CN117820221A - Process for preparing difluoromethylated 2, 4-quinolinedione derivatives - Google Patents
Process for preparing difluoromethylated 2, 4-quinolinedione derivatives Download PDFInfo
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- YZMVLKJJJCMVGX-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline-2,4-dione Chemical class C1=CC=C2NC(=O)CC(=O)C2=C1 YZMVLKJJJCMVGX-UHFFFAOYSA-N 0.000 title claims description 39
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical compound OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 claims abstract description 18
- DORMTBIPKNPJPY-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.IC1=CC=CC=C1 DORMTBIPKNPJPY-UHFFFAOYSA-N 0.000 claims abstract description 17
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 239000011261 inert gas Substances 0.000 claims abstract description 10
- 239000012298 atmosphere Substances 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 238000010898 silica gel chromatography Methods 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 230000011987 methylation Effects 0.000 claims description 4
- 238000007069 methylation reaction Methods 0.000 claims description 4
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 238000007872 degassing Methods 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- -1 difluoro methylated 2, 4-quinolinedione derivatives Chemical class 0.000 abstract description 13
- 239000002904 solvent Substances 0.000 abstract description 6
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 abstract description 5
- 239000007800 oxidant agent Substances 0.000 abstract description 5
- 230000001590 oxidative effect Effects 0.000 abstract description 5
- 239000003504 photosensitizing agent Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 238000005286 illumination Methods 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- VXPGKSAYOBZMSX-UHFFFAOYSA-N 1,3-dioxane;1,3-dioxolane Chemical compound C1COCO1.C1COCOC1 VXPGKSAYOBZMSX-UHFFFAOYSA-N 0.000 description 3
- FZTLLUYFWAOGGB-UHFFFAOYSA-N 1,4-dioxane dioxane Chemical compound C1COCCO1.C1COCCO1 FZTLLUYFWAOGGB-UHFFFAOYSA-N 0.000 description 3
- 230000001678 irradiating effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- PMWGIVRHUIAIII-UHFFFAOYSA-N 2,2-difluoropropanoic acid Chemical compound CC(F)(F)C(O)=O PMWGIVRHUIAIII-UHFFFAOYSA-N 0.000 description 1
- YRQNSTAWTLXCEZ-UHFFFAOYSA-N 2-(difluoromethylsulfonyl)pyridine Chemical compound FC(F)S(=O)(=O)C1=CC=CC=N1 YRQNSTAWTLXCEZ-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000000852 hydrogen donor Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
Abstract
The invention discloses a preparation method of difluoro methylated 2, 4-quinolinedione derivatives, which is characterized in that difluoro acetic acid, iodobenzene acetate and N-o-cyano aryl acrylamide compounds are used as reaction raw materials in an organic solvent, inert gas atmosphere and visible light irradiation are adopted, and stirring reaction is carried out at room temperature to obtain the difluoro methylated 2, 4-quinolinedione derivatives. The invention relates to a method for preparing difluoro methylated 2, 4-quinolinedione derivatives, which is mainly based on a reaction system promoted by visible light without a photosensitizer, uses commercial difluoro acetic acid as a difluoro methyl source, uses commercial iodobenzene acetate as an oxidant, and can realize the synthesis of a target product by irradiation of visible light under the conditions of an organic solvent, inert gas and room temperature. The synthesis method used by the invention does not need external photosensitizer or metal participation, and the reaction can only occur by illumination in the green solvent of 2-methyltetrahydrofuran, so that the technical scheme of the invention is more economical.
Description
Technical Field
The invention relates to the technical field of compound synthesis. More particularly, the present invention relates to a process for the preparation of difluoromethylated 2, 4-quinolinedione derivatives.
Background
As an important heterocyclic compound, 2, 4-quinolinedione derivatives play an important role in the fields of pharmaceutical chemistry, material chemistry and the like, and research on construction strategies thereof has been one of hot subjects of study by researchers. Difluoromethyl is an isostere of thiol, hydroxamic acid, amide and other structures, is also a lipophilic hydrogen donor, and has special physicochemical properties, so that the difluoromethyl is widely applied in the field of pharmaceutical chemistry. The difluoromethyl is introduced into the molecule while the 2, 4-quinoline dione skeleton is synthesized by developing a strategy with high efficiency and mild, so that a series of difluoromethylated 2, 4-quinoline dione derivatives with potential application value can be constructed.
