CN106977486A - A kind of preparation method and application of chiral flavanone kind composition and its derivative - Google Patents

A kind of preparation method and application of chiral flavanone kind composition and its derivative Download PDF

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CN106977486A
CN106977486A CN201710379364.9A CN201710379364A CN106977486A CN 106977486 A CN106977486 A CN 106977486A CN 201710379364 A CN201710379364 A CN 201710379364A CN 106977486 A CN106977486 A CN 106977486A
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CN106977486B (en
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汪君
熊东路
周文茜
陆志武
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Southwest University of Science and Technology
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

The present invention provides a kind of chiral flavanone kind composition and its derivative and its preparation method and application, methods described is to occur Asymmetric hydrogen transfer reaction in raw material shown in base metal silicon hydrogen catalyst catalysis following formula I to obtain chiral flavanone kind composition and its derivative shown in Formula II, the preparation method of the present invention selects cheap non-precious metal catalyst, cost is low, ambient influnence is smaller, make hydrogen source from silane, it is easy to operate and safe, reactions steps are few, raw material is easy to get, reaction condition is gentle, corresponding selection is up to more than 90%, even as high as more than 94%, high income, product yield can reach more than 80%, substantially increase the corresponding selection and yield of product, the chiral flavanone kind composition and its derivative prepared is widely used.

Description

A kind of preparation method and application of chiral flavanone kind composition and its derivative
Technical field
The invention belongs to compound synthesis technical field, it is related to a kind of chiral flavanone kind composition and its derivative Preparation method.
Background technology
Flavanone kind composition, is a kind of micro flavone compound being present in plant and Chinese herbal medicine.Many two Hydrogen flavones all has extensive physiological function and activity, and such as anti-oxidant, antitumor, antibacterial, anti-inflammatory effect are listed below one A little representational flavanone natural products for having a bioactivity：
Thio flavanone, dihydro quinoline ketone compound are the analogs of flavanone compound, although they are planting Content is not so good as flavanone kind composition among thing, but it has similar structure with flavanone, it is possible to which bioactivity is more It is high.
C2 substitution flavone compound asymmetric reduction reaction be obtain optical voidness flavanone most directly it is most effective Method.Transition metal-catalyzed asymmetric hydrogenation has effect on environment small, and Atom economy is high, excellent easily to operate Point.These features of asymmetric hydrogenation are confirmed by academia and industrial quarters already.Munster, Germany university Glorius etc. What people reported in 2013 utilizes chiral ruthenium azepine carbene complex (Ru-NHC) catalytic asymmetric reduction flavone compound.He Strategy be first flavone compound to be reduced into completely xanthan alcohol compound, then pass through the selective oxidations of PCC again Secondary alcohol is so as to obtain C2 optical voidness flavanone compounds.This method substrate applicability is wide, and yield is high, and enantioselectivity reaches 91% (Ruthenium-NHC-Catalyzed Asymmetric Hydrogenation of Flavones and Chromones:General Access to Enantiomerically Enriched Flavanones,Flavanols, Chromanones, and Chromanols Dongbing Zhao, Bernhard Beiring, and Frank Glorius, Angew.Chem.Int.Ed.2013,52,8454)。
2013, Dresden university Metz et al. reported a kind of Kinetic Resolution of non-enzymatic catalysis and obtains flavanone Method.They are obtained to high corresponding selection in high yield using rhodium (III) compound in the presence of formic acid and triethylamine Dihydro flavanones and flavanols.Also using this method, efficiently asymmetric hydrogen migration has synthesized a kind of active contain for they Flavanone (the A Practical Access to Highly Enantiomerically Pure of prenyl Flavanones by Catalytic Asymmetric Transfer Hydrogenation；Marie-Kristin Lemke,Pia Schwab,Petra Fischer,Sandra Tischer,Morris Witt,Laurence Noehringer,Victor Rogachev,Anne J_ger,Olga Kataeva,Roland and Peter Metz.Angew.Chem.Int.Ed.2013,52,11651)。
Above-mentioned catalyst system and catalyzing belongs to noble metal catalyst, and catalytic effect is very excellent.But, it is with high costs, and to ring Border influence is very big.Moreover, (Ru-NHC) catalyst of above-mentioned Glorius et al. reports is to the C=O and C in flavone compound =C makees catalyst with it and can only obtain xanthotoxol through single step reaction, to obtain chiral flavanone kind composition without selectivity It must be selectively oxidized again.Therefore, the Non-precious Metal Catalysts system of this patent report has significantly excellent in this Gesture.
In recent years, reported using the research of base metal (such as iron, nickel, copper, cobalt, titanium etc.) catalysis asymmetry hydrogenation reaction See not fresh through thread, non-precious metal catalyst shows effect more more preferable than noble metal catalyst in some asymmetric hydrogenations Really.For example, (P-NH-N-P) the Fe catalyst system and catalyzings of the Robert H.Morris reports of University of Toronto are in catalysis ketone and imines Asymmetric hydrogen transfer reaction (Amine (imine) diphosphine Iron Catalysts for Asymmetric Transfer Hydrogenation of Ketones and Imines；iwei Zuo,Alan J.Lough,Young Feng Li,Robert H.Morris；Science 2013,342,1080), and Princeton University Paul Chirik report Chiral diphosphine Co catalyst system and catalyzings all achieve very outstanding catalytic effect Cobalt in catalyzed alkene asyininetric hydrogenation Precursors for High-Throughput Discovery of Base Metal Asymmetric Alkene Hydrogenation Catalysts, Max R.Friedfeld, Michael Shevlin, Jordan M.Hoyt, Shane W.Krska,Matthew T.Tudge,Paul J.Chirik；Science 2013,342,1076).
Therefore, exploitation one kind is needed to prepare chiral flavanone using non-precious metal catalyst and its spread out in this area The method of raw compounds.
The content of the invention
In view of the shortcomings of the prior art, it is an object of the invention to provide a kind of chiral flavanone kind composition and its spread out Biology and its preparation method and application.
