CN105669546A - Synthesis method of difluoroalkyl substituted pyridone or pyrone - Google Patents

Synthesis method of difluoroalkyl substituted pyridone or pyrone Download PDF

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CN105669546A
CN105669546A CN201610134319.2A CN201610134319A CN105669546A CN 105669546 A CN105669546 A CN 105669546A CN 201610134319 A CN201610134319 A CN 201610134319A CN 105669546 A CN105669546 A CN 105669546A
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贺春阳
李晓飞
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Zunyi Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • 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
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
    • 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
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

The invention discloses a synthesis method of difluoroalkyl substituted pyridone or pyrone under simple conditions.The method specifically comprises the steps that simple pyridine, pyrone and halogenated difluoroalkyl compounds (chloro, bromo and iodo) are used as raw materials, complexes with iridium or ruthenium as cores are used as catalysts, and various kinds of difluoroalkyl substituted pyridone or pyrone are obtained with high efficiency.According to the method, the pyridine, pyrone and halogenated difluoroalkyl compounds (chloro, bromo and iodo) which are easy to obtain are used as the raw materials, and therefore the method has the advantages that the catalyst dosage is small, the substrate application range is wide, operation is easy and convenient, and the reaction efficiency is high.The obtained structure is the important fluorine-containing building blocks at present, and has the wide application prospect in the field of biological medicine.

Description

The pyridone of a kind of fluoroalkyl replacement or the synthetic method of pyranone
Technical field
The present invention relates to organic synthesis field, be specifically related to the pyridone of a kind of fluoroalkyl replacement or the synthetic method of pyranone.
Background technology
Pyridone and pyranone are highly important construction units of class, have very extensive and important application in biological medicine, are one of the mother nucleus structures of most patent medicine potentiality. On the one hand, its stable chemical nature, the site being available for modifying is more.
The special nature that on the other hand, has due to fluorine atom and fluoro-containing group (as: the highly lipophilic etc. of the little atomic radius of fluorine atom, high electronegativity and fluoro-containing group) fluorochemical is received significant attention at field of medicaments. According to statistics, Drugs Containing Fluorine accounts for the ratio of whole medicine more than 20%; But unfortunately, the pyridone and the pyranone synthetic method that replace for fluoroalkyl are extremely limited. Thus significantly constraining the application in new drug development of this kind of new construction. Therefore, the synthetic method exploring a kind of fluoroalkyl substituted pyridinone more efficient, succinct, blanket or pyranone has significant meaning.
Summary of the invention
The invention is intended to the synthetic method of pyridone or the pyranone providing a kind of fluoroalkyl to replace, to solve the defect of pyridone that the synthesis fluoroalkyl that prior art cannot be efficient, succinct replaces or pyranone.
The pyridone of a kind of fluoroalkyl replacement in this programme or the synthetic method of pyranone, comprise the following steps:
In atent solvent, under illumination condition, with the complex containing iridium or ruthenium for photocatalyst, in the presence of a base,
Pyridone and pyranone A, D or F and formula B compound are reacted, thus forming compound C, E or the G that formula fluoroalkyl replaces;
Above-mentioned various in, R1、R2、R3It is each independently H, C1-30Alkyl, halo C1-30Alkyl, C2-30Thiazolinyl, halo C2-30Thiazolinyl, C2-30Alkynyl, the C replaced by halogen or phenyl2-30Alkynyl ,-CONR6R7、-COOC1-30Alkyl, C1-30Alkyl-carbonyl, formoxyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted-C=C-COOC1-30One or more in alkyl; Wherein, R1、R2、R3In replacement to refer to that one or more H in group are selected from the substituent group of lower group replaced: halogen, C1-30Alkyl, C1-20Alkoxyl ,-CONR6R7、-COOC1-20Alkyl, C1-20Alkyl-carbonyl or formoxyl;R1And R2Collectively form benzo base or by one or more R6Replaced benzo base, wherein, R6For selected from the group of lower group: hydrogen, cyano group, halogen, C1-10Alkyl, halo C1-10Alkyl, C2-10Thiazolinyl, halo C2-10Thiazolinyl, C2-10Alkynyl, halo C2-10Alkynyl, C1-10Alkoxyl, halo C1-10Alkoxyl ,-CONR6R7、-COOC1-10Alkyl, C1-10Alkyl-carbonyl, formoxyl, phenyl or by one or more selected from halogen, C1-6Alkyl, C1-6Alkoxyl ,-CONR6R7、-COOC1-10Alkyl, C1-10The replaced phenyl of the group of alkyl-carbonyl or formoxyl ,-C=C-COOC1-10Alkyl;
