CN110590820B - Process for preparing chiral organoboron compounds - Google Patents
Process for preparing chiral organoboron compounds Download PDFInfo
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- CN110590820B CN110590820B CN201910803642.8A CN201910803642A CN110590820B CN 110590820 B CN110590820 B CN 110590820B CN 201910803642 A CN201910803642 A CN 201910803642A CN 110590820 B CN110590820 B CN 110590820B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 42
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 229920001661 Chitosan Polymers 0.000 claims abstract description 74
- 239000003054 catalyst Substances 0.000 claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 150000001639 boron compounds Chemical class 0.000 claims abstract description 32
- 239000002904 solvent Substances 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 31
- 239000012418 sodium perborate tetrahydrate Substances 0.000 claims abstract description 19
- IBDSNZLUHYKHQP-UHFFFAOYSA-N sodium;3-oxidodioxaborirane;tetrahydrate Chemical compound O.O.O.O.[Na+].[O-]B1OO1 IBDSNZLUHYKHQP-UHFFFAOYSA-N 0.000 claims abstract description 19
- -1 benzyloxy phenyl Chemical group 0.000 claims description 38
- 239000003446 ligand Substances 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 23
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 11
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 11
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 11
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 11
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 11
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 11
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 11
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 11
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000003944 tolyl group Chemical group 0.000 claims description 9
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 claims description 7
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 claims description 6
- 229960002866 duloxetine Drugs 0.000 claims description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 124
- 229910052802 copper Inorganic materials 0.000 abstract description 28
- 239000010949 copper Substances 0.000 abstract description 28
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 abstract description 26
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 abstract description 22
- 238000006555 catalytic reaction Methods 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 8
- 229910052796 boron Inorganic materials 0.000 abstract description 7
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 7
- 239000000758 substrate Substances 0.000 abstract description 7
- 238000007259 addition reaction Methods 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 239000007800 oxidant agent Substances 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- VBXDEEVJTYBRJJ-UHFFFAOYSA-N diboronic acid Chemical compound OBOBO VBXDEEVJTYBRJJ-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 168
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- 238000000605 extraction Methods 0.000 description 28
- 239000007858 starting material Substances 0.000 description 28
- 239000000463 material Substances 0.000 description 27
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 24
- 238000001914 filtration Methods 0.000 description 24
- 230000003197 catalytic effect Effects 0.000 description 23
- 238000004440 column chromatography Methods 0.000 description 22
- 239000012046 mixed solvent Substances 0.000 description 20
- 239000003208 petroleum Substances 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- 238000001035 drying Methods 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 17
- 238000000926 separation method Methods 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 238000002390 rotary evaporation Methods 0.000 description 15
- 239000007832 Na2SO4 Substances 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- DVJAMEIQRSHVKC-BDAKNGLRSA-N Dutogliptin Chemical class OB(O)[C@@H]1CCCN1C(=O)CN[C@H]1CNCC1 DVJAMEIQRSHVKC-BDAKNGLRSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- JJLJMEJHUUYSSY-UHFFFAOYSA-L Copper hydroxide Chemical compound [OH-].[OH-].[Cu+2] JJLJMEJHUUYSSY-UHFFFAOYSA-L 0.000 description 4
- 239000005750 Copper hydroxide Substances 0.000 description 4
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 4
- 239000005751 Copper oxide Substances 0.000 description 4
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 description 4
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 4
- 229910001956 copper hydroxide Inorganic materials 0.000 description 4
- 229910000431 copper oxide Inorganic materials 0.000 description 4
- 229910000365 copper sulfate Inorganic materials 0.000 description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 4
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 4
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002131 composite material Substances 0.000 description 3
- 229950003693 dutogliptin Drugs 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 238000010568 chiral column chromatography Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000002028 Biomass Substances 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000004696 coordination complex 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
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000007210 heterogeneous catalysis Methods 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 239000002815 homogeneous catalyst Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- PEYVWSJAZONVQK-UHFFFAOYSA-N hydroperoxy(oxo)borane Chemical compound OOB=O PEYVWSJAZONVQK-UHFFFAOYSA-N 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000696 magnetic material Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AZQWKYJCGOJGHM-UHFFFAOYSA-N para-benzoquinone Natural products O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229910001428 transition metal ion Inorganic materials 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
- B01J31/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of the platinum group metals, iron group metals or copper
- B01J31/30—Halides
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/32—Addition reactions to C=C or C-C triple bonds
- B01J2231/323—Hydrometalation, e.g. bor-, alumin-, silyl-, zirconation or analoguous reactions like carbometalation, hydrocarbation
Abstract
The invention relates to the field of compound synthesis, in particular to a method for preparing a chiral organic boron compound by catalysis of functionalized chitosan supported copper, and also relates to application of the method for preparing the chiral organic boron compound by catalysis of functionalized chitosan supported copper in synthesizing a delta-hydroxy compound and drug molecules for treating diabetes. The invention takes functionalized chitosan solid-supported copper as a catalyst, uses diboronic acid pinacol ester (as a reaction reagent, water as a solvent and sodium perborate tetrahydrate as an oxidant), selectively generates boron addition reaction aiming at substrates containing different substituents respectively, and further prepares the delta-hydroxy compound through continuous oxidation reaction.
Description
Technical Field
The invention relates to the field of compound synthesis, in particular to a method for preparing a chiral organic boron compound by catalysis of functionalized chitosan supported copper, and also relates to application of the method for preparing the chiral organic boron compound by catalysis of the functionalized chitosan supported copper in synthesizing a delta-hydroxy compound and molecules of a medicament for treating diabetes.
Background
To date, various organic and inorganic materials, such as alumina, zeolites, polymers, and magnetic materials have been investigated as heterogeneous carriers. Their use is still very limited due to their instability at ambient conditions, high energy consumption and time requirements during the preparation process. Therefore, the search for new green, renewable, environmentally friendly, low cost heterogeneous catalytic materials has become an urgent and highly interesting issue. Polysaccharide has become the most popular biomass resource in recent years due to the characteristics of biodegradability, reproducibility, environmental friendliness and the like. In addition, polysaccharides have a variety of functional groups, thus possessing modification and optimization potential. And the chitosan has excellent characteristics of antibacterial property, high metal affinity, water solubility and the like. Therefore, the functionalized chitosan is used for loading different transition metal ions, is applied to the field of catalysis, and is explored for application in other functional fields. The material has the significance of overcoming the problems of the current heterogeneous catalysis material and meeting the requirements of people in the 21 st century on green and environmental protection of the material.
