Preparation method of chiral dihydroisoflavone compound and product thereof
阅读说明：本技术 一种手性二氢异黄酮化合物的制备方法及其产物 (Preparation method of chiral dihydroisoflavone compound and product thereof ) 是由 熊东路 易松 杨轩 龙绪俭 徐涛 肖增钧 陈林生 李斌仁 于 2020-06-02 设计创作，主要内容包括：本发明公开了一种手性二氢异黄酮化合物的制备方法,采用特定的催化剂,以环外共轭的化合物为底物制备得到了手性二氢异黄酮化合物,该方法简便易行,适于大规模的工业生产,具有推广价值。(The invention discloses a preparation method of chiral isoflavanone compound, which adopts a specific catalyst and takes a compound conjugated outside a ring as a substrate to prepare the chiral isoflavanone compound.)
1. A method for preparing a chiral dihydroisoflavone compound is characterized by comprising the following steps: carrying out hydrogenation reduction reaction on a compound with a structure shown as a formula 1 under the action of a chiral catalyst to obtain a chiral isoflavanone compound;
formula 1:
wherein R is1、R2Each independently selected from one of hydrogen atom, alkyl, aryl, alkoxy, ester group, nitro, halogen, cyano and heterocyclic substituent;
the preparation raw material of the chiral catalyst comprises a chiral ligand and a metal compound.
2. The process for producing chiral dihydroisoflavone compound according to claim 1, wherein the metal compound is an iridium-containing compound and/or a rhodium-containing compound.
3. The process for preparing chiral dihydroisoflavone compounds according to claim 2, wherein the iridium-containing compounds are selected from [ Ir (COD) Cl]2、[Ir(COD)2]X、Ir(ethylene)2(acac)、[Ir(η2-ethylene)2Cl]2A mixture of one or more of; wherein X is a monovalent anion.
4. The process for the preparation of chiral dihydroisoflavone compounds as claimed in claim 3, wherein the monovalent anion is selected from BF4 -、ClO4 -、SbF6 -、PF6 -、OTf-、B(Y)4 -A mixture of one or more of; wherein Y is bis (trifluoromethyl) benzene or fluorobenzene.
5. The process for preparing chiral dihydroisoflavone compounds as claimed in claim 2, wherein the rhodium-containing compounds are [ Rh (acac) (CO)]2、[Rh(COD)Cl]2、Rh(ethylene)2(acac) mixtures of one or more of (a), (b), (c), (d.
6. The method for preparing chiral dihydroisoflavone compound according to any of claims 1 to 5, wherein the chiral ligand is selected from one of formula 2, formula 3, and formula 4, formula 2:formula 3:formula 4:
wherein Ar is selected from one of phenyl, 4-methylphenyl, 3, 5-dimethylphenyl, 2,4, 6-trimethylphenyl, 3, 5-di (trifluoromethyl) phenyl, 4-methoxy-3, 5-dimethylphenyl and 4-methoxy-3, 5-di-tert-butylphenyl, and R is selected from one of isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl and benzyl.
7. The process for preparing chiral dihydroisoflavone compounds according to claim 1, wherein the hydrogenation reduction is carried out in a solvent; the solvent is selected from one or more of 1, 4-dioxane, tetrahydrofuran, acetonitrile, toluene and dichloromethane.
8. The method for preparing chiral isoflavanone compound according to claim 1, wherein the hydrogenation reduction reaction is carried out at-40 to 120 ℃.
9. The method for preparing chiral dihydroisoflavone compound according to claim 1, wherein the hydrogenation reduction is carried out at a pressure of 2 to 100 bar.
10. A chiral dihydroisoflavone compound characterized by being produced by the production method according to any one of claims 1 to 9.
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of a chiral dihydroisoflavone compound and a product thereof.
Background
Isoflavones are a class of compounds derived from isoflavones (3-phenylchromones). The C ═ C double bond in the isoflavone molecule is hydrogenated and is called isoflavanone or isoflavanone. Homoisoflavonoids (homoisoids) are a special class of flavonoids, the parent structure of which is one carbon atom more than that of isoflavones. Such compounds are rare in plants, and are mainly distributed in plants of the genus Ophiopogon (Ophiopogon), Sciula (Sciua), Polo (Eucomis) and Muscari (Muscari) of the family Liliaceae, and are also found in a small amount in plants of the genus Caesalpinia (Caesalpinia pulcherrima), Caesalpinia sappan (C.sappan), Aralia oleracea (C.bonduceta) and the like of the genus Caesalpinia of the family Leguminosae.
The isoflavone compound is not only from plants, but also has wide biological activity. Such as: the following compound A has the effects of inhibiting growth, promoting sporulation, promoting the formation of enzymes involved in the plant parasite infection mechanism, and broad-spectrum antibacterial activity.