R4Independently be H, C1-30Alkyl, halo C1-30Alkyl, C2-30Thiazolinyl, halo C2-30Thiazolinyl, C2-30Alkynyl, the C replaced by halogen or phenyl2-30Alkynyl ,-CONR6R7、-COOC1-30Alkyl, C1-30Alkyl-carbonyl, formoxyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted-C=C-COOC1-30In alkyl; Wherein, R4In replacement to refer to that one or more H in group are selected from the substituent group of lower group replaced: halogen, C1-30Alkyl, C1-20Alkoxyl ,-CONR6R7、-COOC1-20Alkyl, C1-20Alkyl-carbonyl or formoxyl;
R5It is each independently H, cyano group, C1-20Alkyl, halo C1-20Alkyl, C2-20Thiazolinyl, halo C2-20Thiazolinyl, C2-20Alkynyl, halo C2-20Alkynyl ,-COOC1-20Alkyl, C1-20Alkyl-carbonyl, substituted or unsubstituted phenyl, C1-20The phosphonate group of alkyl replacement, C1-20The phosphonous acid base that alkyl replaces, substituted or unsubstituted thiophene, substituted or unsubstituted furan;
X is Cl, Br or I.
In another preference, described pyridone and pyranone A, D or F compound, photocatalyst, alkali, formula B compound mol ratio be 1-8:0.001-1:0.1-8:1-8.
In another preference, the just visible ray that described reaction is selected, it is mainly blue light or green glow.
In another preference, described photocatalyst is selected from: Ir (PPy)3、Ru(bpy)3PF6、Ru(bpy)3Cl2·6H2O or Ir (PPy)2(dtbbpy)PF6。
In another preference, described alkali is selected from: carbonate, carboxylate, phosphate, phosphite, villiaumite and organic amine its one or more.
In another preference, described atent solvent is selected from: N-Methyl pyrrolidone, DMF, dimethyl sulfoxide, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2-pyrimidones, Isosorbide-5-Nitrae-dioxane, N,N-dimethylacetamide one or its combination.
The present inventor is by research deep for a long time, it is found that the synthetic method of pyridone that a kind of fluoroalkyl replaces or pyranone, in atent solvent, under blue light or green glow irradiate, with containing iridium, ruthenium complex for photocatalyst, in the presence of a base, pyridone/pyranone and formula B compound are reacted, thus forming the pyridone of formula fluoroalkyl replacement or the short-cut method of pyranone. The method has that raw material is simple, is easy to get, and catalyst amount is few, wide application range of substrates, easy and simple to handle, reaction efficiency advantages of higher. On this basis, inventor completes the present invention.
Beneficial effects of the present invention: the method reactions steps of (1) present invention is short, and raw material and reagent are simple and easy to get, it is not necessary to process through pre-activate, adopts the light being widely present in nature as energy source, and reaction is green succinct.
(2), in the method for the present invention, catalyst amount few (a large amount of preparations can lower than 5/1000ths), wide application range of substrates (halogen for existing in pyridone and pyranone can well be compatible) reaction efficiency is high.
(3) pyridone of the fluoroalkyl replacement that the present invention prepares or pyranone, the structure of gained is more current important fluoro-building blocks, has bigger application prospect at biomedicine field.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus constituting new or preferred technical scheme. As space is limited, tired no longer one by one state at this.
As used herein, term " C1-30Alkyl " refer to the straight or branched alkyl with 1-30 carbon atom, for instance methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, hexyl, heptyl, octyl group, nonyl, decyl or similar group.
Term " C2-30Thiazolinyl " refer to the thiazolinyl with the straight or branched of 2-30 carbon atom, for instance vinyl, pi-allyl, 1-acrylic, isopropenyl, 1-butylene base, crotyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decene base or similar group.
Term " C2-30Alkynyl " refer to the alkynyl of the straight or branched with 2-30 carbon atom, for instance acetenyl, propinyl, butynyl, pentynyl, hexin base, heptyne base, octynyl, n-heptylacetylene base, decynyl or similar group.