Chiral organic boron compounds are important intermediates and are widely applied to synthesis of natural products and drug molecules, because C-B bonds can be simply and conveniently converted into C-O, C-N and C-C bonds. The conversion of chiral organic boron compounds to delta-hydroxy compounds is a very important field of application. Wherein the geminal diaryl borate is an electron-deficient olefin compound with a special structure and widely exists in medicines. In the synthesis method of the compounds, two benzene substitutes are mostly subjected to multi-step reaction of bonding after boronization, and the actual production potential is low. In recent years, a few documents (ACS Catal.2016,6, 442-446) report that the experimental procedure is simplified by the direct formation of a geminal diarylboronate via a one-step addition reaction of a p-benzoquinone methyl compound (p-QMs). However, the methods have the defects that monovalent copper homogeneous catalysts which are sensitive to water and air and have higher price are used, and the consumption is large, so that metal residues are easily caused in the drug synthesis, and the health of human bodies is seriously harmed; strong alkali must be added into the reaction system and organic solvent is used, which causes great pollution to the environment.
Thus, if a more stable, inexpensive and efficient heterogeneous catalyst could be used to effect this conversion, followed by a continuous conversion to the delta-hydroxy compound without separation, the synthetic procedures and separation conditions for the natural product would be simplified, and the cost would be reduced, which would facilitate the use of such reactions in practical production. The invention utilizes the stable, cheap and low-toxic divalent copper load and the chitosan, reduces the dosage of the catalyst, can be recycled and reused, and avoids metal residue in the drug synthesis; meanwhile, water is used as a solvent, so that the environment is protected; and can achieve gram-scale reaction with high yield.
In addition, the organic boron compound itself has wide practical applications, such as an initiator of polymerization, an antioxidant, a bactericide, a neutron-capturing agent, a drug for treating brain tumor, an anticancer drug, a drug for treating diabetes, and the like. Therefore, if the developed novel method can be applied to the synthesis of the medicine molecules for treating diabetes, the method has important practical significance.
Disclosure of Invention
The invention aims to provide a method for preparing a chiral organic boron compound by catalysis of functionalized chitosan supported copper, which realizes boron addition of a substrate under mild conditions to prepare chiral organic boron compounds containing different substituents. The preparation method is easy and convenient to operate, and takes the functionalized chitosan solid-supported copper as the catalyst and the pinacol ester diboron (B)2(pin)2) The reaction reagent can reach high reaction activity in pure water. The catalyst has low consumption, can be recycled, is easy to separate after the reaction is finished, has no metal residue, has mild reaction conditions and simple post-treatment, and is suitable for large-scale production.
The invention also aims to provide application of the chiral organic boron compound prepared by the catalysis of the functionalized chitosan supported copper in synthesizing delta-hydroxy compounds and molecules of drugs for treating diabetes. After the chiral organic boron compound is prepared by boron addition, functional group conversion is directly realized, and the functional molecular delta-hydroxy compound is prepared by a one-pot method, so that the method has more practical application value. Meanwhile, the method is applied to the synthesis of the molecular duloxetine (Dutogliptin) derivative serving as a medicament for treating diabetes, the target molecule is synthesized by simple three-step conversion, and duloxetine (Dutogliptin) and the derivative thereof are very important boron-containing medicaments and are used for researching and treating type 2 diabetes at present. In order to achieve the purpose, the invention adopts the following technical measures:
The technical conception is as follows: chiral organic boron prepared by catalysis of functionalized chitosan supported copperThe method of the compound takes functionalized Chitosan supported Copper (HBCS @ Cu) as a catalyst, wherein the prepared catalyst comprises functionalized Chitosan supported Copper hydroxide (HBCS @ Cu (OH)2) The chitosan-copper-based composite material comprises functional chitosan-supported copper oxide (HBCS @ CuO), functional chitosan-supported copper cyanide (HBCS @ CuCN), and functional chitosan-supported copper sulfate (HBCS @ CuSO)4) Functionalized chitosan immobilized copper chloride (HBCS @ CuCl)2) Functionalized chitosan immobilized copper fluoride (HBCS @ CuF)2) And functionalized chitosan immobilized copper bromide (HBCS @ CuBr)2). Biboric acid pinacol ester (B)2(pin)2) The method comprises the steps of (national chemical reagent company) taking reaction reagents, water as a solvent and sodium perborate tetrahydrate (Aldrich company) as an oxidant, selectively carrying out boron addition reaction on substrates containing different substituents respectively, and further preparing a delta-hydroxy compound through continuous oxidation reaction.
The structural general formula of the chiral organic boron compound II is as follows:
wherein, the R group is phenyl, halogenated phenyl, benzyloxy phenyl, methyl phenyl, single or multi-methoxy phenyl or benzyl.
Specifically, the R group is phenyl, 4-chlorphenyl, 4-bromophenyl, 4-benzyloxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-bromophenyl, 3-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethoxyphenyl, 1-benzyl or 2-benzyl.
The invention also provides a preparation method of the chiral organic boron compound II, which comprises the following steps: reacting the compound I with pinacol diboron under the conditions of a catalyst, solvent water, a ligand and room temperature to obtain an organic boron compound II;
wherein:
the structural formula of the compound I is
The R group is phenyl, halogenated phenyl, benzyloxy phenyl, methyl phenyl, mono-or poly-methoxy phenyl or benzyl;
the catalyst is a functionalized chitosan immobilized copper catalyst;
the ligand is L1, L2, L3 or L4, and each structural formula is as follows:
specifically, the method comprises the following steps:
the R group is phenyl, 4-chlorphenyl, 4-bromophenyl, 4-benzyloxy phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-bromophenyl, 3-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethoxyphenyl, 1-benzyl or 2-benzyl;
the functionalized chitosan immobilized copper catalyst is functionalized chitosan immobilized copper hydroxide, functionalized chitosan immobilized copper oxide, functionalized chitosan immobilized copper cyanide, functionalized chitosan immobilized copper sulfate, functionalized chitosan immobilized copper chloride, functionalized chitosan immobilized copper fluoride or functionalized chitosan immobilized copper bromide.