For up to this purpose, the present invention uses following technical scheme：
On the one hand, the present invention provides a kind of preparation method of chiral flavanone kind composition and its derivative, the side Method is to occur Asymmetric hydrogen transfer reaction in raw material shown in base metal silicon hydrogen catalyst catalysis following formula I to obtain chiral shown in Formula II Flavanone kind composition and its derivative, reaction equation are as follows：
Wherein X is O, S, NH or N-R1, R1For imines protection group；R is hydrogen, C1-C6 alkyl, and C1-C6 alkoxies, C1-C6 are complete Any one in fluoroalkyl, halogen, phenyl, benzyl, naphthyl, ester group, heterocyclic substituent, amino or amido or at least two Combination；R' is C1-C8 alkyl, phenyl, benzyl, naphthyl, ester group, heterocyclic substituent or amido；* positional representation asymmetric carbon atom, M For titanium, zinc, iron, copper, cobalt, nickel or tin, n is 0-4 integer.
In the present invention, noble metal is replaced to be used for the asymmetric hydrogen migration of raw material shown in Formulas I with cheap metal, so as to Chiral flavanone kind composition and its derivative shown in Formula II are obtained merely through single step reaction, current prior art is solved and closes Catalyst is expensive into flavanone and its similar structures compound, the problem of polluting environment, while so that non-noble is golden Belong to silicon hydrogen catalyst as hydrogen source, it is easy to operate and safe, and the selectivity of product of chiral synthetic reaction can be improved so that production Thing yield is greatly improved.
Preferably, the derivative is chiral thio flavanone kind composition and/or chiral dihydro quinoline ketone chemical combination Thing.
Preferably, the R1For benzyloxycarbonyl group (Cbz), tertbutyloxycarbonyl (Boc), tablet held before the breast by officials methoxycarbonyl group (Fmoc), allyl oxygen Carbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), methoxycarbonyl group, carbethoxyl group, p-toluenesulfonyl (Tos), trifluoro second Acyl group (Tfa), ortho-nitrophenyl sulfonyl (Ns), to ortho-nitrophenyl sulfonyl, pivaloyl group, benzoyl trityl (Trt), 2,4- dimethoxy-benzyls (Dmb), to any one in methoxy-benzyl (PMB) or benzyl (Bn).
Preferably, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
In the present invention, as shown in Formulas I and Formula II, R is the substituent on phenyl ring, and its number is n, and n is whole for 0-4's Number, i.e. n can be 0,1,2,3 or 4.The R be C1-C6 alkyl, C1-C6 alkoxies, C1-C6 perfluoroalkyls, halogen, phenyl, In benzyl, naphthyl, ester group, heterocyclic substituent, hydroxyl, amino or amido any one or at least two combination, wherein institute Combination is stated to refer to, in the nuclear substituted multiple groups (most 4) of benzene, can be the same or different each other, for example, work as benzene When having two positions to be substituted with such substituents as described above on ring, n=2, R can select one or both of above-mentioned group, and for example R can Think phenyl and benzyl.
In the present invention, the C1-C6 alkyl is the alkyl that carbon number is 1-6 (such as 1,2,3,4,5 or 6), described C1-C8 atomic number of alkyl carbon is 1-8 (such as 1,2,3,4,5,6,7 or 8) alkyl, can be specifically methyl, ethyl, third Base, isopropyl, butyl, isobutyl group, amyl group, isopentyl, hexyl, octyl group etc..
In the present invention, the C1-C6 alkoxies are the alkoxy that carbon number is 1-6 (such as 1,2,3,4,5 or 6), Can be specifically methoxyl group, ethyoxyl, propoxyl group, butoxy etc..
In the present invention, the C1-C6 perfluoroalkyls are the perfluor alkane that carbon number is 1-6 (such as 1,2,3,4,5 or 6) Base, such as trifluoromethyl or pentafluoroethyl group.
In the present invention, the ester group can be carbomethoxy, ethoxycarbonyl, propyl ester base etc..
In the present invention, the heterocyclic substituent be the group containing hetero atom O, S or N, preferably pyridine radicals, furyl or Thienyl.
Preferably, the preparation method of the base metal silicon hydrogen catalyst comprises the following steps：
(1) base metal salt reacts to form base metal complex compound with chiral ligand；
(2) the base metal complex compound that step (1) is obtained reacts with silicon hydrogen reagent, forms metallic silicon hydrogen catalyst.
Preferably, step (1) the base metal salt is non-noble metal metal halide, sulfate, nitrate, high chlorine Appointing in hydrochlorate, acetate, trifluoroacetate, trifluoro-methanyl sulfonate, tetrafluoroborate, hexafluorophosphate or hexafluoro antimonate Meaning it is a kind of or at least two combinations.
Preferably, step (1) described chiral ligand is with the part of structure as shown in formula A-P or with being tied shown in formula A-P Any one in the part of structure has the part of opposite configuration：
Wherein, in formula A-L and formula N, Ar is phenyl, 4- aminomethyl phenyls, 3,5- 3,5-dimethylphenyls, 2,4,6- trimethylbenzenes Base, 3,5- bis- (trifluoromethyl) phenyl, 4- methoxyl group -4,5- 3,5-dimethylphenyls, 4- methoxyl group -3,5- di-tert-butyl-phenyls；Formulas I Middle R is methyl, ethyl, the third different base, Ben Ji Huo Benzyl bases；Ar is the tert-butyl group, phenyl, 3,5- 3,5-dimethylphenyls or cyclohexyl in formula G； In formula M, O, PtBu represents the tert-butyl group.
Preferably, the chiral ligand is the part with the structure as shown in formula B, formula F, formula H or formula G.
In the present invention, the structure shown in formula G is ferrocene phosphorus compound, and Me represents methyl, and Et represents that ethyl, Ph are represented Phenyl ring.
Preferably, the mol ratio of contained metallic element and chiral ligand is 1 in step (1) the base metal salt:1.1~ 1:5, such as 1:1.1、1:1.3、1:1.5、1:1.8、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5 or 1:5.
