CN113968882A - Optically pure (S) -2- (diphenylphosphine acyl) chromium-4-ketone and preparation method thereof - Google Patents
Optically pure (S) -2- (diphenylphosphine acyl) chromium-4-ketone and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 239000003446 ligand Substances 0.000 claims abstract description 20
- VWBYXJRDIQCSLW-UHFFFAOYSA-N O=[P](c1ccccc1)c1ccccc1 Chemical group O=[P](c1ccccc1)c1ccccc1 VWBYXJRDIQCSLW-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- -1 aryl phosphine compound Chemical class 0.000 claims abstract description 8
- 230000003197 catalytic effect Effects 0.000 claims abstract description 8
- 238000006845 Michael addition reaction Methods 0.000 claims abstract description 7
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002131 composite material Substances 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 238000004440 column chromatography Methods 0.000 claims description 11
- 238000010791 quenching Methods 0.000 claims description 10
- 230000000171 quenching effect Effects 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- HQCCNFFIOWYINW-UHFFFAOYSA-N 1-(5-bromo-2-hydroxyphenyl)ethanone Chemical compound CC(=O)C1=CC(Br)=CC=C1O HQCCNFFIOWYINW-UHFFFAOYSA-N 0.000 claims description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- 150000004777 chromones Chemical class 0.000 claims 2
- 238000011160 research Methods 0.000 abstract description 7
- 229910052751 metal Inorganic materials 0.000 abstract description 6
- 239000002184 metal Substances 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 19
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 150000003003 phosphines Chemical class 0.000 description 2
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- JZYCZVLVWUCHTP-UHFFFAOYSA-N 7-methoxy-2-oxochromene-6-carbaldehyde Chemical compound O1C(=O)C=CC2=C1C=C(OC)C(C=O)=C2 JZYCZVLVWUCHTP-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- SISAYUDTHCIGLM-UHFFFAOYSA-N bromine dioxide Inorganic materials O=Br=O SISAYUDTHCIGLM-UHFFFAOYSA-N 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- DOTMOQHOJINYBL-UHFFFAOYSA-N molecular nitrogen;molecular oxygen Chemical compound N#N.O=O DOTMOQHOJINYBL-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910052706 scandium Inorganic materials 0.000 description 1
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
- C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
- B01J31/2252—Sulfonate ligands
- B01J31/2256—Sulfonate ligands being perfluorinated, i.e. comprising at least one perfluorinated moiety as substructure in case of polyfunctional ligands
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses an optically pure (S) -2- (diphenylphosphinoyl) chromium-4-ketone and a preparation method thereof, wherein 1-benzopyran-4-ketone and diphenylphosphine oxide are subjected to Michael addition reaction under the catalytic action of a composite catalyst to obtain the optically pure (S) -2- (diphenylphosphinoyl) chromium-4-ketone. The invention creatively researches the preparation method of optically pure (S) -2- (diphenylphosphinoyl) chromium-4-ketone, fills the vacancy of synthesizing the organic aryl phosphine compound in the Michael addition reaction in the metal catalysis asymmetry, effectively expands the synthesis method of the organic phosphine compound and improves the catalytic efficiency in the metal catalysis asymmetry; through the research on the conditions of raw material characteristics, ligand structures, catalytic effects and the like, the inventors select an addition catalyst and a metal to match with a corresponding solvent in a targeted manner, so that the smooth proceeding of the reaction process is ensured, and the yield, the purity and the enantioselectivity of the product are improved.
Description
Technical Field
The invention belongs to the technical field of chemical preparation, and particularly relates to optically pure (S) -2- (diphenylphosphine acyl) chromium-4-ketone and a preparation method thereof.
Background
Organic phosphine compounds having high optical activity are very important in synthetic chemistry. Chiral phosphonates, for example, are precursors to a number of molecules of biological and pharmaceutical interest. However, the chiral organic phosphine compound is difficult to obtain directly from nature, and often needs chemical synthesis, and the main methods are as follows: racemate resolution, synthesis using stoichiometric chiral auxiliaries and catalytic asymmetric synthesis. The racemate resolution mainly adopts chromatographic separation, so the operation is inconvenient and the racemate resolution has limitation; the chiral auxiliary is large in synthetic dosage, so that waste is caused; however, many known methods for catalyzing asymmetric synthesis of chiral phosphine still have the defects of poor substrate applicability, long reaction time and the like. Therefore, there is a need to develop more efficient metal-catalyzed asymmetric processes for synthesizing chiral phosphine compounds.