Under the catalysis of functionalized chitosan supported copper (HBCS @ Cu), a substrate and diboron pinacol ester (B)2(pin)2The structure is shown by the chemical reaction equation) are adsorbed on the catalyst surface and are close to each other. Copper and ligand, and diboronic acid pinacol ester form a composite metal complex, and the addition reaction is carried out on a substrate. And transferring the boron group connected with the copper to a substrate in a six-membered ring transition state, and selectively completing the direct boron addition process by 1,6 to prepare the chiral organic boron compound. After the reaction is finished, recovering a functionalized chitosan supported copper (HBCS @ Cu) catalyst through simple filtering operation, adding sodium perborate into a residual reaction system, and directly oxidizing the chiral organic boron compound into a delta-hydroxy compound. When the starting material is unsaturated carbonyl compound I, chiral organic boron compound II is prepared, and the chemical reaction equation is as follows:
the structural formula of the chiral organic boron compound II is as follows:
the definition of the R group in the compound I, II and III is the same, and the R group is phenyl, 4-chlorophenyl, 4-bromophenyl, 4-benzyloxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethoxyphenyl, 1-benzyl and 2-benzyl;
Specifically, the method for preparing the chiral organic boron compound II by the catalysis of the functionalized chitosan supported copper comprises the following steps:
A. adding a functionalized chitosan supported copper catalyst (HBCS @ Cu) and a ligand into a 3mL reaction bottle, adding 2.5mL of water, and stirring at room temperature (20-25 ℃, the same below) for 1 hour; the functionalized chitosan immobilized copper catalyst (HBCS @ Cu) is functionalized chitosan immobilized copper hydroxide (HBCS @ Cu (OH)2) The chitosan-copper-based composite material comprises functional chitosan-supported copper oxide (HBCS @ CuO), functional chitosan-supported copper cyanide (HBCS @ CuCN), and functional chitosan-supported copper sulfate (HBCS @ CuSO)4) And the functional chitosan immobilized copper chloride (HBCS @ CuCl)2) And the functional chitosan immobilized copper fluoride (HBCS @ CuF)2) And functionalized chitosan immobilized copper bromide (HBCS @ CuBr)2) At least one, more preferably functionalized chitosan-supported copper chloride (HBCS @ CuCl); the dosage of the functionalized chitosan supported copper catalyst (HBCS @ Cu) is 5mg, 15mg and 25mg, and more preferably 5 mg; the ligand is at least one of L1, L2, L3 and L4 in a reaction formula, and is more preferably L3; the ratio of the amount of the ligand to the amount of the starting material I is 0.06, and the ratio of the amount of the starting material I to the amount of the solvent water in milliliters is 0.1;
B. Respectively and continuously and sequentially adding the initial raw material I and the coupling into the system obtained in the step APinacol ester borate (B)2(pin)2) (ii) a The pinacol ester diborate B2(pin)2The amount of substance to starting material I is 1.2 to 2.0, more preferably 1.2;
C. the whole reaction system is stirred at room temperature for reaction; the reaction time is 10-14 hours;
D. after completion of the reaction, the whole reaction system was filtered and washed with 3mL of tetrahydrofuran. The filtrate is evaporated and concentrated by rotation, and the residue is subjected to column chromatography by ethyl acetate/petroleum ether mixed solvent with different proportions, separated and purified. The proportion of the ethyl acetate/petroleum ether mixed solvent is 10:1-3:1, and silica gel is adopted as a stationary phase for column chromatography. Finally separating by high performance liquid chromatography through a Chiralcel OD-H chiral column to obtain a target product II, wherein the ratio of the mobile phase n-hexane/isopropanol is 99:1-90:10, and the flow rate is 1mL/min
The invention also provides a chiral delta-hydroxy compound III, which has the following structural general formula:
wherein, the R group is phenyl, halogenated phenyl, benzyloxy phenyl, methyl phenyl, single or multi-methoxy phenyl or benzyl.
Specifically, the method comprises the following steps: the R group is phenyl, 4-chlorphenyl, 4-bromophenyl, 4-benzyloxy phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-bromophenyl, 3-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethoxyphenyl, 1-benzyl or 2-benzyl.
The invention also provides a preparation method of the chiral delta-hydroxy compound III, which comprises the following steps:
1) reacting the compound I with pinacol diboron under the conditions of a catalyst, solvent water, a ligand and room temperature to obtain an organic boron compound II;
2) reacting the organic boron compound II obtained in the step 1) with sodium perborate tetrahydrate to obtain a chiral delta-hydroxy compound III;
wherein:
the structural formula of the compound I is
The R group is phenyl, halogenated phenyl, benzyloxy phenyl, methyl phenyl, mono-or poly-methoxy phenyl or benzyl;
the catalyst is a functionalized chitosan immobilized copper catalyst;
the ligand is
Specifically, the method comprises the following steps:
the R group is phenyl, 4-chlorphenyl, 4-bromophenyl, 4-benzyloxy phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-bromophenyl, 3-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethoxyphenyl, 1-benzyl or 2-benzyl;
the functionalized chitosan immobilized copper catalyst is functionalized chitosan immobilized copper hydroxide, functionalized chitosan immobilized copper oxide, functionalized chitosan immobilized copper cyanide, functionalized chitosan immobilized copper sulfate, functionalized chitosan immobilized copper chloride, functionalized chitosan immobilized copper fluoride or functionalized chitosan immobilized copper bromide
Specifically, the application of the chiral organic boron compound II prepared by the catalysis of the functionalized chitosan supported copper in the synthesis of the chiral delta-hydroxy compound III has the following chemical reaction equation:
the definition of the R group in the compound I, II and III is the same, and the R group is phenyl, 4-chlorophenyl, 4-bromophenyl, 4-benzyloxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethoxyphenyl, 1-benzyl and 2-benzyl;
the method comprises the following steps:
A. adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction tube2) And ligand L3, adding 2.5mL water, stirring at room temperature for 1 hour; the functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl)2) The dosage of the composition is 5 mg; the ratio of the amount of the ligand to the amount of the starting material I substance is 0.06, and the ratio of the amount of the starting material I substance to the amount of the solvent water in milliliters is 0.1;
B. to the above system, the starting material I and the pinacol ester diborate (B) were continuously added in this order2(pin)2) (ii) a The mass ratio of the pinacol diboron the starting material I is 1.2;
C. the whole reaction system is stirred at room temperature for reaction; the reaction time is 11-13 hours;
D. After completion of the reaction, the whole reaction system was filtered and washed with 3mL of tetrahydrofuran. 244mg of sodium perborate tetrahydrate was added directly to the residue, and the whole was stirred at room temperature for 3 to 5 hours.