Preferably, the temperature of step (1) described reaction be 0 DEG C~60 DEG C, such as 0 DEG C, 5 DEG C, 10 DEG C, 15 DEG C, 18 DEG C, 20 DEG C, 23 DEG C, 25 DEG C, 28 DEG C, 30 DEG C, 33 DEG C, 35 DEG C, 40 DEG C, 45 DEG C, 50 DEG C, 55 DEG C or 60 DEG C.
Preferably, the time of step (1) described reaction is 0.5~12 hour, such as 0.5 hour, 1 hour, 2 hours, it is 3 small When, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours.
Preferably, step (2) the silicon hydrogen reagent is many polysilanes or the silane with following structure：R”2+2m-nSimHn, Wherein 1≤n ＜ 2+2m, m >=1, R " are the alkyl or alkoxy of 1-6 carbon that is identical or differing, and such as R " is methyl, second Base, propyl group, isopropyl, butyl, isobutyl group, amyl group, isopentyl, hexyl, methoxyl group, ethyoxyl, propoxyl group, butoxy etc..
Preferably, step (2) the silicon hydrogen reagent is in diethoxymethylsilane, triethoxysilane or many polysilane Any one or at least two combination.
Preferably, the mol ratio of step (2) the base metal complex compound and silicon hydrogen reagent is 1:(1-10), such as 1:1、 1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8、1:8.5、 1:9、1:9.5 or 1:10, preferably 1:(1-5).
Preferably, the temperature of step (2) described reaction be 0-35 DEG C, such as 0 DEG C, 3 DEG C, 5 DEG C, 8 DEG C, 10 DEG C, 15 DEG C, 18 DEG C, 20 DEG C, 23 DEG C, 25 DEG C, 28 DEG C, 30 DEG C, 33 DEG C or 35 DEG C.
Preferably, the time of step (2) described reaction be 0.5~12 hour, such as 0.5 hour, 1 hour, 1.5 hours, 2 Hour, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours.
Preferably, step (1) and step (2) reaction are carried out in organic solvent, and the organic solvent is benzene, first Benzene, hexamethylene, ethylbenzene, dimethylbenzene, carbon tetrachloride, ethyl acetate, acetonitrile, dichloromethane, chloroethanes, dichloroethanes, 1,2- bis- Chloropropane, chloropropane, acetone, chloroform, n-hexane, tetrahydrofuran, preferably Isosorbide-5-Nitrae-dioxane, tetrahydrofuran or toluene.
Preferably, when occurring Asymmetric hydrogen transfer reaction, the material of metallic element in the base metal silicon hydrogen catalyst Amount is 0.001 with the ratio between amount of substance of raw material shown in Formulas I:1~0.1:1, such as 0.001:1、0.005:1、0.008:1、0.01: 1、0.03:1、0.05:1、0.08:1 or 0.1:1, preferably 0.005:1~0.05:1.
Preferably, the temperature of the Asymmetric hydrogen transfer reaction be 0 DEG C~100 DEG C, such as 0 DEG C, 3 DEG C, 5 DEG C, 8 DEG C, 10 DEG C, 15 DEG C, 20 DEG C, 30 DEG C, 40 DEG C, 50 DEG C, 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C or 100 DEG C.
Preferably, the time of the Asymmetric hydrogen transfer reaction be 0.1~48 hour, such as 0.1 hour, 0.5 hour, 1 Hour, 2 hours, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 24 hours, it is 28 small When, 30 hours, 32 hours, 36 hours, 40 hours, 43 hours, 46 hours or 48 hours.
In the present invention, after the Asymmetric hydrogen transfer reaction terminates, acid solution stirring is added, is then concentrated organic molten Agent, isolated chiral flavanone kind composition and its derivative.
Preferably, the acid solution is any one in hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or nitric acid, preferably hydrochloric acid.
Preferably, the concentration of the acid solution is 0.5-1.5M, such as 0.5M, 0.8M, 1M, 1.2M, 1.4M or 1.5M.
Preferably, the stirring is is stirred at room temperature 0.5~2 hour, such as 0.5 hour, 0.7 hour, 0.9 hour, 1 Hour, 1.2 hours, 1.4 hours, 1.6 hours, 1.8 hours or 2 hours.
Preferably, the method for the separation is column chromatography, thin-layer chromatography or recrystallization.
Preferably, the eluent that the column chromatography is used is the mixed liquor of petroleum ether and ethyl acetate.
Preferably, the volume ratio of petroleum ether and ethyl acetate is 5:1~80:1, such as 5:1、8:1、10:1、12:1、15: 1、18:1、20:1、25:1、30:1、35:1、40:1、45:1、50:1、55:1、60:1、65:1、70:1、75:1 or 80:1.
As the preferred technical solution of the present invention, the preparation method of the chiral flavanone kind composition and its derivative Specifically include following steps：
(1) base metal salt reacts to form base metal complex compound with chiral ligand；
(2) the base metal complex compound that step (1) is obtained reacts with silicon hydrogen reagent, forms metallic silicon hydrogen catalyst；
(3) the base metal silicon hydrogen catalyst prepared in step (2) is catalyzed the asymmetric hydrogen of raw material generation shown in following formula I Transfer reaction obtains chiral flavanone kind composition and its derivative shown in Formula II, and reaction equation is as follows：
Wherein X is O, S, NH or N-R1, R1For imines protection group；R is C1-C6 alkyl, C1-C6 alkoxies, C1-C6 perfluors In alkyl, halogen, phenyl, benzyl, naphthyl, ester group, heterocyclic substituent, amino or amido any one or at least two group Close；R' is C1-C8 alkyl, phenyl, benzyl, naphthyl, ester group, heterocyclic substituent or amido；* positional representation asymmetric carbon atom, M can Be for titanium, zinc, iron, copper, cobalt, nickel or tin, n be 0-4 integer.
On the other hand, the invention provides the chiral flavanone chemical combination prepared by preparation method as described above Thing and its derivative.The chiral flavanone kind composition and its derivative pair prepared by preparation method of the present invention Should selectivity height, high income.
On the other hand, the invention provides chiral flavanone kind composition and its derivative as described above in flavonoids Application in medicine or the preparation of flavonoids pharmaceutical composition.