Term " C1-30Alkoxyl " refer to the straight or branched alkoxyl with 1-30 carbon atom, for instance methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or similar group.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " halo " refers to that the H in group is replaced by identical or different one or more halogen atoms, for instance trifluoromethyl, pentafluoroethyl group, trifluoromethoxy, difluoroethylene base or similar group.
Term " C1-30Alkyl-carbonyl " refer to C1-30Alkyl-(C=O)-.
Term " benzheterocycle base " refers to the two or more rings containing phenyl ring condensed ring together, including 5 yuan of heterocycles of benzo, 6 yuan of heterocycles of benzo, or three ring benzheterocycle bases of 5 yuan of heterocycle-phenyl ring-5 yuan heterocycles or 5 yuan of heterocycle--6 yuan of heterocycles of phenyl ring, it is preferably 5 yuan of heterocycles of benzo or 5 yuan of heterocycle-phenyl ring-5 yuan heterocycles, for instance three rings of benzothiophene ring, benzopyrrole ring, benzofuran ring, thiophene-phenyl ring-thiophene composition.
" fluoro benzheterocycle-Heteroaryl ring structures " as herein described, " derivant of fluoro benzheterocycle-hetero-aromatic ring ", " fluoro benzheterocycle-hetero-aromatic ring building block ", " fluoro benzheterocycle-assorted aromatic hydrocarbons building block compound " or " fluoro benzheterocycle-assorted aromatic hydrocarbons building block ", it is used interchangeably, refers both to the compound as shown in formula C.
Detailed description of the invention
The invention provides the synthetic method of the pyridone of a kind of fluoroalkyl replacement or pyranone. Preferably, described method includes step: in atent solvent, under the irradiation of blue light or green glow, with containing iridium, the complex of ruthenium is photocatalyst, by formula pyridone/pyranone (i.e. A, D or F) and formula B compound) react a period of time (such as 1-36 hour) thus forming pyridone or the pyranone (compound C, E or G) that formula fluoroalkyl replaces;
In various, R1、R2、R3、R4、R5, X defined as described above.
It is highly preferred that described formula A, E, F compound is the compound selected from lower group:
Wherein, described formula B compound is preferably selected from the compound of lower group:
ClCF2R5、BrCF2R5、ICF2R5。
In various, R4As mentioned above.
It is highly preferred that described formula B compound is the compound selected from lower group:
ClCF2COOEt、BrCF2COOEt、ICF2COOEt、ClCF2CON(Et)2、BrCF2CON(Et)2、ICF2CON(Et)2、BrCF2Ar、BrCF2P(O)(OEt)2、ICF2Ar、ICF2P(O)(OEt)2、ClCF2Ar、BrCF2P(O)(OEt)2、ClCF2P(O)(OEt)2Or ICF2P(O)(OEt)2。
Formula A, D, F and formula B compound can be prepared by the method known by commercially available or those skilled in the art of the invention.But the actual conditions of the method, for instance reactant, solvent, the amount of compound used therefor, reaction temperature, reaction required time etc. are not limited to explanation below.
Photocatalyst well-known to those skilled in the art, Ir (PPy) can be selected as photocatalyst3、Ru(bpy)3PF6、Ru(bpy)3Cl2·6H2O、Ir(PPy)2(dtbbpy)PF6, wherein, Ru (bpy)3PF6Formal name used at school be three (2,2'-bipyridyl) ruthenium two (hexafluorophosphoric acid) salt, Ru (bpy)3Cl2·6H2The formal name used at school of O is Tris(2,2'-bipyridyl) ruthenium (II) chloride hexahydrate.
In this reaction system, the molar percentage of the photocatalyst used is the 0.1%-100% of formula A compound mole, it is preferred to 0.5-2%.
Alkali of the present invention includes: carbonate, phosphate, acetate, phosphite, villiaumite or organic amine salt.
Described atent solvent includes the solvent being selected from lower group: N-Methyl pyrrolidone (NMP), N, dinethylformamide, dimethyl sulfoxide, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2-pyrimidone (DMPU), Isosorbide-5-Nitrae-dioxane, N,N-dimethylacetamide or its combination. Preferably, dimethyl sulfoxide is adopted.