E. To the above system was added ethyl acetate (3 mL) to dilute the solution, the solution was extracted with ethyl acetate (3X 10mL), the organic phase was separated, and anhydrous sodium sulfate (Na) was added2SO4) Drying, filtering and rotary evaporating to remove solvent. Purifying the residue by column chromatography with ethyl acetate/petroleum ether mixed solvent at different ratio of 10:1-3:1, wherein the column chromatography adopts silica gel as stationary phase. And finally, separating by using a high performance liquid chromatography through a Chiralcel OD-H chiral column to obtain a target product III, wherein the ratio of the mobile phase n-hexane/isopropanol is 98:2-90:10, and the flow rate is 1 mL/min.
The invention also provides a preparation method of duloxetine, which comprises the following steps:
1) reacting the compound IV with pinacol diboron under the conditions of a catalyst, solvent water, a ligand and room temperature to obtain an intermediate compound;
2) hydrogenating and reducing the intermediate compound obtained in the step 1) to obtain duloxetine;
wherein:
the structural formula of the compound IV is as follows:
the catalyst is a functionalized chitosan immobilized copper catalyst;
The intermediate compound has a structural formula:
the ligand is
Specifically, the application of the chiral organic boron compound prepared by the catalysis of the functionalized chitosan supported copper in the synthesis of the molecule Dutogliptin V which is a medicament for treating diabetes mellitus has the chemical reaction equation:
the method comprises the following steps:
A. adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction tube2) And ligand L3, adding 2.5mL water, stirring at room temperature for 1 hour; the functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl)2) The dosage of the composition is 5 mg; the ratio of the amount of the ligand to the amount of the starting material IV is 0.06, and the ratio of the amount of the starting material IV to the amount of the solvent water in milliliters is 0.1;
B. to the above system, the starting material IV and the pinacol ester diboron (B) were continuously added in this order2(pin)2) (ii) a The pinacol ester diborate (B)2(pin)2) The mass ratio to starting material IV was 1.2;
C. the whole reaction system is stirred at room temperature for reaction; the reaction time is 11-13 hours;
D. after the reaction is finished, filtering the whole reaction system, washing with 3mL of tetrahydrofuran, directly adding 2mL of dilute hydrochloric acid into the residue, and stirring the whole system at room temperature for 4-6 hours;
E. To the above system was added ethyl acetate (3 mL) to dilute the solution, the solution was extracted with ethyl acetate (3X 10mL), the organic phase was separated, and anhydrous sodium sulfate (Na) was added2SO4) Drying, filtering and rotary evaporating to remove solvent. 3mL of methanol and 5mg of an activated carbon-supported palladium catalyst (Pd/C) were added to the residue, and the mixture was stirred at room temperature under 1 atm of hydrogen for 11 to 13 hours;
F. filtering to remove the active carbon supported palladium catalyst, carrying out rotary concentration on the filtrate to remove the solvent, and then purifying the residue by using ethyl acetate/petroleum ether (2: 1) mixed solvent column chromatography, wherein the silica gel is used as a stationary phase in the column chromatography. And finally, separating by using a high performance liquid chromatography through a chiral column to obtain a target product V, wherein the mobile phase is n-hexane/isopropanol.
Compared with the prior art, the invention has the following advantages and effects:
1. the method is easy to implement, simple and convenient to operate, rich in raw material source and low in cost, such as functionalized chitosan, copper chloride and the like, and the method is favorable for application in actual production;
2. the method can realize higher conversion number of reactants only by using lower catalyst dosage;
3. the method has mild reaction conditions, is simple and easy to operate, and can be used for carrying out reaction at room temperature;
4. the method has wide applicability, can be suitable for various substrates of different types, and successfully prepares the corresponding target compound;
5. In the method, the whole reaction system is heterogeneous, and the catalyst can be conveniently removed by filtration after the reaction is finished;
6. the method can still ensure high yield in gram-level reaction, and has practical application prospect.
The functionalized chitosan immobilized copper chloride catalytic material can be recycled, and catalytic reaction is carried out without activity loss. The recycling experimental data are as follows: taking I-1 as a raw material to generate a product III-1 as an example, after the reaction is finished, the functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) is recovered by filtration2) Directly for the next oneThe reaction is repeated for five times to obtain the target products with the yields of>90％,>90％,90％,90％,>And 90 percent, proving that the catalyst has almost no loss of activity and can be recycled.
Detailed Description
The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
The outstanding features of the invention are further clarified below by the examples, which are intended to be purely illustrative and in no way limiting. When the starting material is an unsaturated carbonyl compound I, a chiral organic boron compound II is prepared and then converted into a delta-hydroxy compound III; when the initial raw material is pyrrole amide compound IV, chiral organic boron compound is prepared and then converted into Dutogliptin V.
Example 1:
the preparation method of the compound III-1 comprises the following steps:
A. adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle2)5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5 mL of water was added and stirred at room temperature (20 or 22 or 24 or 25 ℃ C., the same applies hereinafter) for 1 hour;
B. to the above system, the starting material I-1(58.9mg,0.2mmol) and pinacol ester diboron (B) were added successively2(pin)2)(60.9mg,0.24mmol)；
C. The whole reaction system is stirred for 12 hours at room temperature to carry out reaction;
D. after the reaction, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and sodium perborate tetrahydrate (244mg,0.8mmol) was added directly to the residue, and the whole system was stirred at room temperature for 4 hours;
E. to the above system was added ethyl acetate 3mL to dilute the mixture, and the mixture was extracted with ethyl acetate (3X 10mL) to separate an organic phase,with anhydrous Na2SO4Drying, filtering and rotary evaporation to remove the solvent. Purifying the residue by ethyl acetate/petroleum ether mixed solvent 10:1 column chromatography, and separating by chiral column to obtain III-157.6 mg with yield>90％。
1H NMR(400MHz,Chloroform-d)δ7.46–7.42(m,2H),7.40–7.35(m,2H), 7.31–7.26(m,1H),7.20(s,2H),5.81(d,J＝3.3Hz,1H),5.22(s,1H),2.19(d, J＝3.4Hz,1H),1.44(s,18H).
13C NMR(400MHz,Chloroform-d)δ153.34,144.13,135.86,134.55,128.35, 127.26,126.41,123.67,76.77,34.41,30.27.