Relative to prior art, the invention has the advantages that：
Cheap Non-precious Metal Catalysts are selected in the flavanone kind composition of the present invention and its preparation method of derivative Agent, cost is low, and ambient influnence is smaller, and hydrogen source is made from silane, and easy to operate and safe, reactions steps are few, and raw material is easy to get, and reacts bar Part is gentle, and corresponding selection is up to more than 90%, even as high as more than 94%, and high income, product yield can reach more than 80%, The chiral flavanone kind composition and its derivative prepared can be used for a variety of flavonoids medicines or flavonoids drug regimen The preparation of thing, it is widely used, have a good application prospect.
Brief description of the drawings
Fig. 1 is the nucleus magnetic hydrogen spectrum of the synthesis characterization for the base metal silicon hydrogen catalyst that the embodiment of the present invention 1 is prepared, its Middle a) figure is many polysilane PMHS nucleus magnetic hydrogen spectrum；B) figure is (R)-DTBM-segphos nucleus magnetic hydrogen spectrum；C) figure is copper acetate With the nucleus magnetic hydrogen spectrum of the metal complex of (R)-DTBM-segphos formation；D) figure is the nuclear-magnetism hydrogen of base metal silicon hydrogen catalyst Spectrum.
Embodiment
Technical scheme is further illustrated below by embodiment.Those skilled in the art should be bright , the embodiment be only to aid in understand the present invention, be not construed as to the present invention concrete restriction.
Embodiment 1
In the present embodiment, 2- ethyl flavanones are prepared, its structural formula is as follows：
Preparation method comprises the following steps：
Dry 10mL reaction tube is taken, loads magnetic stir bar, 0.9mg, 2.5mol% vinegar is added in glove box In the 1mL tetrahydrofuran solutions of sour copper and 4.0mg 2.6mol% parts (R)-DTBM-segphos (part i.e. shown in formula B), 30min is stirred at room temperature, and solution shows light blue.Then, many polysilane 40.2mg are slowly added to, continue that 60min is stirred at room temperature, it is molten Liquid color gradually becomes golden yellow and arrives dark-brown, obtains base metal silicon hydrogen catalyst.Afterwards, it is disposable to add 2- ethyl chromones 34.8mg is into above-mentioned system, and book layer chromatography TLC monitorings at room temperature treat raw material reaction completely (about 6h).It is slowly added to the dilute of 1M Hydrochloric acid solution three to four drips, and continues to stir 30min at room temperature.Rotary evaporation removes solvent and carries out column chromatography for separation, from 100- The silica gel of 200 mesh, mobile phase is that volume ratio is petroleum ether：Ethyl acetate=20：1.
Obtained base metal silicon hydrogen catalyst is characterized, as shown in figure 1, a) figure is many polysilane PMHS nuclear-magnetism Hydrogen is composed；B) figure is (R)-DTBM-segphos nucleus magnetic hydrogen spectrum；C) figure is copper acetate and the gold of (R)-DTBM-segphos formation Belong to the nucleus magnetic hydrogen spectrum of complex compound；D) figure is the nucleus magnetic hydrogen spectrum for the copper hydrogen catalyst to be formed；Solvent is deuterated benzene (C6D6).Contrast Us are respectively composed above can be found that it is to urge a new peak occur in the d=2.55ppm of the nuclear-magnetism spectrum of the copper hydrogen catalyst of d) figure Cu-H in agent, this and document G.V.Goeden, K.G.Caulton, J.Am.Chem.Soc.1981,103,7354. reports Achiral Cu-H catalyst in Cu-H to go out peak position similar), by a)-d) contrast can prove that the present invention is successfully obtained Base metal silicon hydrogen catalyst.
Product is water white transparency oily thing (yield 98%)；Specific rotatory power(c=0.07, CH2Cl2)；It is right It is 98% to answer selectivity ee.
Structural characterization data are as follows：
1H NMR(500MHz,CDCl3) δ 7.89 (dd, J=7.8,1.7Hz, 1H), 7.53-7.39 (m, 1H), 7.06- 6.95 (m, 2H), 4.39 (qd, J=7.5,5.5Hz, 1H), 2.76-2.64 (m, 2H), 1.91 (td, J=14.5,7.3Hz, 1H), 1.83-1.73 (m, 1H), 1.09 (t, J=7.5Hz, 3H)13C NMR(126MHz,CDCl3)δ192.74(s),161.72 (s), 135.97 (s), 126.94 (s), 121.07 (d, J=18.1Hz), 117.93 (s), 79.05 (s), 42.55 (s), 27.98 (s),9.32(s).HRMS(ESI-ion trap)m/z:[M+H]+Calculated value C11H13O2, 177.0970, measured value 177.0973.
Embodiment 2
In the present embodiment, 2- tert-butyl group flavanones are prepared, its structural formula is as follows：
Preparation method comprises the following steps：
Dry 10mL reaction tube is taken, loads magnetic stir bar, 1.7mg, 5mol% acetic acid is added in glove box In ferrous and 6.5mg 5.2mol% parts (R)-Binap (part i.e. shown in formula A) 5mL toluene solutions, stir at room temperature 30min, solution shows light green.Then, be slowly added to triethoxysilane 50mg, continue to be stirred at room temperature 60min, solution colour by Crossfade into golden yellow and arrive dark-brown, obtain base metal silicon hydrogen catalyst and (the correct of its structure is demonstrated by structural characterization Property).Afterwards, the disposable 2- tert-butyl group chromone 40.4mg that add are to above-mentioned iron hydrogen system, and anti-TLC monitorings at room temperature treat that raw material reacts Completely (about 24h).The 1M drop of dilute hydrochloric acid solution three to four is slowly added to, continues to stir 30min at room temperature.Rotary evaporation removes molten Agent carries out column chromatography for separation, from the silica gel of 100-200 mesh, and mobile phase is that volume ratio is petroleum ether：Ethyl acetate=30：1.
Product is water white transparency oily mucus (yield 92%)；Specific rotatory power(c 0.69,CH2Cl2)；It is right It is 99% to answer selectivity ee.