Of the many metal-catalyzed asymmetric processes, the phosphine Michael addition reaction of α, β -unsaturated ketones has received much attention and research from various scientists. Meanwhile, through research and research, the chiral double nitrogen-oxygen ligand is not reported in the phosphine Michael addition reaction; meanwhile, exocyclic α, β -unsaturated benzocycloketones are more valuable as electrophiles than the widely studied asymmetric addition of nitroolefins, α, β -unsaturated aldehydes, α, β -unsaturated esters, ketones or cyclic α, β -unsaturated enols, and we attempted to synthesize optically pure (S) -2- (diphenylphosphino) chromium-4-ones by catalyzing the addition reaction of exocyclic α, β -unsaturated benzocycloketones with diarylphosphines using metallic scandium.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide optically pure (S) -2- (diphenylphosphine acyl) chromium-4-ketone with high yield and high product purity and a preparation method thereof aiming at the defects of the prior art.
The technical scheme is as follows: the invention relates to an optically pure (S) -2- (diphenylphosphine acyl) chromium-4-ketone, which is shown as a formula (I):
wherein: r is 6-F, 6-Cl, 6-Br, 6-OMe, 6-CO2Me、6-NO25-Me, 6-Me, 7-Me or 8-Me;
ar is C6H5-、2-Me-C6H4-、3-Me-C6H4-、4-Me-C6H4-、4-F-C6H4-or 2-naphthyl-.
The invention also provides a preparation method of the optically pure (S) -2- (diphenylphosphinoyl) chromium-4-ketone, which comprises the step of carrying out Michael addition reaction on 1-benzopyran-4-ketone and diphenylphosphine oxide under the catalytic action of a composite catalyst to obtain the optically pure (S) -2- (diphenylphosphinoyl) chromium-4-ketone; the composite catalyst is a mixture of a chiral dinitrogen ligand and scandium trifluoromethanesulfonate, wherein the structural formula of the chiral dinitrogen ligand is shown as the formula (II):
further, as a preferred embodiment, the specific preparation process of the optically pure (S) -2- (diphenylphosphinoyl) chromium-4-one is as follows:
(1) adding a mixture of 1: 6-8 parts of 2-hydroxy-5-bromoacetophenone (V) and sodium hydride, adding a solvent, reacting for 2-4 hours at the temperature of-2 ℃, adding a quenching agent after the reaction is finished, extracting, drying, evaporating the solvent, and performing column chromatography separation by using petroleum ether/ethyl acetate to obtain a first intermediate shown in a formula (VI);
(2) adding a second palladium catalyst, a second phosphine ligand, a second alkali reagent and a second solvent into the first intermediate, reacting for 10-14 hours under the conditions of carbon monoxide and 90-110 ℃, adding a quenching agent after the reaction is finished, extracting, drying, evaporating the solvent, and performing column chromatography separation by using petroleum ether/ethyl acetate to obtain a second intermediate shown in a formula (III);
(3) in a glove box, a reaction flask was charged with a mixture of 1: 1-3 of 1-benzopyran-4-one and diphenylphosphine oxide, adding a chiral bis-nitroxide ligand as a chiral ligand, adding scandium trifluoromethanesulfonate as Lewis acid, adding alkali, a solvent and 4-dimethylaminopyridine into the system, reacting for 40-50 hours at-5 ℃, and performing column chromatography separation after the reaction is finished to obtain a chiral target product (S) -2- (diphenylphosphinoyl) chromium-4-one as shown in a formula (I); the specific reaction process is as follows:
further, as a preferred embodiment, the first solvent in step (1) is ethyl formate, and the quenching agent is methanol.