Example 2:
the preparation method of the compound III-2 comprises the following steps:
A. adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle 2) 5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and stirred at room temperature (20 or 22 or 24 or 25 ℃ C., the same applies hereinafter) for 1 hour;
B. to the above system, the starting material I-2(65.8mg,0.2mmol) and pinacol ester diboron (B) were added successively2(pin)2)(60.9mg,0.24mmol)；
C. The whole reaction system is stirred for 12 hours at room temperature to carry out reaction;
D. after the reaction, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and sodium perborate tetrahydrate (244mg,0.8mmol) was added directly to the residue, and the whole system was stirred at room temperature for 4 hours;
E. to the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10mL), separation of the organic phase, and then extraction with anhydrous Na2SO4Drying, filtering and rotary evaporation to remove the solvent. Purifying the residue by ethyl acetate/petroleum ether mixed solvent 10:1 column chromatography, and separating by chiral column to obtain III-265.2 mg with yield>90％。
1H NMR(400MHz,Chloroform-d)δ7.36–7.27(m,4H),7.12(s,2H),5.72(d,J ＝2.7Hz,1H),5.21(s,1H),2.21(d,J＝3.1Hz,1H),1.40(s,18H).
13C NMR(100MHz,Chloroform-d)δ153.47,142.54,135.99,134.16,132.80, 128.36,127.70,123.56,76.06,34.35,30.19.
The other implementation steps are the same as in example 1.
Example 3:
preparation of Compound III-3:
A. adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle2) 5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and stirred at room temperature (20 or 22 or 24 or 25 ℃ C., the same applies hereinafter) for 1 hour;
B. To the above system, the starting material I-3(74.7mg,0.2mmol) and pinacol ester diboron (B) were added successively2(pin)2)(60.9mg,0.24mmol)；
C. The whole reaction system is stirred for 12 hours at room temperature to carry out reaction;
D. after the reaction, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and sodium perborate tetrahydrate (244mg,0.8mmol) was added directly to the residue, and the whole system was stirred at room temperature for 4 hours;
E. to the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10mL), separation of the organic phase, and then extraction with anhydrous Na2SO4Drying, filtering and rotary evaporation to remove the solvent. Purifying the residue by ethyl acetate/petroleum ether mixed solvent 10:1 column chromatography, and separating by chiral column to obtain III-372.6 mg with yield>90％。
1H NMR(400MHz,Chloroform-d)δ7.45(d,J＝8.5Hz,2H),7.28(d,J＝8.4 Hz,2H),7.12(s,2H),5.71(d,J＝3.1Hz,1H),5.21(s,1H),2.17(d,J＝3.3Hz, 1H),1.40(s,18H).
13C NMR(100MHz,Chloroform-d)δ153.50,143.07,136.02,134.09,131.32, 128.06,123.56,120.97,76.13,34.37,30.20.
The other implementation steps are the same as in example 1 or example 2.
Example 4:
preparation of Compound III-4
A. Adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle2)
5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and stirred at room temperature (20 or 22 or 24 or 25 ℃ C., the same applies hereinafter) for 1 hour;
B. to the above system, the starting material I-4(80.1mg,0.2mmol) and pinacol ester diboron (B) were added successively 2(pin)2)(60.9mg,0.24mmol)；
C. The whole reaction system is stirred for 12 hours at room temperature to carry out reaction;
D. after the reaction, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and sodium perborate tetrahydrate (244mg,0.8mmol) was added directly to the residue, and the whole system was stirred at room temperature for 4 hours;
E. to the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10mL), separation of the organic phase, and then extraction with anhydrous Na2SO4Drying, filtering and rotary evaporation to remove the solvent. Purifying the residue by ethyl acetate/petroleum ether mixed solvent (5: 1) column chromatography, and separating by chiral column to obtain III-480.5 mg with high yield>90％。
1H NMR(400MHz,Chloroform-d)δ7.45–7.40(m,2H),7.40–7.34(m,2H), 7.33-7.29(m,5.8Hz,3H),7.15(s,2H),6.97–6.92(m,2H),5.73(d,J＝2.6Hz, 1H),5.17(s,1H),5.06(s,2H),2.12(d,J＝3.2Hz,1H),1.41(s,18H).
13C NMR(100MHz,Chloroform-d)δ157.91,153.15,136.96,136.69,135.72, 134.62,128.50,127.86,127.66,127.40,123.44,114.61,76.21,69.94,34.32, 30.21.
The other implementation steps are the same as in example 1 or example 2.
Example 5:
preparation of Compound III-5:
A. adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle2) 5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and stirred at room temperature (20 or 22 or 24 or 25 ℃ C., the same applies hereinafter) for 1 hour;
B. to the above system, the starting material I-5(61.7mg,0.2mmol) and pinacol ester diboron (B) were added successively2(pin)2)(60.9mg,0.24mmol)；
C. The whole reaction system is stirred for 12 hours at room temperature to carry out reaction;
D. after the reaction, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and sodium perborate tetrahydrate (244mg,0.8mmol) was added directly to the residue, and the whole system was stirred at room temperature for 4 hours;
E. To the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10mL), separation of the organic phase, and then extraction with anhydrous Na2SO4Drying, filtering and rotary evaporation to remove the solvent. The residue was purified by ethyl acetate/petroleum ether mixed solvent ═ 10: purifying with 1 column chromatography, and separating with chiral column to obtain III-561.7 mg with yield>90％。
1H NMR(400MHz,Chloroform-d)δ7.25–7.21(m,2H),7.21–7.19(m,1H), 7.17(s,2H),7.06(d,J＝7.7Hz,1H),5.73(d,J＝2.9Hz,1H),5.18(s,1H),2.34 (s,3H),2.17(d,J＝3.3Hz,1H),1.41(s,18H).
13C NMR(100MHz,Chloroform-d)δ153.25,144.02,137.90,135.76,134.54, 128.20,127.97,127.03,123.57,123.37,76.76,34.35,30.22,21.49.
The other implementation steps are the same as in example 1 or example 2.
Example 6:
preparation of Compound III-6:
adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle2)5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and the mixture was stirred at room temperature for 1 hour. To the above system, the starting material I-6 (64.6mg,0.2mmol) and pinacol ester diboron (B) were added successively2(pin)2) (60.9mg,0.24 mmol). The whole reaction system was stirred at room temperature for 12 hours to effect a reaction. After the reaction was completed, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and sodium perborate tetrahydrate (244mg, 0.8mmol) was added directly to the residue, and the whole was stirred at room temperature for 4 hours. To the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10mL), separation of the organic phase, and then extraction with anhydrous Na 2SO4Drying, filtering and rotary evaporation to remove the solvent. The residue was purified by column chromatography using a mixed solvent of ethyl acetate/petroleum ether (10: 1) to give III-663.0 mg in 92% yield.