Structural characterization data are as follows：
1H NMR(500MHz,CDCl3) δ 7.88 (dd, J=8.0,1.6Hz, 1H), 7.56-7.40 (m, 1H), 7.06- (s, the 9H) of 6.92 (m, 2H), 4.07 (dd, J=13.1,3.6Hz, 1H), 2.69 (qd, J=16.5,8.4Hz, 2H), 1.0813C NMR(126MHz,CDCl3)δ193.57(s),162.20(s),135.90(s),126.88(s),121.03(s),120.77 (s),117.91(s),85.25(s),38.45(s),34.16(s),25.50(s).HRMS(ESI-ion trap)m/z:[M+H ]+C13H17O2, calculated value 205.1223, measured value 205.1222.
Embodiment 3
In the present embodiment, 2- methyl -6,7- dichloro-dihydro flavones is prepared, its structural formula is as follows：
Preparation method comprises the following steps：
Dry 100mL reaction tube is taken, loads magnetic stir bar, 2.7mg, 1mol% chlorinations is added in glove box In zinc and 6.5mg 1.1mol% parts (R)-DTBM-segphos (part i.e. shown in formula B) 1mL toluene solutions, at room temperature Stir 60min.Then, diphenylmethylsilane 400mg is slowly added to, continues that 60min is stirred at room temperature, base metal silicon hydrogen is obtained Catalyst (correctness that its structure is demonstrated by structural characterization).Afterwards, 2- methyl -6,7- dichloro chromones 456mg is added to arrive Above-mentioned zinc hydrogen system, at room temperature anti-TLC monitorings treat raw material reaction completely (about 24h).It is slowly added to 1M dilute hydrochloric acid solution 3- 4mL, continues to stir 60min at room temperature.Rotary evaporation removes solvent and carries out column chromatography for separation, from the silica gel of 100-200 mesh, stream Dynamic phase is that volume ratio is petroleum ether：Ethyl acetate=20：1.
Product is white solid (yield 84%)；Fusing point (90.6-91.7 DEG C), specific rotatory power(c= 1.31, CH2Cl2)；Corresponding selection ee is 94%.
Structural characterization data are as follows：
1H NMR(500MHz,CDCl3) δ 7.78 (d, J=1.9Hz, 1H), 7.56 (d, J=1.9Hz, 1H), 4.80-4.54 (m,1H),2.87-2.58(m,2H),1.69-1.50(m,4H)。13C NMR(126MHz,CDCl3)δ190.50(s),155.90 (s),135.52(s),126.39(s),125.07(s),123.90(s),122.33(s),75.46(s),43.90(s),20.73 (s).HRMS(ESI-ion trap)m/z:[M+H]+C10H9O2Cl2Calculated value 230.9974, measured value 230.9973.
Embodiment 4
In the present embodiment, 2- ethoxycarbonyl -6- fluorine flavanones are prepared, its structural formula is as follows：
Preparation method comprises the following steps：
Dry 100mL reaction tube is taken, loads magnetic stir bar, 18mg, 1mol%Cu is added in glove box (OTf)25mL1,4- dioxane with 6.5mg 1.1mol% parts (R)-MeO-BIPHEP (part i.e. shown in formula C) is molten In liquid, 60min is stirred at room temperature.Then, tetramethyl disiloxane TMDS402mg is slowly added to, continues that 60min is stirred at room temperature, Obtain base metal silicon hydrogen catalyst (correctness that its structure is demonstrated by structural characterization).Afterwards, 2- ethoxycarbonyies -6- is added Fluorine chromone 472mg is to above-mentioned copper hydrogen system, and anti-TLC, which is monitored, at room temperature treats raw material reaction completely (about 24h).It is slowly added to the dilute of 1M Hydrochloric acid solution 3-4mL, continues to stir 60min at room temperature.Rotary evaporation removes solvent and carries out column chromatography for separation, from 100-200 Purpose silica gel, mobile phase is that volume ratio is petroleum ether：Ethyl acetate=20：1.
Product is water white transparency oily mucus (yield 80%), specific rotatory power(c=0.09, CH2Cl2), Corresponding selection ee is>99%.
Structural characterization data are as follows：
1H NMR(400MHz,CDCl3) δ 7.54 (dd, J=8.1,3.2Hz, 1H), 7.26 (ddd, J=9.1,7.5, 2.9Hz, 1H), 7.11 (dd, J=9.1,4.2Hz, 1H), 5.08 (dd, J=8.4,5.7Hz, 1H), 4.38-4.10 (m, 2H), 3.27-2.95 (m, 2H), 1.29 (dd, J=13.5,6.3Hz, 3H)13C NMR(101MHz,CDCl3)δ188.82(s), 168.45 (s), 158.79 (s), 156.39 (d, J=1.9Hz), 124.05 (s), 123.80 (s), 121.39 (s), 119.86 (d, J=7.4Hz), 112.11 (s), 111.88 (s), 75.37 (s), 62.16 (s), 39.31 (d, J=1.3Hz), 14.05 (s).HRMS(ESI-ion trap)m/z:[M+H]+C12H12O4F calculated values 239.0707, measured value 239.0714.
Embodiment 5
In the present embodiment, 2- isopropyl dihydrogen phosphorothioate flavones is prepared, its structural formula is as follows：
Preparation method comprises the following steps：
Dry 10mL reaction tube is taken, loads magnetic stir bar, 1mg, 1.0mol%Cu is added in glove box (OTf)2In 6.8mg 1.1mol% parts CTH- (R)-P-Phos (a kind of part that formula E is represented) 5mL tetrahydrofurans, room The lower stirring 60min of temperature.Then, many polysilane 402mg are slowly added to, continue that 60min is stirred at room temperature, base metal silicon hydrogen is obtained and urges Agent (correctness that its structure is demonstrated by structural characterization).Afterwards, 2- ethoxycarbonyl -6- fluorine chromone 472mg are added to above-mentioned Copper hydrogen system, at room temperature anti-TLC monitorings treat raw material reaction completely (about 24h).It is slowly added to 1M dilute hydrochloric acid solution 3-4mL, room Temperature is lower to be continued to stir 60min.Rotary evaporation removes solvent and carries out column chromatography for separation, and from the silica gel of 100-200 mesh, mobile phase is Volume ratio is petroleum ether：Ethyl acetate=20：1.