Through literature studies, the preparation method of the difluoromethylated 2, 4-quinolinedione derivative is less researched. In 2019, university of national institute of middle and south Liu Jikai teaches that the subject group uses difluoromethyl (2-pyridyl) sulfone as a difluoromethyl radical precursor, noble metal fac-Ir (ppy) 3 As photosensitizers, a series of difluoromethylated 2, 4-quinolinedione derivatives (Organic) were prepared in moderate yields under irradiation with visible light&Biomolecular Chemistry,2019,17,6629-6638). In recent years, development of a light sensitizer-free photocatalytic system provides a greener and milder synthetic idea for organic synthesis.
Disclosure of Invention
The invention aims to develop a preparation method for synthesizing a difluoromethylated 2, 4-quinolinedione derivative without metal participation based on a photosensitizer-free visible light catalytic system, wherein the method can realize one-step construction of two C-C bonds without adding other catalysts by only irradiating visible light in a green solvent of 2-methyltetrahydrofuran, and simultaneously realize difluoromethylation acylation reaction of olefin to synthesize a series of difluoromethylated 2, 4-quinolinedione derivatives.
In order to achieve these objects and other advantages and in accordance with the purpose of the invention, there is provided a process for preparing a difluoromethylated 2, 4-quinolinedione derivative, wherein in an organic solvent, difluoroacetic acid, iodobenzene acetate, N-o-cyanoaryl acrylamide compound is used as a reaction raw material, and the process comprises the steps of irradiating with an inert gas atmosphere and a visible light, and stirring at room temperature to react; the reaction formula is as follows:
wherein R is 1 Represents any one of a hydrogen group, a methyl group, a halogenated group and a phenyl group attached to a benzene ring; r is R 2 Represents one of substituents such as methyl and benzyl; r is R 3 Represents one of substituents such as methyl, benzyl, aryl, ester, sulfinyl, etc.
PreferablyThe preparation method of the difluoromethylated 2, 4-quinolinedione derivative is preferable, and the organic solvent is Tetrahydrofuran (THF) or acetonitrile (CH 3 CN), 1,4-dioxane (1, 4-dioxane), 1,3-dioxolane (1, 3-dioxane), 2-methyltetrahydrofuran (2-MeTHF), dichloromethane (DCM), dimethyl sulfoxide (DMSO), or N, N-Dimethylformamide (DMF).
Preferably, in the preparation method of the difluoromethylated 2, 4-quinolindione derivative, the irradiation condition of visible light is specifically blue light LED lamp irradiation.
Preferably, in the preparation method of the difluoromethylated 2, 4-quinolinedione derivative, the feeding ratio of the N-o-cyano aryl acrylamide compound to the difluoroacetic acid is 1:8.
Preferably, in the preparation method of the difluoromethylated 2, 4-quinolinedione derivative, the feeding ratio of the N-o-cyano aryl acrylamide compound to the iodobenzene acetate is 1:8.
Preferably, the preparation method of the difluoromethylated 2, 4-quinolinedione derivative specifically comprises the following steps: sequentially adding N-o-cyano aryl acrylamide compounds, difluoroacetic acid and iodobenzene acetate into an organic solvent in a reaction tube, degassing, placing the mixture under the irradiation of visible light in an inert gas atmosphere at room temperature, stirring and reacting for 48 hours, concentrating the mixture by a rotary evaporator, and separating the mixture by silica gel column chromatography to obtain the difluoromethylated 2, 4-quinolinedione derivative.
Preferably, in the preparation method of the difluoromethylated 2, 4-quinolinedione derivative, an eluent of an ethyl acetate-petroleum ether system is adopted in the silica gel column chromatographic separation process.
The invention at least comprises the following beneficial effects:
the invention discloses a preparation method of difluoro methylated 2, 4-quinolinedione derivatives, which takes difluoro acetic acid, iodobenzene acetate and N-o-cyano aryl acrylamide compounds as reaction raw materials, and can be constructed in one step by using visible light irradiation in a green organic solvent 2-methyltetrahydrofuran without adding other catalysts, and simultaneously realizes difluoro methylation acylation reaction of olefins to synthesize a series of difluoro methylated 2, 4-quinolinedione derivatives. Compared with the existing method for preparing the difluoromethylated 2, 4-quinolinedione derivative, the synthesis method used by the invention does not need external photosensitizer or metal, and the reaction can be carried out only by illumination in the green solvent 2-methyltetrahydrofuran, so that the technical scheme of the invention is more economical.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Detailed Description
The present invention is described in further detail below with reference to examples to enable those skilled in the art to practice the same by referring to the description.