1H NMR(400MHz,Chloroform-d)δ7.24(t,J＝7.9Hz,1H),7.17(s,2H),7.00 –6.95(m,2H),6.82–6.76(m,1H),5.73(d,J＝2.9Hz,1H),5.18(s,1H),3.79 (s,3H),2.23(d,J＝3.3Hz,1H),1.41(s,18H).
13C NMR(100MHz,Chloroform-d)δ159.63,153.37,145.84,135.86,134.40, 129.37,123.63,118.83,112.76,111.90,76.68,55.25,34.40,30.28.
The other implementation steps are the same as in example 1 or example 2.
Example 7:
preparation of Compound III-7:
adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle2)5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and the mixture was stirred at room temperature for 1 hour. To the above system, the starting material I-7 (62.5mg,0.2mmol) and pinacol ester diboron (B) were added successively2(pin)2) (60.9mg,0.24 mmol). The whole reaction system was stirred at room temperature for 12 hours to effect a reaction. After the reaction was completed, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and sodium perborate tetrahydrate (244mg, 0.8mmol) was added directly to the residue, and the whole was stirred at room temperature for 4 hours. To the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10mL), separation of the organic phase, and then extraction with anhydrous Na2SO4Drying, filtering and rotary evaporation to remove the solvent. The residue was purified by column chromatography using a mixed solvent of ethyl acetate/petroleum ether (10: 1) to give III-763.1 mg in 95% yield.
1H NMR(400MHz,Chloroform-d)δ7.33–7.25(m,1H),7.19–7.10(m,4H), 6.96-6.91(m,1H),5.75(d,J＝2.9Hz,1H),5.22(s,1H),2.20(d,J＝3.3Hz,1H), 1.41(s,18H).
13C NMR(100MHz,Chloroform-d)δ153.53,146.75,146.69,136.01,134.06, 129.77,129.69,123.62,121.91,121.89,114.08,113.86,113.34,113.12,76.15, 76.13,34.37,30.19.
The other implementation steps are the same as in example 1 or example 2.
Example 8:
preparation of Compound III-8:
adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle2)5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and the mixture was stirred at room temperature for 1 hour. Into the above systemSeparately, the starting material I-8 (74.7mg,0.2mmol) and pinacol ester diboron (B) were successively added2(pin)2) (60.9mg,0.24 mmol). The whole reaction system was stirred at room temperature for 12 hours to effect a reaction. After the reaction was completed, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and sodium perborate tetrahydrate (244mg, 0.8mmol) was added directly to the residue, and the whole was stirred at room temperature for 4 hours. To the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10mL), separation of the organic phase, and then extraction with anhydrous Na2SO4Drying, filtering and rotary evaporation to remove the solvent. The residue was purified by column chromatography using a mixed solvent of ethyl acetate/petroleum ether (10: 1) and then separated by a chiral column to give III-875.0 mg in 96% yield.
1H NMR(400MHz,Chloroform-d)δ7.58(t,J＝1.9Hz,1H),7.39-7.36(m,1H), 7.31(d,J＝7.7Hz,1H),7.19(t,J＝7.8Hz,1H),7.13(s,2H),5.71(d,J＝2.4Hz, 1H),5.22(s,1H),2.23(d,J＝3.1Hz,1H),1.41(s,18H).
13C NMR(100MHz,Chloroform-d)δ153.61,146.39,136.08,133.98,130.25, 129.89,129.44,124.97,123.70,122.49,76.13,34.42,30.25.
The other implementation steps are the same as in example 1 or example 2.
Example 9:
preparation of Compound III-9:
Adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle2)5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and the mixture was stirred at room temperature for 1 hour. To the above system, the starting material I-9 (61.7mg,0.2mmol) and pinacol ester diboron (B) were added successively2(pin)2) (60.9mg,0.24 mmol). The whole reaction system was stirred at room temperature for 12 hours to effect a reaction. After the reaction was completed, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and perboric acid was directly added to the residueSodium tetrahydrate (244mg, 0.8mmol), the whole was stirred at room temperature for 4 hours. To the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10mL), separation of the organic phase, and then extraction with anhydrous Na2SO4Drying, filtering and rotary evaporation to remove the solvent. The residue was purified by column chromatography using a mixed solvent of ethyl acetate/petroleum ether (10: 1) and then separated by a chiral column to obtain III-960.5 mg in 93% yield.
1H NMR(400MHz,Chloroform-d)δ7.58(d,J＝6.3Hz,1H),7.27–7.22(m, 1H),7.19-7.17(m,1H),7.12(s,3H),5.91(d,J＝1.7Hz,1H),5.17(s,1H),2.25 (s,3H),2.12(s,1H),1.39(s,18H).
13C NMR(100MHz,Chloroform-d)δ153.21,141.91,135.71,135.02,133.39, 130.27,127.10,125.99,125.65,124.02,73.59,34.31,30.20,19.46.
The other implementation steps are the same as in example 1 or example 2.
Example 10:
preparation of Compound III-10:
adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle2)5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and the mixture was stirred at room temperature for 1 hour. To the above system, the starting material I-10 (64.9mg,0.2mmol) and pinacol ester diboron (B) were added successively 2(pin)2) (60.9mg,0.24 mmol). The whole reaction system was stirred at room temperature for 12 hours to effect a reaction. After the reaction was completed, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and sodium perborate tetrahydrate (244mg, 0.8mmol) was added directly to the residue, and the whole was stirred at room temperature for 4 hours. To the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10mL), separation of the organic phase, and then extraction with anhydrous Na2SO4Drying, filtering and rotary evaporation to remove the solvent. The residue was purified by column chromatography using a mixed solvent of ethyl acetate and petroleum ether (10: 1)Purifying by chromatography, and separating by chiral column to obtain III-1065.8 mg with yield of 95%.
1H NMR(400MHz,Chloroform-d)δ7.27–7.20(m,4H),6.97–6.91(m,1H), 6.89(m,1H),5.99(d,J＝4.7Hz,1H),5.15(s,1H),3.84(s,3H),3.02(d,J＝5.0 Hz,1H),1.41(s,18H).
13C NMR(100MHz,Chloroform-d)δ156.65,152.96,135.41,133.54,132.35, 128.35,127.59,123.58,120.74,110.53,72.64,55.33,34.33,30.26.
The other implementation steps are the same as in example 1 or example 2.