Product is light amber mucus (yield 87%), specific rotatory power(c 0.38,CH2Cl2), correspondence Selective ee is 97%.
Structural characterization data are as follows：
1H NMR(500MHz,CDCl3) δ 8.09 (dd, J=7.9,1.3Hz, 1H), 7.43-7.35 (m, 1H), 7.34- 7.25 (m, 1H), 7.23-7.12 (m, 1H), 3.41 (ddd, J=12.1,6.3,2.8Hz, 1H), 3.04 (dd, J=16.2, 2.8Hz, 1H), 2.88 (dd, J=16.2,12.1Hz, 1H), 1.99 (dq, J=13.4,6.7Hz, 1H), 1.10 (dd, J= 6.6,5.6Hz,6H).13C NMR(126MHz,CDCl3)δ195.34(s),142.12(s),133.41(s),130.61(s), 128.88(s),127.73(s),124.76(s),48.50(s),43.80(s),32.02(s),19.82(s),19.64(s) .HRMS(ESI-ion trap)m/z:[M+H]+C12H15OS calculated values 207.0838, measured value 207.0837.
Embodiment 6
In the present embodiment, 2- phenyl dihydro quinoline ketone is prepared, its structural formula is as follows：
Preparation method comprises the following steps：
Dry 10mL reaction tube is taken, loads magnetic stir bar, 2.5mol%Co (acac) is added in glove box21.3mg and (R, R)-QuinoxP* (part shown in formula O) 1.8mg 2.6mol%, then adds in 2mL ether, is stirred at room temperature Triethyl silicane 64uL is added after 30 minutes to continue to stir 40 minutes.Afterwards, 2- phenyl-quinoline ketone 44.2mg (0.2mmol) is added To above-mentioned cobalt hydrogen system, anti-TLC monitorings at room temperature treat raw material reaction completely (about 12h).It is slowly added to 1M dilute hydrochloric acid solution 3-4 Drop, continues to stir 60min at room temperature.Rotary evaporation removes solvent and carries out column chromatography for separation, from the silica gel of 100-200 mesh, stream Dynamic phase is that volume ratio is petroleum ether：Ethyl acetate=5：1.
Product is faint yellow solid (yield 89%), mp 150-152 DEG C；Specific rotatory power(c 0.42, CHCl3), corresponding selection is 97%.
Structural characterization data are as follows：
1H NMR(300MHz,CDCl3, δ ppm) and 2.72 (dd, J=4.5,15.3Hz, 1H), 2.97 (dd, J=3.6, 15.3Hz, 1H), 5.17 (dd, J=8.4,3.3Hz, 1H), 5.57 (br s, 1H), 6.79-6.83 (m, 2H), 7.26-7.32 (m,4H),7.42-7.43(m,2H),7.94-7.99(m,1H)；13C NMR(75MHz,CDCl3,δppm)45.9,57.9, 115.5,117.9,118.5,126.2,127.1,128.0,128.5,135.0,140.6,151.2,192.9；HRMS(ESI- ion trap)m/z:[M+H]+C15H13NO calculated values 224.1076, measured value 224.2500.
Embodiment 7
In the present embodiment, 2- (2 '-furyl) dihydro quinoline ketone is prepared, its structural formula is as follows：
Dry 10mL reaction tube is taken, loads magnetic stir bar, 2.5mol%Cu (acac) is added in glove box21.3mg and (R, R)-Me-DUPHOS (part shown in Formulas I) 1.5mg 2.6mol%, then adds in 1mL acetonitriles, is stirred at room temperature Dimethylphenylsilaneand 64uL is added after 30 minutes to continue to stir 40 minutes.Afterwards, 2- (2 '-furyl)-quinoline ketone is added 42.2mg (0.2mmol) arrives above-mentioned copper hydrogen system, and anti-TLC monitorings at room temperature treat raw material reaction completely (about 12h).It is slowly added to 1M Dilute hydrochloric acid solution 3-4 drops, at room temperature continue stir 60min.Rotary evaporation removes solvent and carries out column chromatography for separation, from 100- The silica gel of 200 mesh, mobile phase is that volume ratio is petroleum ether：Ethyl acetate=5：1.
Product is faint yellow solid (yield 92%), mp 92-93 DEG C；Corresponding selection is 95%.
Structural characterization data are as follows：
1H NMR(300MHz,CDCl3,δppm)2.81-2.89(m,1H),3.01-3.06(m,1H),5.45-5.56(m, 1H),5.87(br s,1H)6.36-6.50(m,2H),6.78-6.86(m,2H),7.25-7.27(m,1H),7.55-7.58(m, 1H),7.94-7.97(m,1H)；13C NMR(75MHz,CDCl3,δppm)39.3,47.5,104.8,111.4,117.0, 117.9,123.2,127.0,131.0,142.1,149.6,152.4,192.4；HRMS(ESI-ion trap)m/z:[M+H]+ C13H11NO2 calculated values 214.0869, measured value 214.0988.
Comparative example 1
Using disclosed metallic catalyst is used in the reaction described in embodiment 1 in the prior art as follows, i.e., using as follows Disclosed metallic catalyst carrys out the Asymmetric hydrogen transfer reaction of raw material shown in catalysis type I in the prior art：The prior art is such as Under：[1]Ruthenium–NHC-Catalyzed Asymmetric Hydrogenation of Flavones and Chromones:General Access to Enantiomerically Enriched Flavanones,Flavanols, Chromanones, and Chromanols Dongbing Zhao, Bernhard Beiring, and Frank Glorius, Angew.Chem.Int.Ed.2013,52,8454；[2]A Practical Access to Highly Enantiomerically Pure Flavanones by Catalytic Asymmetric Transfer Hydrogenation；Marie-Kristin Lemke,Pia Schwab,Petra Fischer,Sandra Tischer, Morris Witt,Laurence Noehringer,Victor Rogachev,Anne J_ger,Olga Kataeva, Roland and Peter Metz.Angew.Chem.Int.Ed.2013,52,11651；[3] Enantioselective Conjugate Reduction ofα,β-Unsaturated Carboxamides with Semicorrin Cobalt Catalysts Peter von Matt and Andreas Pfaltz Tetmhedron: Asymmetry 1991,2,691；[4]Chemoselective Reduction ofα,β-Unsaturated Aldehydes, Ketones,Carboxylic Acids,and Esters with Nickel Boride in Methanol—Water Jitender Mohan Khurana and Purnima Sharma,Bulletin of the Chemical Society of Japan,2004,77,549[5]Amine(imine)diphosphine Iron Catalysts for Asymmetric Transfer Hydrogenation of Ketones and Imines；iwei Zuo,Alan J.Lough,Young Feng Li,Robert H.Morris；Science 2013,342,1080.