The dihydro-homoisoflavone compound is a compound in which double bonds at 2, 3 positions of homoisoflavone are reduced into single bonds, and has various activities of inhibiting angiogenesis COX-l, COX-2 and the like. In 2006, the Gibbons group isolated the natural compound (S) -7, 8-methylenedioxy-4' -methoxydihydrohomoisoflavone (compound C above) from Chlorophytin and demonstrated that this compound has inhibitory effect on four rapidly proliferating mycobacteria M.fortuitum, M.smegmatis, M.phlei, M.aurum, with the lowest inhibitory concentration being 16-256. mu.g/mL. Compound B having R configuration, (R) -dihydrodaidzein is a hepatoprotective agent; the compound D with S configuration, (S) -equol can be obtained by reducing corresponding dihydro homoisoflavone, is a selective estrogen receptor regulator, and is a strong antioxidant.
The synthesis method of the chiral dihydroisoflavone compound comprises the following steps: the method of hydrogen transfer is utilized to realize the resolution of racemic isoflavonoid compounds Peter Metz (org. Lett.2017, 19, 11, 2981-2984); asymmetric hydrogenation of isoflavones to Haifeng Du (ANGEW CHEM INT ED, 2019, 59, 4498-4504); intramolecular asymmetric hydroacylation reaction of hydroxyalkylated salicylaldehyde Frank Glorius (ANGEW CHEM INT ED, 2011, 50, 4983-4987); asymmetric alkylation reaction of isoflavone compounds Karl A.Scheidt (org.Lett.2009, 11, 17, 4010-; asymmetric addition reaction of mercaptan to isoflavone compound with exocyclic conjugated alkene structure Qi-Lin Zhou (org. Lett.2019, 21, 23, 9391-9395); hydroacylation of salicylaldehyde to alkynes in tandem with intramolecular oxamichael addition reactions levim.stanley (org.lett.2015, 17, 3276-3279), and so on.
These asymmetric hydrogenation reactions are widely studied because of their advantages of high reactivity, high selectivity, high enantioselectivity, cleanliness, atom economy, etc. Asymmetric reduction of isoflavonoids with intra-cyclic conjugation has been reported, but no preparation method for producing chiral isoflavanone compounds from isoflavonoids with extra-cyclic conjugation is available.
Disclosure of Invention
In order to solve the above problems, a first aspect of the present invention provides a method for preparing a chiral dihydroisoflavone compound, comprising the steps of: carrying out hydrogenation reduction reaction on a compound with a structure shown as a formula 1 under the action of a chiral catalyst to obtain a chiral isoflavanone compound;
wherein R is1、R2Each independently selected from one of hydrogen atom, alkyl, aryl, alkoxy, ester group, nitro, halogen, cyano and heterocyclic substituent;
the preparation raw material of the chiral catalyst comprises a chiral ligand and a metal compound.
As a preferable embodiment, the metal compound is an iridium-containing compound and/or a rhodium-containing compound.
As a preferred technical scheme, the iridium-containing compound is selected from [ Ir (COD) Cl]2、[Ir(COD)2]X、Ir(ethylene)2(acac)、[Ir(η2-ethylene)2Cl]2A mixture of one or more of; wherein X is a monovalent anion.
As a preferred embodiment, the monovalent anion is selected from BF4 -、ClO4 -、SbF6 -、PF6 -、OTf-、B(Y)4 -A mixture of one or more of; wherein Y is bis (trifluoromethyl) benzene or fluorobenzene.
As a preferred embodiment, the rhodium-containing compound is [ Rh (acac) (CO) ]]2。
As a preferred technical scheme, the chiral ligand is selected from one of formula 2, formula 3 and formula 4,
wherein Ar is selected from one of phenyl, 4-methylphenyl, 3, 5-dimethylphenyl, 2,4, 6-trimethylphenyl, 3, 5-di (trifluoromethyl) phenyl, 4-methoxy-3, 5-dimethylphenyl and 4-methoxy-3, 5-di-tert-butylphenyl, and R is selected from one of isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl and benzyl.
As a preferred technical scheme, the hydrogenation reduction reaction is carried out in a solvent; the solvent is selected from one or more of 1, 4-dioxane, tetrahydrofuran, acetonitrile, toluene and dichloromethane.
As a preferable technical scheme, the hydrogenation reduction reaction is carried out at the temperature of minus 40-120 ℃.
As a preferable technical scheme, the hydrogenation reduction reaction is carried out under the pressure of 2-100 bar.
In a second aspect of the present invention, there is provided a chiral dihydroisoflavone compound prepared according to the preparation method as described above.
Has the advantages that: the invention provides a preparation method of chiral isoflavanone compound, which adopts a specific catalyst and takes a compound conjugated outside a ring as a substrate to prepare the chiral isoflavanone compound.
