发明的技术方案进行修改或者等同替换作出的各种变型和改进,均应落入本发明的权利要求书确定的保护范围内。
Claims (10)
3.一种制备权利要求1和2所述的手性四齿P,P,P,N配体的方法,包括以下步骤:手性联萘酚、三氯化磷、三乙醇胺在催化剂和碱作用下,反应制备。
4.根据权利要求3所述的方法,其特征在于,所述手性联奈酚选自(R)-1,1’-联-2-萘酚、(R)-6,6’-二溴-1,1’-联-2-萘酚、(R)-3,3’-二叔丁基-1,1’-联-2-萘酚、(R)-3,3’-二苯基-1,1’-联-2-萘酚和(R)-3,3’-二(3,5-三氟甲基苯基)-1,1’-联-2-萘酚中的一种或多种,优选(R)-6,6’-二苯基-1,1’-联-2-萘酚。
5.一种手性钌络合物,包含钌金属前体和权利要求1或2所述的手性四齿P,P,P,N配体。
6.根据权利要求5所述的手性钌络合物,其特征在于,所述的钌金属前体为[Ru(COD)Cl2]、RuI3、RuCl3、Ru(acac)3中的一种或多种,优选RuCl3。
7.一种制备(R)-(-)-1,3-丁二醇的方法,包括以下步骤:使用权利要求5或6所述的手性钌络合物作为催化剂,布朗斯特酸作为助剂,将乙酰乙酸甲酯不对称氢化得到(R)-(-)-1,3-丁二醇。
8.根据权利要求7所述的方法,其特征在在于,所述的手性钌络合物中的钌金属前体与底物乙酰乙酸甲酯的摩尔比为1:300000~600000,优选1:400000~500000。
9.根据权利要求7或8所述的方法,其特征在于,所述布朗斯特酸为磷酸二苯酯、磷酸二苄酯、二(2-乙基己基)磷酸酯中的一种或几种,优选磷酸二苯酯;和/或,所述布朗斯特酸与乙酰乙酸甲酯的摩尔比为0.1%~0.5%:1,优选0.2%~0.3%:1。
10.根据权利要求7-9任一项所述的方法,其特征在于,所述乙酰乙酸甲酯纯度为99.0~99.9%,氧气含量小于10ppb,水含量小于10ppm;和/或,所述不对称氢化反应的温度为80~150℃,优选100~120℃,不对称氢化反应的氢气压力为6~12MPaG,优选8~10MpaG。
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