The structure of metallic catalyst disclosed in above prior art [1]-[5] is as follows：
The equation reacted using the catalyst in prior art described above and catalyst can be with integrating representation For following reaction process：
Product is divided into tri- kinds of A, B, C, during using different metallic catalysts, and its primary product produced is different, yield Difference, the result reacted by the catalyst in prior art described above and using the catalyst is summarized in such as table 1 below In (only gived in table 1 with the application produce product identical C products corresponding selection).
Table 1
Applicant states that the present invention illustrates the method detailed of the present invention, but not office of the invention by above-described embodiment It is limited to above-mentioned method detailed, that is, does not mean that the present invention has to rely on above-mentioned method detailed and could implemented.Art Technical staff it will be clearly understood that any improvement in the present invention, equivalence replacement and auxiliary element to each raw material of product of the present invention Addition, selection of concrete mode etc., within the scope of all falling within protection scope of the present invention and being open.

Claims (10)

1. the preparation method of a kind of chiral flavanone kind composition and its derivative, it is characterised in that methods described is non- Raw material shown in noble metal silicon hydrogen catalyst catalysis following formula I occurs Asymmetric hydrogen transfer reaction and obtains chiral flavanone shown in Formula II Class compound and its derivative, reaction equation are as follows：
Wherein X is O, S, NH or N-R1, R1For imines protection group；R is hydrogen, C1-C6 alkyl, C1-C6 alkoxies, C1-C6 perfluor alkane In base, halogen, phenyl, benzyl, naphthyl, ester group, heterocyclic substituent, amino or amido any one or at least two group Close；R' is C1-C8 alkyl, phenyl, benzyl, naphthyl, ester group, heterocyclic substituent or amido；* positional representation asymmetric carbon atom, M can Be for titanium, zinc, iron, copper, cobalt, nickel or tin, n be 0-4 integer.
2. preparation method according to claim 1, it is characterised in that the derivative is chiral thio flavanone Compound and/or chiral dihydro quinoline ketone compound.
3. preparation method according to claim 1 or 2, it is characterised in that the R1For benzyloxycarbonyl group, tertbutyloxycarbonyl, tablet held before the breast by officials Methoxycarbonyl group, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, methoxycarbonyl group, carbethoxyl group, p-toluenesulfonyl, trifluoroacetyl Base, ortho-nitrophenyl sulfonyl, to ortho-nitrophenyl sulfonyl, pivaloyl group, benzoyl trityl, 2,4- dimethoxy benzyls Base, to any one in methoxy-benzyl or benzyl；
Preferably, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
4. the preparation method according to any one of claim 1-3, it is characterised in that the base metal silicon hydrogen catalyst Preparation method comprise the following steps：
(1) base metal salt reacts to form base metal complex compound with chiral ligand；
(2) the base metal complex compound that step (1) is obtained reacts with silicon hydrogen reagent, forms metallic silicon hydrogen catalyst.
5. preparation method according to claim 4, it is characterised in that step (1) the base metal salt is base metal Metal halide, sulfate, nitrate, perchlorate, acetate, trifluoroacetate, trifluoro-methanyl sulfonate, tetrafluoro boric acid In salt, hexafluorophosphate or hexafluoro antimonate any one or at least two combination.
6. the preparation method according to claim 4 or 5, it is characterised in that step (1) described chiral ligand is with such as formula The part of structure shown in A-P or the part with any one in the part of structure shown in formula A-P with opposite configuration：
Wherein, in formula A-L and formula N, Ar be phenyl, 4- aminomethyl phenyls, 3,5- 3,5-dimethylphenyls, 2,4,6- trimethylphenyls, 3,5- bis- (trifluoromethyl) phenyl, 4- methoxyl group -3,5- 3,5-dimethylphenyls, 4- methoxyl group -3,5- di-tert-butyl-phenyls；R in Formulas I For methyl, ethyl, isopropyl, Ben Ji Huo Benzyl bases；Ar is the tert-butyl group, phenyl, 3,5- 3,5-dimethylphenyls or cyclohexyl in formula G；Formula In M, formula O and formula PtBu represents the tert-butyl group；.
Preferably, the chiral ligand is the part with the structure as shown in formula B, formula F, formula H or formula G.