Detailed Description
The invention will be further understood by reference to the following detailed description of preferred embodiments of the invention and the examples included therein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. To the extent that a definition of a particular term disclosed in the prior art is inconsistent with any definitions provided herein, the definition of the term provided herein controls.
As used herein, a feature that does not define a singular or plural form is also intended to include a plural form of the feature unless the context clearly indicates otherwise. It will be further understood that the term "prepared from …," as used herein, is synonymous with "comprising," including, "comprising," "having," "including," and/or "containing," when used in this specification means that the recited composition, step, method, article, or device is present, but does not preclude the presence or addition of one or more other compositions, steps, methods, articles, or devices. Furthermore, the use of "preferred," "preferably," "more preferred," etc., when describing embodiments of the present application, is meant to refer to embodiments of the invention that may provide certain benefits, under certain circumstances. However, other embodiments may be preferred, under the same or other circumstances. In addition, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.
In order to solve the above problems, a first aspect of the present invention provides a method for preparing a chiral dihydroisoflavone compound, comprising the steps of: carrying out hydrogenation reduction reaction on a compound with a structure shown as a formula 1 under the action of a chiral catalyst to obtain a chiral isoflavanone compound;
wherein R is1、R2Are respectively independentThe substituent is selected from one of hydrogen atom, alkyl, aryl, alkoxy, ester group, nitro, halogen, cyano and heterocyclic substituent.
The term "hydrogenation reduction reaction" herein refers to a reaction in which a reactant reacts with hydrogen to convert an unsaturated bond into a saturated bond.
The carbonyl and carbon-carbon double bond in the structure shown in the formula 1 form an exocyclic conjugated structure, and the carbon-carbon double bond is reduced by hydrogen to prepare the isoflavanone compound.
In some preferred embodiments, R is1One selected from hydrogen atom, alkyl and aryl; further preferably, R is1Is an aryl group.
In some preferred embodiments, R is2One selected from hydrogen atom, alkyl group and heterocyclic substituent.
Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and a pentyl group.
The aryl group in the present application is a substituted aryl group or an unsubstituted aryl group, and in some preferred embodiments, the aryl group is selected from one of phenyl, 4-methoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-tolyl, 3-tolyl, 2-tolyl, 4-ethylphenyl, 3-ethylphenyl, 2-ethylphenyl; more preferably, the aryl group is selected from one of phenyl, 4-methoxyphenyl, 4-fluorophenyl and 4-tolyl.
Examples of the heterocyclic substituent include 1, 3-dioxolane, furan, tetrahydrofuran, ethylene oxide, propylene oxide, pyran, pyridine, imidazole, pyrrole, and the like.
As examples of the compound having the structure shown in formula 1, formula 5 to formula 12, formula 5:
in some preferred embodiments, the starting materials for the preparation of the chiral catalyst comprise a chiral ligand and a metal compound.
The term "chiral" in this context means that an object does not coincide with its mirror image.
The term "chiral catalyst" herein is a metal complex of a chiral ligand and a metal ion.
In some preferred embodiments, the metal compound is an iridium-containing compound and/or a rhodium-containing compound.
In some preferred embodiments, the iridium-containing compound is selected from [ Ir (COD) Cl]2、[Ir(COD)2]X、Ir(ethylene)2(acac)、[Ir(η2-ethylene)2Cl]2A mixture of one or more of; wherein X is a monovalent anion.
COD in the compound is 1, 5-cyclooctadiene, ethylene is ethylene, acac is acetylacetone; among the above compounds, [ Ir (COD) Cl]2Is bis (1, 5-cyclooctadiene) iridium (I) chloride dimer (CAS number: 12112-67-3), Ir (ethylene)2(acac) is iridium (I) bis (ethylene) acetylacetonate, [ Ir (η)2-ethylene)2Cl]2Is dichlorotetra (ethylene) diiridium (I) (CAS number: 39722-81-1).
In some preferred embodiments, the monovalent anion is selected from BF4 -、ClO4 -、SbF6 -、PF6 -、OTf-、B(Y)4 -A mixture of one or more of; wherein Y is bis (trifluoromethyl) benzene or fluorobenzene.
Among the above anions, BF4 -Is boron tetrafluoride ion, ClO4 -Is perchlorate ion, SbF6 -Is antimony hexafluoride ion, PF6 -Is phosphorus hexafluoride ion, OTf-Is trifluoromethanesulfonic acid ion, B (Y)4 -Is tetra [3, 5-bis (trifluoromethyl) benzene]Boron ion (abbreviated as BARF)-) Or tetrakis (4-fluorobenzene) boron ion.
In some preferred embodiments, the rhodium-containing compound is [ Rh (acac) (CO) ]]2(rhodium (I) dicarbonylacetylacetonate, CAS number: 14874-82-9).