In described reaction system, the reaction density of formula A compound or formula B compound is 0.01～1mmol/mL; Preferably, it is 0.1～0.5mmol/mL.
Formula C, E, the G compound that as required present invention can be prepared carries out further modifying thus preparing all kinds of potential bioactive molecule, provides basis for new drug development.
The product that preparation method of the present invention prepares can be easily separated purification by multiple method, and described method includes: recrystallization, thin layer chromatography, column chromatography etc. Above purification process is the conventional method of this area, for instance, when carrying out recrystallization, the mixed solvent of polar solvent and non-polar solven can be adopted, it is preferred to ethyl acetate-light petrol, the mixed solvent such as ethanol-petroleum ether. When using thin layer chromatography and column chromatography, the solvent that developing solvent used can be single, it is possible to adopt mixed solvent, for instance the mixed solvent etc. of petroleum ether or ethyl acetate-light petrol.
The features described above that the present invention mentions, or the feature that embodiment is mentioned can be in any combination. The disclosed all features of this case description can with any composition forms use, each feature disclosed in description, it is possible to identical by any offer, impartial or similar purpose alternative characteristics replaces. Therefore except having special instruction, disclosed feature to be only impartial or similar features general example.
Below in conjunction with being embodied as, the present invention is expanded on further. Should be understood that these embodiments are merely to illustrate the present invention rather than restriction the scope of the present invention. The experimental technique of unreceipted actual conditions in the following example, generally conventionally condition, or according to manufacturer it is proposed that condition. Unless otherwise indicated, otherwise percentage ratio and number are calculated by weight.
The post-processing approach all adopting this area conventional in following example is purified.
Embodiment 1
In the reaction tube of 25mL, add 1.3mg (0.5mol%) Ir (PPy)3, K2HPO4(0.8mmol), compound A-1 (0.4mmol, 1 equivalent), nitrogen adds 3mL dimethyl sulfoxide (DMSO) after replacing three times, inject 100 μ L (0.80mmol) compound B-1, after stirring 24 hours under blue light illumination, obtaining compound C-1. productivity is 84%.
1HNMR(400MHz,CDCl3) δ 8.11 (s, 1H), 7.64 (t, J=7.2Hz, 2H), 7.37 (d, J=8.8Hz, 1H), 7.29 (t, J=7.4Hz, 1H), 4.37 (q, J=7.2Hz, 2H), 3.67 (s, 3H), 1.33 (t, J=7.2Hz, 3H).19FNMR(376MHz,CDCl3)δ-109.5(s,2F).13C-NMR(100MHz,CDCl3) δ 163.1 (t, J=32.6Hz), 159.2 (t, J=4.4Hz), (140.2,137.3 t, J=7.1Hz), 132.3,130.0,124.7 (t, J=24.1Hz), 122.8,118.7, (114.2,111.2 t, J=247.6Hz), 62.9,29.2,13.8.
Embodiment 2
In the reaction tube of 25mL, add 1.3mg (0.5mol%) Ir (PPy)3, K2HPO4(0.8mmol), compound A-1 (0.4mmol, 1 equivalent), nitrogen adds 3mL dimethyl sulfoxide (DMSO) after replacing three times, inject 100 μ L (0.80mmol) compound B-1, after stirring 24 hours under green glow irradiates, obtaining compound C-1. productivity is 50%.
Embodiment 3
In the reaction tube of 25mL, add 1.3mg (0.5mol%) Ir (PPy)3, Na2CO3(0.8mmol), compound A-1 (0.4mmol, 1 equivalent), nitrogen adds 3mL dimethyl sulfoxide (DMSO) after replacing three times, inject 100 μ L (0.80mmol) compound B-1, after stirring 24 hours under blue light illumination, obtaining compound C-1. productivity is 66%.
Embodiment 4
In the reaction tube of 25mL, add 1.3mg (0.5mol%) Ir (PPy)3, K2CO3(0.8mmol), compound A-1 (0.4mmol, 1 equivalent), nitrogen adds 3mL dimethyl sulfoxide (DMSO) after replacing three times, inject 100 μ L (0.80mmol) compound B-1, after stirring 24 hours under blue light illumination, obtaining compound C-1. productivity is 55%.