Further, as a preferred embodiment, in the step (2), the second palladium ligand is palladium acetate, the second phosphine ligand is 1, 3-bis (diphenylphosphino) propane, the second base is N, N-diisopropylethylamine, the second solvent is dimethyl sulfoxide and methanol, and the quencher is water.
Further, as a preferred embodiment, in the step (3), the base is lithium carbonate, and the solvent is tetrahydrofuran.
Further, as a preferred embodiment, the addition amount of the chiral ligand in the step (3) is 6 mol%; the addition amount of the scandium trifluoromethanesulfonate was 5 mol%.
Further, in order to improve the purity of the product, the chiral target product is obtained by performing column chromatography separation on petroleum ether or ethyl acetate after the reaction in the step (3) is finished.
Has the advantages that: (1) the invention creatively researches the preparation method of optically pure (S) -2- (diphenylphosphinoyl) chromium-4-ketone, fills the vacancy of synthesizing the organic aryl phosphine compound in the Michael addition reaction in the metal catalysis asymmetry, effectively expands the synthesis method of the organic phosphine compound and improves the catalytic efficiency in the metal catalysis asymmetry; (2) in the invention, through the research on the conditions such as raw material characteristics, ligand structure, catalytic effect and the like, the addition catalyst and the metal are selected to match with the corresponding solvent in a targeted manner, so that the smooth proceeding of the reaction process is ensured, and the yield, the purity and the enantioselectivity of the product are improved.
Drawings
FIG. 1 is a drawing of the product of example 11H NMR spectrum;
FIG. 2 is a drawing of the product of example 113C NMR spectrum;
FIG. 3 is the product of example 21H NMR spectrum;
FIG. 4 is a graph of the product of example 213C NMR spectrum;
FIG. 5 is a photograph of the product of example 31H NMR spectrum;
FIG. 6 is a graph of the product of example 313C NMR spectrum;
FIG. 7 is a graph of the product of example 331A P NMR spectrum;
FIG. 8 is an HPLC chromatogram of the product of example 3.
Detailed Description
The technical solution of the present invention is described in detail below with reference to the accompanying drawings, but the scope of the present invention is not limited to the embodiments. The reaction drugs used in the examples are all conventionally commercially available.
Example 1: preparation of the first intermediate
Adding 645mg of 2-hydroxy-5-bromoacetophenone into a dry reaction bottle, adding 6ml of ethyl formate solution, cooling the reaction system to 0 ℃, and keeping the temperature for 5 minutes; adding 720mg of sodium hydride into the reaction system for four times in 2 hours, heating to room temperature, reacting for 30 minutes, quenching by 1.3ml of methanol, adding 12.5ml of concentrated hydrochloric acid, and stirring at room temperature for reacting overnight; after the reaction, 10ml of ethyl acetate was dissolved, washed with 10ml of water, 10ml of saturated sodium bicarbonate, 10ml of x 3 times of ethyl acetate, and the resulting organic phases were combined and dried, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography eluting with n-hexane and ethyl acetate at a ratio of 10:1 to give 544mg of the first intermediate in 81% yield.
The structural characterization data for the product (VI) obtained in example 1 are as follows:
1H NMR(500MHz,CDCl3):δ7.85(d,J＝6.1Hz,1H),7.82(dd,J＝8.2,3.1Hz,1H),7.46(dd,J＝9.2,4.2Hz,1H),7.38(ddd,J＝9.2,7.6,3.1Hz,1H),6.32(d,J＝6.0Hz,1H).
13C NMR(126MHz,CDCl3):δ176.76(d,J＝2.3Hz),160.46,158.50,155.42,152.70(d,J＝1.8Hz),126.00(d,J＝7.3Hz),122.08,121.87,120.31(d,J＝8.2Hz),112.20,110.72,110.53.
the successful synthesis of the first intermediate is proved by the nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the product.
HRMS:calculated for C9H5BrO2(M+H)+:223.9473,found:223.9473.
The second intermediate is successfully synthesized, and the yield and the purity are higher.