In some preferred embodiments, the chiral ligand is selected from one of formula 2, formula 3, formula 4,
wherein Ar is selected from one of phenyl, 4-methylphenyl, 3, 5-dimethylphenyl, 2,4, 6-trimethylphenyl, 3, 5-di (trifluoromethyl) phenyl, 4-methoxy-3, 5-dimethylphenyl and 4-methoxy-3, 5-di-tert-butylphenyl, and R is selected from one of isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl and benzyl.
In some preferred embodiments, R is selected from one of isopropyl, sec-butyl, tert-butyl.
As examples of chiral ligands, mention may be made of those of the formulae 13 to 17, wherein Ph represents phenyl, tBu represents tert-butyl, Tol represents tolyl, and sBu represents sec-butyl.
As examples of the chiral catalyst, there can be exemplified those of the formulae 18 to 22,
the preparation method of the chiral catalyst comprises the following steps: under the protection of inert gas, the molar ratio of 1: adding the chiral ligand of 1 and a metal compound into a proper amount of solvent, reacting at normal temperature for 2-4 h, and purifying to obtain the chiral ligand.
Taking the preparation method of the chiral catalyst of formula 18 as an example, the method comprises the following steps: in a glove box filled with argon, 0.25mmol of chiral ligand of formula 13, [ Ir (COD) Cl]2(amount of Ir substance: 0.25mmol), NaBARF (0.375mmol, chemical name: sodium tetrakis (3, 5-bis (trifluoromethyl) phenyl) borate, CAS number: 79060-88-1) were added to a Schlenk tube with a magnetic stirrer, and 3mL of dichloromethane were added, the reaction was reacted at room temperature for 3 hours, completion of the ligand-free reaction was confirmed by thin layer chromatography, the catalyst was further purified by column chromatography, and the mobile phase was dichloromethane/petroleum ether.
The term "thin layer chromatography" as used herein refers to a method in which a suitable stationary phase is applied to a glass plate, plastic or aluminum substrate to form a uniform thin layer, and after spotting and development, the resulting thin layer is compared with a chromatogram obtained by the same method based on a specific shift value (Rf) of a suitable reference substance to identify the drug, check impurities or measure the content of the drug. Thin layer chromatography is an important experimental technique for rapid separation and qualitative analysis of small amounts of substances, and is also used to follow the progress of the reaction. The specific method of monitoring the reaction by thin layer chromatography in the present application may be a procedure well known to those skilled in the art.
The term "column chromatography" as used herein is a technique for separating components of a sample mixture by repeated distribution of the components over a number of cycles, depending on the distribution coefficients of the components in the stationary and mobile phases. The specific method of column chromatography in the present application may be a procedure well known to those skilled in the art.
The inventor finds that, in a careful study, iridium element and rhodium element are easy to lose electrons due to weak constraint of atomic nucleus to outer layer electrons, and corresponding complexes can be used as electrophiles to catalyze hydrogenation reaction; when the chiral ligand has nitrogen and phosphorus, the bonding force with metal is enhanced, the performance of the catalyst is more stable, and the steric hindrance brought by the cyclic group and the branched alkyl enables reactants to be easier to generate interaction with metal ions, the reaction rate is obviously accelerated, and the yield and the product purity are also improved; in addition, the chiral ligand is combined with reactants to form an intermediate product with chirality, and hydrogen can only interact with the reactants from a specific position, so that the final product also has chirality.
In some preferred embodiments, the hydrogenation reduction reaction is carried out in a solvent; the solvent is selected from one or more of 1, 4-dioxane, tetrahydrofuran, acetonitrile, toluene and dichloromethane.
In some preferred embodiments, the hydrogenation reduction reaction is carried out at-40 to 120 ℃; preferably, the hydrogenation reduction reaction is carried out at the temperature of-20 to 80 ℃; furthermore, the hydrogenation reduction reaction is carried out at the temperature of-10 to 50 ℃.
In some preferred embodiments, the hydrogenation reduction reaction is carried out at a pressure of 2 to 100 bar; further preferably, the hydrogenation reduction reaction is carried out at a pressure of 2-50 bar; furthermore, the hydrogenation reduction reaction is carried out under the pressure of 2-10 bar.
The reaction progress of the hydrogenation reduction reaction is monitored by thin-layer chromatography to judge the reaction end point, and the reaction is separated by column chromatography after the reaction is completed.
In some preferred embodiments, the silica gel used in the column chromatography has a mesh size of 200 to 300 mesh.
In some preferred embodiments, the mobile phase petroleum ether/ethyl acetate used in the column chromatography is (2-10): 1.
in a second aspect of the present invention, there is provided a chiral dihydroisoflavone compound prepared according to the preparation method as described above.