Embodiment 5
In the reaction tube of 25mL, add 1.3mg (0.5mol%) Ir (PPy)3, K2CO3(0.8mmol), compound A-1 (0.4mmol, 1 equivalent), nitrogen adds 3mLN after replacing three times, dinethylformamide (DMF), injecting 100 μ L (0.80mmol) compound B-1, after stirring 24 hours under blue light illumination, obtaining compound C-1. productivity is 38%.
Embodiment 6
In the reaction tube of 25mL, add 0.65mg (0.5mol%) Ir (PPy)3, K2HPO4(0.4mmol), compound A-2 (0.2mmol, 1 equivalent), nitrogen adds 3mL dimethyl sulfoxide (DMSO) after replacing three times, inject 100 μ L (0.40mmol) compound B-1, after stirring 24 hours under blue light illumination, obtaining compound C-2. productivity is 75%. The further derivatization of this compound, it is possible to serve as novel fluorescent labeling reagent.
1HNMR(400MHz,d6-acetone) δ 11.30 (s, 1H), 8.39 (s, 1H), 7.84 (d, J=8.8Hz, 1H), 7.67 (d, J=1.6Hz, 1H), 7.47 (dd, J=8.6Hz, 1.8Hz, 1H), 4.32 (q, J=7.1Hz, 2H), 1.26 (t, J=7.1Hz, 3H).19FNMR(376MHz,d6-acetone)δ-106.0(s,2F).13CNMR(100MHz,d6-acetone) δ 163.2 (t, J=32.7Hz), 160.0 (t, J=4.3Hz), 141.4,138.9 (t, J=7.2Hz), 132.0,126.88, (126.86,126.7 t, J=23.7Hz), 118.9,118.0,112.2 (t, J=246.0Hz), 63.5,14.1.
Embodiment 7
In the reaction tube of 25mL, add 1.3mg (0.5mol%) Ir (PPy)3, K2HPO4(0.8mmol), compound A-3 (0.4mmol, 1 equivalent), nitrogen adds 3mL dimethyl sulfoxide (DMSO) after replacing three times, inject 100 μ L (0.80mmol) compound B-1, after stirring 24 hours under blue light illumination, obtaining compound C-3. productivity is 60%.
1HNMR(400MHz,CDCl3) δ 7.75 (d, J=7.2Hz, 1H), 7.46 (d, J=6.4Hz, 1H), 6.28 (t, J=6.8Hz, 1H), 4.33 (q, J=7.2Hz, 2H), 3.53 (s, 3H), 1.31 (t, J=7.2Hz, 3H).19FNMR(376MHz,CDCl3)δ-106.5。
Embodiment 8
In the reaction tube of 25mL, add 2.6mg (1mol%) Ir (PPy)3, K2HPO4(0.8mmol), compound A-3 (0.4mmol, 1 equivalent), nitrogen adds 3mL dimethyl sulfoxide (DMSO) after replacing three times, inject 100 μ L (0.80mmol) compound B-1, after stirring 24 hours under blue light illumination, obtaining compound C-3. productivity is 42%.
Embodiment 9
In the reaction tube of 25mL, add 2.6mg (1mol%) Ir (PPy)3, K2HPO4(0.8mmol), compound A-3 (0.4mmol, 1 equivalent), nitrogen adds 3mL dimethyl sulfoxide (DMSO) after replacing three times, inject 100 μ L (0.80mmol) compound B-1, after stirring 24 hours under blue light illumination, obtaining compound C-3. productivity is 36%.
1HNMR(400MHz,CDCl3)δ8.23(s,1H),4.37(m,4H),1.34(m,6H).19FNMR(376MHz,CDCl3) δ-62.8 (t, J=10.5Hz, 3F) ,-98.2 (q, J=10.5Hz, 2F) ,-106.4 (s, 2F).
Embodiment 10
In the reaction tube of 25mL, add 2.6mg (1mol%) Ir (PPy)3, K2HPO4(0.8mmol), compound D-1 (0.4mmol, 1 equivalent), nitrogen adds 3mL dimethyl sulfoxide (DMSO) after replacing three times, inject 100 μ L (0.80mmol) compound B-1, after stirring 24 hours under blue light illumination, obtaining compound E-1. productivity is 40%.
Embodiment 11
In the reaction tube of 25mL, add 2.6mg (1mol%) Ir (PPy)3, K2HPO4(0.8mmol), compound D-2 (0.4mmol, 1 equivalent), nitrogen adds 3mL dimethyl sulfoxide (DMSO) after replacing three times, inject 100 μ L (0.80mmol) compound B-1, after stirring 24 hours under blue light illumination, obtaining compound E-2. productivity is 36%.