Example 2: preparation of the second intermediate
544mg of the first intermediate, 108mg of palladium acetate, 198mg of 1, 3-bis (diphenylphosphino) propane, 2.2ml of N, N-diisopropylethylamine were added to a dry two-necked reaction flask, followed by addition of 7.2ml of a dimethyl sulfoxide solution and 7.2ml of a methanol solution; replacing carbon monoxide gas for three times for the reaction system, and then heating the reaction system to 100 ℃ to react for 12 hours at the temperature; after the reaction, 20ml of water is added for quenching, 20ml of ethyl acetate with the power of 3 times is used for quenching, the obtained organic phases are combined and dried, and the solvent is removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography eluting with n-hexane and ethyl acetate at a ratio of 10:1 to give 413mg of the second intermediate in 85% yield.
The structural characterization data of the product (III) obtained in example 2 are as follows:
1H NMR(500MHz,CDCl3):δ8.84(d,J＝2.1Hz,1H),8.28(dd,J＝8.8,2.2Hz,1H),7.85(d,J＝6.0Hz,1H),7.48(d,J＝8.8Hz,1H),6.35(d,J＝6.1Hz,1H),3.92(s,3H).
13C NMR(126MHz,CDCl3):δ176.81,165.57,158.82,155.35,134.29,128.22,124.43,118.59,113.38,52.36.
the successful synthesis of the second intermediate is proved by the nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the product.
HRMS:calculated for C11H8O4(M+H)+:204.0423,found:204.0423.
The second intermediate is successfully synthesized, and the yield and the purity are higher.
Example 3: optically pure (S) -2- (diphenylphosphinoyl) chromium-4-one
In a glove box, adding 46mg of the second intermediate, 6.2mg of scandium trifluoromethanesulfonate, 9.3mg of chiral dinitrogen ligand, 3.1mg of 4-dimethylaminopyridine and 35mg of lithium carbonate into a dry reaction tube in sequence, adding 2.5ml of tetrahydrofuran solution, stirring vigorously at room temperature for 1 hour, cooling the reaction system to 0 ℃ after stirring, keeping the temperature for 5 minutes, quickly adding 50mg of diphenylphosphine oxide into the reaction system, and reacting for 48 hours at 0 ℃; after the reaction is finished, the solvent is removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography eluting with n-hexane and ethyl acetate in a ratio of 2:1 to give 55mg of optically pure (S) -2- (diphenylphosphinoyl) chromium-4-one in 54% yield and 90% ee, the enantiomeric purity being determined by chiral HPLC analysis.
The structural characterization data of the product (I) obtained in example 1 are shown below:
1H NMR(500MHz,CDCl3):δ8.55(d,J＝2.2Hz,1H),8.13(dd,J＝8.8,2.2Hz,1H),7.99–7.85(m,4H),7.67–7.58(m,2H),7.59–7.50(m,4H),7.00(d,J＝8.7Hz,1H),5.35(dt,J＝13.7,3.4Hz,1H),3.90(s,3H),3.10–2.93(m,2H).
13C NMR(126MHz,CDCl3):δ188.74(d,J＝13.0Hz),165.74,163.70(d,J＝11.4Hz),136.87,132.93(t,J＝3.5Hz),132.25(d,J＝9.2Hz),131.48(d,J＝9.3Hz),129.80,129.53,128.96(dd,J＝23.7,12.1Hz),128.34,127.54,124.57,120.71,118.18,75.61(d,J＝87.2Hz),52.29,35.85.
31P NMR(162MHz,CDCl3):δ26.73.
the successful synthesis of the optically pure (S) -2- (diphenylphosphine) chromium-4-one compound is proved by the nuclear magnetic resonance hydrogen spectrum, carbon spectrum and phosphine spectrum of the product.
The specific optical rotation of the compound of formula (I) [ alpha ]]D 25＝-30°(c＝0.10,MeOH).
HRMS:calculated for C23H19O3P(M+H)+:407.1043,found 407.1043.
HPLC:Daicel Chiralpak IA-3column,n-hexane/i-PrOH(80/20),1.0mL/min,254nm,15.548min(minor enantiomer),17.301min(major enantiomer).
The results prove that the optically pure (S) -2- (diphenylphosphine acyl) chromium-4-ketone is successfully synthesized, the yield and the purity are high, and high enantioselectivity can be obtained.