Example 11:
preparation of Compound III-11:
adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle2)5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and the mixture was stirred at room temperature for 1 hour. To the above system, the starting material I-11 (70.9mg,0.2mmol) and pinacol ester diboron (B) were added successively2(pin)2) (60.9mg,0.24 mmol). The whole reaction system was stirred at room temperature for 12 hours to effect a reaction. After the reaction was completed, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and sodium perborate tetrahydrate (244mg, 0.8mmol) was added directly to the residue, and the whole was stirred at room temperature for 4 hours. To the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10mL), separation of the organic phase, and then extraction with anhydrous Na 2SO4Drying, filtering and rotary evaporation to remove the solvent. The residue was purified by column chromatography using an ethyl acetate/petroleum ether mixed solvent ═ 5:1, and then separated by chiral column chromatography to give III-1170.2 mg in 94% yield.
1H NMR(400MHz,Chloroform-d)δ7.17(s,2H),7.00(d,J＝1.9Hz,1H), 6.91-6.88(m,1H),6.83(d,J＝8.3Hz,1H),5.73(d,J＝2.4Hz,1H),5.19(s,1H), 3.87(s,6H),2.19(d,J＝3.2Hz,1H),1.41(s,18H).
13C NMR(100MHz,Chloroform-d)δ153.30,148.85,148.18,136.78,135.82, 134.51,123.57,118.81,110.83,109.67,76.49,55.91,55.85,34.40,30.27.
The other implementation steps are the same as in example 1 or example 2.
Example 12:
preparation of Compound III-12:
adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle2)5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and the mixture was stirred at room temperature for 1 hour. To the above system, the starting material I-12 (76.9mg,0.2mmol) and pinacol ester diboron (B) were added successively2(pin)2) (60.9mg,0.24 mmol). The whole reaction system was stirred at room temperature for 12 hours to effect a reaction. After the reaction was completed, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and sodium perborate tetrahydrate (244mg, 0.8mmol) was added directly to the residue, and the whole was stirred at room temperature for 4 hours. To the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10mL), separation of the organic phase, and then extraction with anhydrous Na2SO4Drying, filtering and rotary evaporation to remove the solvent. The residue was purified by column chromatography using a mixed solvent of ethyl acetate/petroleum ether (4: 1) and then separated by chiral column chromatography to give III-1278.2 mg in 97% yield.
1H NMR(400MHz,Chloroform-d)δ7.19(s,2H),6.65(s,2H),5.70(d,J＝2.6 Hz,1H),5.21(s,1H),3.83(d,J＝3.4Hz,9H),2.28(s,1H),1.42(s,18H).
13C NMR(100MHz,Chloroform-d)δ153.44,153.12,139.76,137.01,135.89, 134.19,123.63,103.47,76.79,60.87,56.10,34.42,30.27.
The other implementation steps are the same as in example 1 or example 2.
Example 13:
preparation of Compound III-13:
adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle2)5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and the mixture was stirred at room temperature for 1 hour. To the above system, the starting material I-13 (76.9mg,0.2mmol) and pinacol ester diboron (B) were added successively2(pin)2) (68.9mg,2.4 mmol). The whole reaction system was stirred at room temperature for 12 hours to effect a reaction. After the reaction was completed, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and sodium perborate tetrahydrate (244mg, 0.8mmol) was added directly to the residue, and the whole was stirred at room temperature for 4 hours. To the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10mL), separation of the organic phase, and then extraction with anhydrous Na2SO4Drying, filtering and rotary evaporation to remove the solvent. The residue was purified by column chromatography using a mixed solvent of ethyl acetate and petroleum ether at 10:1, and then separated by chiral column to obtain III-1370.1 mg in 97% yield.
1H NMR(400MHz,Chloroform-d)δ8.12–8.06(m,1H),7.86-7.84(m,1H), 7.78(d,J＝8.3Hz,1H),7.65(d,J＝7.2Hz,1H),7.52–7.41(m,3H),7.22(s, 2H),6.49(s,1H),5.18(s,1H),2.31(d,J＝3.2Hz,1H),1.37(s,18H).
13C NMR(100MHz,Chloroform-d)δ154.03,140.01,136.47,134.47,134.30, 131.49,129.36,128.77,126.61,126.12,126.05,124.76,124.72,124.69,74.39, 35.05,30.92.
The other implementation steps are the same as in example 1 or example 2.
Example 14:
preparation of Compound III-14:
Adding into a 3mL reaction bottleFunctionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl)2)5mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and the mixture was stirred at room temperature for 1 hour. To the above system, the starting material I-14 (76.9mg,0.2mmol) and pinacol ester diboron (B) were added successively2(pin)2) (68.9mg,2.4 mmol). The whole reaction system was stirred at room temperature for 12 hours to effect a reaction. After the reaction was completed, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and sodium perborate tetrahydrate (244mg, 0.8mmol) was added directly to the residue, and the whole was stirred at room temperature for 4 hours. To the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10mL), separation of the organic phase, and then extraction with anhydrous Na2SO4Drying, filtering and rotary evaporation to remove the solvent. The residue was purified by column chromatography using a mixed solvent of ethyl acetate/petroleum ether (10: 1) and then separated by a chiral column to give III-1468.2 mg in 94% yield.
1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.87–7.77(m,3H),7.50– 7.42(m,3H),7.21(s,2H),5.93(d,J＝2.9Hz,1H),5.19(s,1H),2.27(d,J＝3.3 Hz,1H),1.40(s,18H).
13C NMR(100MHz,Chloroform-d)δ153.39,141.46,135.90,134.38,133.26, 132.73,128.06,128.01,127.61,125.99,125.71,124.84,124.65,123.75,76.85, 34.36,30.22.
The other implementation steps are the same as in example 1 or example 2.
Example 15:
a gram-scale preparation method of a compound III-1, which comprises the following steps:
F. adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 100mL reaction bottle 2)100mg and ligand L3(60.0mg,0.24mmol,6 mol%), 20mL of water was added and stirred at room temperature (20 or 22 or 24 or 25 ℃ C., the same applies hereinafter) for 2 hours;
G. into the above system, respectively, successivelyStarting Material I-1(1.178g,4.0mmol) and pinacol diboron ester (B) were added2(pin)2)(1.218g,4.8mmol)；
H. The whole reaction system is stirred for 12 hours at room temperature to carry out reaction;
I. after the reaction was completed, the whole reaction system was filtered, washed with 50mL of tetrahydrofuran, and sodium perborate tetrahydrate (4.88g,16mmol) was directly added to the residue, and the whole system was stirred at room temperature for 4 hours;
J. to the above system was added 50mL of ethyl acetate to dilute the mixture, the mixture was extracted with ethyl acetate (3X 100mL), and the organic phase was separated and then extracted with anhydrous Na2SO4Drying, filtering and rotary evaporation to remove the solvent. The residue was purified by column chromatography using ethyl acetate/petroleum ether mixed solvent ═ 10:1, and then separated by chiral column to give III-11.147 g in yield>90％。
1H NMR(400MHz,Chloroform-d)δ7.46–7.42(m,2H),7.40–7.35(m,2H), 7.31–7.26(m,1H),7.20(s,2H),5.81(d,J＝3.3Hz,1H),5.22(s,1H),2.19(d, J＝3.4Hz,1H),1.44(s,18H).