Embodiment 12
In the reaction tube of 25mL, add 1.3mg (0.5mol%) Ir (PPy)3, K2HPO4(0.4mmol), compound F-1 (0.2mmol, 1 equivalent), nitrogen adds 3mL dimethyl sulfoxide (DMSO) after replacing three times, inject 100 μ L (0.40mmol) compound B-1, after stirring 24 hours under blue light illumination, obtaining compound G-1. productivity is 64%. This compound has II phase metabolic enzyme inducing action.
1HNMR(400MHz,CDCl3) δ 8.17 (s, 1H), 7.68-7.60 (m, 2H), 7.42-7.34 (m, 2H), 4.38 (q, J=7.0Hz, 2H), 1.34 (t, J=7.0Hz, 3H).19FNMR(376MHz,CDCl3)δ-106.2(s,2F).13CNMR (100MHz,CDCl3) δ 162.2 (t, J=32.6Hz), 158.0 (t, J=4.1Hz), 154.2,141.9 (t, J=7.0Hz), 133.7,129.2, (125.2,121.1 t, J=25.4Hz), 117.4,117.0,110.4 (t, J=249.5Hz), 63.6,13.8.
Embodiment 13
In the reaction tube of 25mL, add 1.3mg (0.5mol%) Ir (PPy)3, K2HPO4(0.4mmol), compound F-2 (0.2mmol, 1 equivalent), nitrogen adds 3mL dimethyl sulfoxide (DMSO) after replacing three times, inject 100 μ L (0.40mmol) compound B-1, after stirring 24 hours under blue light illumination, obtaining compound G-2. productivity is 45%. This compound has II phase metabolic enzyme inducing action.
1HNMR(400MHz,CDCl3) δ 8.12 (s, 1H), 7.46 (d, J=8.2Hz, 1H), 7.41 (s, 1H), 7.27 (d, J=8.2Hz, 1H), 4,39 (q, J=7.2Hz, 2H), 2.44 (s, 3H), 1.35 (t, J=7.2Hz, 3H).19FNMR(376MHz,CDCl3)δ-106.1(s,2F).13CNMR(100MHz,CDCl3) δ 162.2 (t, J=32.6Hz), 158.2 (t, J=4.5Hz), (152.3,141.9 t, J=6.8Hz), 135.0,134.7,128.9, (120.8 t, J=25.4Hz), 117.2, (116.6,110.5 t, J=249.2Hz), 63.5,20.7,13.8.
The all documents mentioned in the present invention are incorporated as reference all in this application, are individually recited as reference such just as each section of document. In addition, it is to be understood that after the above-mentioned teachings having read the present invention, the present invention can be made various changes or modifications by those skilled in the art, these equivalent form of values fall within the application appended claims limited range equally.

Claims (6)

1. a fluoroalkyl replaces pyridone or the synthetic method of pyranone, it is characterized in that, comprise the following steps: in atent solvent, under illumination condition, with containing iridium or/and the complex of ruthenium is for photocatalyst, in the presence of a base, by pyridone and pyranone A, D or F and formula B compound react, thus forming compound C, E or G that formula fluoroalkyl replaces;
Above-mentioned various in, R1、R2、R3It is each independently H, C1-30Alkyl, halo C1-30Alkyl, C2-30Thiazolinyl, halo C2-30Thiazolinyl, C2-30Alkynyl, the C replaced by halogen or phenyl2-30Alkynyl ,-CONR6R7、-COOC1-30Alkyl, C1-30Alkyl-carbonyl, formoxyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted-C=C-COOC1-30One or more in alkyl;Wherein, R1、R2、R3In replacement to refer to that one or more H in group are selected from the substituent group of lower group replaced: halogen, C1-30Alkyl, C1-20Alkoxyl ,-CONR6R7、-COOC1-20Alkyl, C1-20Alkyl-carbonyl or formoxyl; R1And R2Collectively form benzo base or by one or more R6Replaced benzo base, wherein, R6For selected from the group of lower group: hydrogen, cyano group, halogen, C1-10Alkyl, halo C1-10Alkyl, C2-10Thiazolinyl, halo C2-10Thiazolinyl, C2-10Alkynyl, halo C2-10Alkynyl, C1-10Alkoxyl, halo C1-10Alkoxyl ,-CONR6R7、-COOC1-10Alkyl, C1-10Alkyl-carbonyl, formoxyl, phenyl or by one or more selected from halogen, C1-6Alkyl, C1-6Alkoxyl ,-CONR6R7、-COOC1-10Alkyl, C1-10The replaced phenyl of the group of alkyl-carbonyl or formoxyl ,-C=C-COOC1-10Alkyl;