As noted above, while the present invention has been shown and described with reference to certain preferred embodiments, it is not to be construed as limited thereto. Various changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (8)
1. An optically pure (S) -2- (diphenylphosphinoyl) chromium-4-one, characterized by the formula (I):
wherein: r is 6-F, 6-Cl, 6-Br, 6-OMe, 6-CO2Me、6-NO25-Me, 6-Me, 7-Me or 8-Me;
ar is C6H5-、2-Me-C6H4-、3-Me-C6H4-、4-Me-C6H4-、4-F-C6H4-or 2-naphthyl-.
2. A process for the preparation of optically pure (S) -2- (diphenylphosphinoyl) chromium-4-one according to claim 1, characterized in that: carrying out Michael addition reaction on 1-benzopyran-4-one and diphenylphosphine oxide under the catalytic action of a composite catalyst to obtain optically pure (S) -2- (diphenylphosphinoyl) chromium-4-one; the composite catalyst is a mixture of a chiral dinitrogen ligand and scandium trifluoromethanesulfonate, wherein the structural formula of the chiral dinitrogen ligand is shown as the formula (II):
3. the process for preparing optically pure (S) -2- (diphenylphosphinoyl) chromium-4-one according to claim 2, comprising the steps of:
(1) adding a mixture of 1: 6-8 parts of 2-hydroxy-5-bromoacetophenone (V) and sodium hydride, adding a first solvent, reacting for 2-4 hours at the temperature of-2 ℃, adding a quenching agent after the reaction is finished, extracting, drying, evaporating the solvent, and performing column chromatography separation by using petroleum ether/ethyl acetate to obtain a first intermediate shown in a formula (VI);
(2) adding a second palladium catalyst, a second phosphine ligand, a second alkali reagent and a second solvent into the first intermediate, reacting for 10-14 hours under the conditions of carbon monoxide and 90-110 ℃, adding a quenching agent after the reaction is finished, extracting, drying, evaporating the solvent, and performing column chromatography separation by using petroleum ether/ethyl acetate to obtain a second intermediate shown in a formula (III);
(3) in a glove box, a reaction flask was charged with a mixture of 1: 1-3 of a second intermediate and a diphenylphosphine oxide, adding a chiral bis-nitroxide ligand as a chiral ligand, adding scandium trifluoromethanesulfonate as a Lewis acid, adding an alkali, a solvent and 4-dimethylaminopyridine into the system, reacting for 40-50 hours at-5 ℃, and performing column chromatography separation after the reaction is finished to obtain a chiral target product 2- (diphenylphosphine acyl) chromium-4-ketone, wherein the formula is shown in the formula (I);
the specific reaction process is as follows:
4. the method for preparing an optical chromone derivative according to claim 3, wherein: in the step (1), the first solvent is ethyl formate, and the quenching agent is methanol.
5. The method for preparing an optical chromone derivative according to claim 3, wherein: in the step (2), the second palladium ligand is palladium acetate, the second phosphine ligand is 1, 3-bis (diphenylphosphino) propane, the second base is N, N-diisopropylethylamine, the second solvent is dimethyl sulfoxide and methanol, and the quenching agent is water.
6. The process for preparing optically pure (S) -2- (diphenylphosphinoyl) chromium-4-one according to claim 3, wherein: the alkali is lithium carbonate, and the solvent is tetrahydrofuran.
7. The process for preparing optically pure (S) -2- (diphenylphosphinoyl) chromium-4-one according to claim 3, wherein: the addition amount of the chiral ligand is 6 mol%; the addition amount of the scandium trifluoromethanesulfonate was 5 mol%.
8. The process for preparing optically pure (S) -2- (diphenylphosphinoyl) chromium-4-one according to claim 3, wherein: after the reaction is finished, performing column chromatography separation by using petroleum ether or ethyl acetate to obtain a chiral target product.
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| RYOTA ISSHIKI ET AL: "Decarbonylative C-P Bond Formation Using Aromatic Esters and Organophosphorus Compounds", 《ORG. LETT.》 * |
| 张欣: "新型手性双氮氧铟络合物催化酮的不对称烯丙基化反应研究", 《四川大学博士学位论文》 * |
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