13C NMR(400MHz,Chloroform-d)δ153.34,144.13,135.86,134.55,128.35, 127.26,126.41,123.67,76.77,34.41,30.27.
Example 16:
preparation of Dutogliptin derivative V:
adding a functionalized chitosan immobilized copper chloride catalytic material (HBCS @ CuCl) into a 3mL reaction bottle2)55mg and ligand L3(3.0mg,0.012mmol,6 mol%), 2.5mL of water was added and the mixture was stirred at room temperature for 1 hour. To the above system, the starting material IV (39.1mg,0.2mmol) and pinacol ester diboron (B) were added successively 2(pin)2) (60.9mg,0.24 mmol). The whole reaction system was stirred at room temperature for 12 hours to effect a reaction. After the reaction was completed, the whole reaction system was filtered, washed with 3mL of tetrahydrofuran, and 2mL of dilute hydrochloric acid was directly added to the residueStirred at room temperature for 5 hours. To the above system was added ethyl acetate 3mL to dilute, followed by extraction with ethyl acetate (3X 10 mL), separation of the organic phase, and then extraction with anhydrous Na2SO4Drying, filtering and rotary evaporating to remove solvent. To the residue were added 3mL of methanol and 5mg of an activated carbon-supported palladium catalyst (Pd/C), and the mixture was stirred at room temperature under 1 atm of hydrogen gas for 12 hours. The activated carbon-supported palladium catalyst was removed by filtration, the solvent was removed from the filtrate by rotary concentration, and the residue was purified by column chromatography using a mixed solvent of ethyl acetate/petroleum ether 2:1, and then subjected to separation by hand column to give V30.1 mg, 62% yield.
1H NMR(500MHz,d6-DMSO)；δ＝0.99(d,J＝6.9Hz,3H),1.05(d,J＝6.9Hz, 3H),1.72-2.32(m,5H),3.04-3.09(m,1H),3.41-3.53(m,1H),3.57-3.71(m,1H), 4.20-4.24(m,1H)。
HRMS(ESI)calcd for C10H20BN3O3[M+H]+:242.20,found 242.16。
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (5)
1. A method for preparing a chiral organoboron compound, comprising the steps of: reacting the compound I with pinacol diboron under the conditions of a catalyst, solvent water, a ligand and room temperature, and separating to obtain a chiral organic boron compound II;
Wherein:
the structural formula of the compound I is
The R group is phenyl, halogenated phenyl, benzyloxy phenyl, methyl phenyl, monomethoxy phenyl, polymethoxy phenyl or benzyl;
the structural general formula of the chiral organic boron compound II is
(ii) a Wherein, R group is phenyl, halogenated phenyl, benzyloxy phenyl, methyl phenyl, monomethoxy phenyl, polymethoxy phenyl or benzyl;
the catalyst is a functionalized chitosan immobilized copper chloride catalyst;
the ligand is L3, and the structural formula is as follows:
2. a process for preparing a chiral organoboron compound of claim 1, characterized in that:
the R group of the compound I is phenyl, 4-chlorphenyl, 4-bromophenyl, 4-benzyloxy phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-bromophenyl, 3-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethoxyphenyl, 1-benzyl or 2-benzyl;
the R group of the chiral organic boron compound II is phenyl, 4-chlorphenyl, 4-bromophenyl, 4-benzyloxy phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-bromophenyl, 3-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethoxyphenyl, 1-benzyl or 2-benzyl.
3. A method for preparing a chiral δ -hydroxy compound, comprising the steps of:
1) reacting the compound I with pinacol diboron under the conditions of a catalyst, solvent water, a ligand and room temperature, and separating to obtain a chiral organic boron compound II;
2) reacting the chiral organic boron compound II obtained in the step 1) with sodium perborate tetrahydrate, and separating to obtain a chiral delta-hydroxy compound III;
wherein:
the structural formula of the compound I is
The R group is phenyl, halogenated phenyl, benzyloxy phenyl, methyl phenyl, monomethoxy phenyl, polymethoxy phenyl or benzyl;
the structural general formula of the chiral organic boron compound II is
Wherein, R group is phenyl, halogenated phenyl, benzyloxy phenyl, methyl phenyl, monomethoxy phenyl, polymethoxy phenyl or benzyl;
the structural general formula of the chiral delta-hydroxy compound III is
Wherein, R group is phenyl, halogenated phenyl, benzyloxy phenyl, methyl phenyl, monomethoxy phenyl, polymethoxy phenyl or benzyl;
the catalyst is a functionalized chitosan immobilized copper chloride catalyst;
the ligand is
4. A process for the preparation of chiral δ -hydroxy compounds according to claim 3, characterized in that:
The R group of the compound I is phenyl, 4-chlorphenyl, 4-bromophenyl, 4-benzyloxy phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-bromophenyl, 3-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethoxyphenyl, 1-benzyl or 2-benzyl;
the R group of the chiral organic boron compound II is phenyl, 4-chlorphenyl, 4-bromophenyl, 4-benzyloxy phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-bromophenyl, 3-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethoxyphenyl, 1-benzyl or 2-benzyl;
the R group of the chiral delta-hydroxy compound III is phenyl, 4-chlorophenyl, 4-bromophenyl, 4-benzyloxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-bromophenyl, 3-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethoxyphenyl, 1-benzyl or 2-benzyl.
5. The preparation method of duloxetine is characterized by comprising the following steps:
1) reacting the compound IV with pinacol diboron under the conditions of a catalyst, solvent water, a ligand and room temperature, and separating to obtain an intermediate compound;
2) hydrogenating and reducing the intermediate compound obtained in the step 1) to obtain duloxetine;
Wherein:
the structural formula of the compound IV is as follows:
the catalyst is a functionalized chitosan immobilized copper chloride catalyst;
the intermediate compound has a structural formula:
the ligand is
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