R4Independently be H, C1-30Alkyl, halo C1-30Alkyl, C2-30Thiazolinyl, halo C2-30Thiazolinyl, C2-30Alkynyl, the C replaced by halogen or phenyl2-30Alkynyl ,-CONR6R7、-COOC1-30Alkyl, C1-30Alkyl-carbonyl, formoxyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted-C=C-COOC1-30In alkyl; Wherein, R4In replacement to refer to that one or more H in group are selected from the substituent group of lower group replaced: halogen, C1-30Alkyl, C1-20Alkoxyl ,-CONR6R7、-COOC1-20Alkyl, C1-20Alkyl-carbonyl or formoxyl;
R5It is each independently H, cyano group, C1-20Alkyl, halo C1-20Alkyl, C2-20Thiazolinyl, halo C2-20Thiazolinyl, C2-20Alkynyl, halo C2-20Alkynyl ,-COOC1-20Alkyl, C1-20Alkyl-carbonyl, substituted or unsubstituted phenyl, C1-20The phosphonate group of alkyl replacement, C1-20The phosphonous acid base that alkyl replaces, substituted or unsubstituted thiophene, substituted or unsubstituted furan;
X is Cl, Br or I.
2. fluoroalkyl according to claim 1 replaces pyridone or the synthetic method of pyranone, it is characterized in that: described pyridone and pyranone A, D or F compound, photocatalyst, alkali, formula B compound mol ratio be 1～8:0.001～1:0.1～8:1～8.
3. fluoroalkyl according to Claims 2 or 3 replaces pyridone or the synthetic method of pyranone, it is characterised in that: the just visible ray that described reaction is selected.
4. fluoroalkyl according to Claims 2 or 3 replaces pyridone or the synthetic method of pyranone, it is characterised in that: described photocatalyst is selected from: Ir (PPy)3、Ru(bpy)3PF6、Ru(bpy)3Cl2·6H2O or Ir (PPy)2(dtbbpy)PF6。
5. fluoroalkyl according to Claims 2 or 3 replaces pyridone or the synthetic method of pyranone, it is characterised in that: described alkali is selected from: carbonate, carboxylate, phosphate, phosphite, villiaumite and organic amine its one or more.
6. fluoroalkyl according to Claims 2 or 3 replaces pyridone or the synthetic method of pyranone, it is characterized in that: described atent solvent is selected from: N-Methyl pyrrolidone, N, dinethylformamide, dimethyl sulfoxide, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2-pyrimidones, 1,4-dioxane, N,N-dimethylacetamide one or its combination.
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CN107445795A (en) * 2017-08-14 2017-12-08 遵义医学院 A kind of synthetic method of the aryl building block of the fluoro ethyl of 2 bromine 1,1,2,2 four substitution
CN107445795B (en) * 2017-08-14 2020-09-18 遵义医科大学 Synthesis method of 2-bromo-1, 1, 2, 2-tetrafluoroethyl substituted aryl building block
CN108484508A (en) * 2018-06-15 2018-09-04 遵义医学院 A kind of synthetic method of 5- trifluoromethyl uracils
CN108484508B (en) * 2018-06-15 2019-07-23 遵义医科大学 A kind of synthetic method of 5- trifluoromethyl uracil
CN110156550A (en) * 2019-06-17 2019-08-23 遵义医科大学 A method of fluoroalkylation is carried out using phenol and its derivatives for photochemical catalyst
CN111925320A (en) * 2020-08-12 2020-11-13 武汉大学 Method for efficiently synthesizing polysubstituted 2-pyridone compound
CN112574056A (en) * 2020-12-28 2021-03-30 浙江工业大学 Synthetic method of alpha, alpha-difluoro-gamma-hydroxyacetamide derivative
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof

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