7. the preparation method according to any one of claim 4-6, it is characterised in that step (1) the base metal salt In the mol ratio of contained metallic element and chiral ligand be 1:1.1~1:5；
Preferably, the temperature of step (1) described reaction is 0 DEG C~60 DEG C；
Preferably, the time of step (1) described reaction is 0.5~12 hour；
Preferably, step (2) the silicon hydrogen reagent is many polysilanes or the silane with following structure：R”2+2m-nSimHn, wherein 1 ≤ n ＜ 2+2m, m >=1, R " are the alkyl or alkoxy of 1-6 carbon that is identical or differing；
Preferably, step (2) the silicon hydrogen reagent is times in diethoxymethylsilane, triethoxysilane or many polysilanes Meaning it is a kind of or at least two combinations；
Preferably, the mol ratio of step (2) the base metal complex compound and silicon hydrogen reagent is 1:(1-10), preferably 1:(1-5)；
Preferably, the temperature of step (2) described reaction is 0-35 DEG C；
Preferably, the time of step (2) described reaction is 0.5~12 hour；
Preferably, step (1) and step (2) reaction are carried out in organic solvent, and the organic solvent is benzene, toluene, ring Hexane, ethylbenzene, dimethylbenzene, carbon tetrachloride, ethyl acetate, acetonitrile, dichloromethane, chloroethanes, dichloroethanes, 1,2- dichloros third Alkane, chloropropane, acetone, chloroform, n-hexane, tetrahydrofuran, preferably Isosorbide-5-Nitrae-dioxane, tetrahydrofuran or toluene；
Preferably, when occurring Asymmetric hydrogen transfer reaction, in the base metal silicon hydrogen catalyst amount of substance of metallic element with The ratio between amount of substance of raw material shown in Formulas I is 0.001:1~0.1:1, preferably 0.005:1~0.05:1；
Preferably, the temperature of the Asymmetric hydrogen transfer reaction is 0 DEG C~100 DEG C；
Preferably, the time of the Asymmetric hydrogen transfer reaction is 0.1~48 hour；
Preferably, after the Asymmetric hydrogen transfer reaction terminates, acid solution stirring is added, organic solvent is then concentrated, separates To chiral flavanone kind composition and its derivative；
Preferably, the acid solution is any one in hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or nitric acid, preferably hydrochloric acid；
Preferably, the concentration of the acid solution is 0.5-1.5M；
Preferably, the stirring is to be stirred at room temperature 0.5~2 hour；
Preferably, the method for the separation is column chromatography, thin-layer chromatography or recrystallization；
Preferably, the eluent that the column chromatography is used is the mixed liquor of petroleum ether and ethyl acetate；
Preferably, the volume ratio of petroleum ether and ethyl acetate is 5:1~80:1.
8. the preparation method according to any one of claim 1-7, it is characterised in that the chiral flavanone chemical combination The preparation method of thing and its derivative specifically includes following steps：
(1) base metal salt reacts to form base metal complex compound with chiral ligand；
(2) the base metal complex compound that step (1) is obtained reacts with silicon hydrogen reagent, forms metallic silicon hydrogen catalyst；
(3) the base metal silicon hydrogen catalyst prepared in step (2) is catalyzed the asymmetric hydrogen migration of raw material generation shown in following formula I Reaction obtains chiral flavanone kind composition and its derivative shown in Formula II, and reaction equation is as follows：
Wherein X is O, S, NH or N-R1, R1For imines protection group；R be C1-C6 alkyl, C1-C6 alkoxies, C1-C6 perfluoroalkyls, In halogen, phenyl, benzyl, naphthyl, ester group, heterocyclic substituent, amino or amido any one or at least two combination；R' For C1-C8 alkyl, phenyl, benzyl, naphthyl, ester group, heterocyclic substituent or amido；* positional representation asymmetric carbon atom, M can be For titanium, zinc, iron, copper, cobalt, nickel or tin, n is 0-4 integer.
9. chiral flavanone kind composition that the preparation method according to any one of claim 1-8 is prepared and its Derivative.
10. chiral flavanone kind composition according to claim 9 and its derivative are in flavonoids medicine or flavonoids Application in pharmaceutical composition preparation.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111471005A (en) * 2020-05-21 2020-07-31 南方科技大学 Indole-dihydronaphthalene compound and preparation method and application thereof
CN113845478A (en) * 2020-12-18 2021-12-28 四川大学 Intermediate, preparation method and application thereof
CN113979983A (en) * 2021-11-03 2022-01-28 中国人民解放军空军军医大学 Asymmetric synthesis method of fidarestat key intermediate
CN113979982A (en) * 2021-11-03 2022-01-28 中国人民解放军空军军医大学 Preparation method and application of chiral dihydrochromone-2-carboxylic acid compound and derivative thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102056846A (en) * 2008-03-19 2011-05-11 比亚尔-坡特拉有限公司 Catalytic asymetric hydrogenation
CN103524307A (en) * 2013-10-18 2014-01-22 杭州师范大学 Method for preparing chirality halohydrin in copper-catalyzed asymmetry hydrosilation mode

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102056846A (en) * 2008-03-19 2011-05-11 比亚尔-坡特拉有限公司 Catalytic asymetric hydrogenation
CN103524307A (en) * 2013-10-18 2014-01-22 杭州师范大学 Method for preparing chirality halohydrin in copper-catalyzed asymmetry hydrosilation mode

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AKBAR ALI ET AL: "Stereoselective Synthesis of Thiochroman-4-ones by Ring Transformation of Chiral 5-Ylidene-1,3-dioxan-4-ones with 2-Bromothiophenol via Bromo-Lithium Exchange", 《EUR. J. ORG. CHEM.》 *
BUDDHADEB MONDAL ET AL: "Primary amino acid catalyzed asymmetric intramolecular Mannich reaction for the synthesis of 2-aryl-2,3-dihydro-4-quinolones", 《ORG. BIOMOL. CHEM.》 *
DONGBING ZHAO ET AL: "Ruthenium-NHC-Catalyzed Asymmetric Hydrogenation of Flavones and Chromones: General Access to Enantiomerically Enriched Flavanones,Flavanols,Chromanones, and Chromanols", 《ANGEW. CHEM. INT. ED.》 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111471005A (en) * 2020-05-21 2020-07-31 南方科技大学 Indole-dihydronaphthalene compound and preparation method and application thereof
CN111471005B (en) * 2020-05-21 2023-04-07 南方科技大学 Indole-dihydronaphthalene compound and preparation method and application thereof
CN113845478A (en) * 2020-12-18 2021-12-28 四川大学 Intermediate, preparation method and application thereof
CN113845478B (en) * 2020-12-18 2023-11-21 四川大学 Intermediate, and preparation method and application thereof
CN113979983A (en) * 2021-11-03 2022-01-28 中国人民解放军空军军医大学 Asymmetric synthesis method of fidarestat key intermediate
CN113979982A (en) * 2021-11-03 2022-01-28 中国人民解放军空军军医大学 Preparation method and application of chiral dihydrochromone-2-carboxylic acid compound and derivative thereof
CN113979983B (en) * 2021-11-03 2023-10-03 中国人民解放军空军军医大学 Asymmetric synthesis method of fidarestat key intermediate

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