It should be noted that the experimental methods described in the following embodiments, unless otherwise specified, are all conventional methods, and the reagents and materials, unless otherwise specified, are all commercially available;
the N-o-cyano aryl acrylamide compound which is the reaction raw material required to be used in the technology of the invention is synthesized according to the method reported in the literature (Organic & Biomolecular Chemistry,2015,13,5376-5380). The specific synthetic route is as follows:
the preparation method of the difluoro methylation 2, 4-quinoline dione derivative comprises the steps of taking difluoro acetic acid, iodobenzene acetate and N-o-cyano aryl acrylamide compounds as reaction raw materials in an organic solvent, and stirring and reacting the materials at room temperature under the inert gas atmosphere and the irradiation of visible light; the reaction formula is as follows:
wherein R is 1 Represents any one of a hydrogen group, a methyl group, a halogenated group and a phenyl group attached to a benzene ring; r is R 2 Represents methyl group,One of substituents such as benzyl; r is R 3 Represents one of substituents such as methyl, benzyl, aryl, ester, sulfinyl, etc.
In another technical scheme, the preparation method of the difluoromethylated 2, 4-quinolinedione derivative is characterized in that the inert gas is argon.
In another technical scheme, the preparation method of the difluoromethylated 2, 4-quinolinedione derivative comprises the steps of preparing Tetrahydrofuran (THF) and acetonitrile (CH) 3 CN), 1,4-dioxane (1, 4-dioxane), 1,3-dioxolane (1, 3-dioxane), 2-methyltetrahydrofuran (2-MeTHF), dichloromethane (DCM), dimethyl sulfoxide (DMSO), or N, N-Dimethylformamide (DMF).
In another technical scheme, the preparation method of the difluoromethylated 2, 4-quinolindione derivative comprises the step of irradiating visible light under the condition of blue light LED lamp.
In another technical scheme, the preparation method of the difluoromethylated 2, 4-quinolinedione derivative comprises the step of adding the N-o-cyano aryl acrylamide compound and the difluoroacetic acid in a feed ratio of 1:8.
In another technical scheme, the preparation method of the difluoromethylated 2, 4-quinolinedione derivative comprises the step of mixing the N-o-cyano aryl acrylamide compound with iodobenzene acetate in a feeding ratio of 1:8.
In another technical scheme, the preparation method of the difluoromethylated 2, 4-quinolinedione derivative specifically comprises the following steps: sequentially adding N-o-cyano aryl acrylamide compounds, difluoroacetic acid and iodobenzene acetate into an organic solvent in a reaction tube, degassing, placing the mixture under the irradiation of visible light in an inert gas atmosphere at room temperature, stirring and reacting for 48 hours, concentrating the mixture by a rotary evaporator, and separating the mixture by silica gel column chromatography to obtain the difluoromethylated 2, 4-quinolinedione derivative.
In another technical scheme, the preparation method of the difluoromethylated 2, 4-quinolinedione derivative adopts an eluent of an ethyl acetate-petroleum ether system in the silica gel column chromatographic separation process.
The invention relates to a method for preparing difluoro methylated 2, 4-quinolinedione derivatives, which is mainly based on a free radical reaction system promoted by visible light without a photosensitizer, uses commercial difluoro acetic acid as a difluoromethyl source, uses the N-o-cyano aryl acrylamide compound as a reaction raw material synthesized according to a literature method to react with the commercial difluoro methylacetic acid, uses commercial iodobenzene acetate as an oxidant, uses 2-methyltetrahydrofuran as a solvent, and can realize the synthesis of a target product by irradiation of blue light under argon atmosphere and room temperature.
1. Screening of reaction conditions (solvent, raw materials, amount of oxidant)
In the early condition screening research work, the invention selects N- (2-cyanophenyl) -N-methyl methacrylamide as a template substrate, and uses different solvents including Tetrahydrofuran (THF) and acetonitrile (CH) 3 CN), 1,4-dioxane (1, 4-dioxane), 1,3-dioxolane (1, 3-dioxane), 2-methyltetrahydrofuran (2-MeTHF), dichloromethane (DCM), dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), and the amounts of difluoroacetic acid and iodobenzene acetate (x is the equivalent ratio of difluoroacetic acid to N-methyl-N-o-cyanophenyl acrylamide, y is the equivalent ratio of iodobenzene acetate oxidant to N-methyl-N-o-cyanophenyl acrylamide) were selected, and the optimization conditions were designed as shown in table 1.
TABLE 1 optimization Condition design
Remarks: b, product Yield (Yield).
As shown in Table 1, 2-methyltetrahydrofuran is selected as an organic solvent, the equivalent ratio of difluoroacetic acid to N-methyl-N-o-cyanophenyl acrylamide is 8, the equivalent ratio of oxidant to N-o-cyanoaryl acrylamide is 8, and the yield of the corresponding product difluoromethylated 2, 4-quinolinedione derivative can be up to 88%.
The optimal conditions for the reaction obtained by the invention are as follows: 0.2mmol of N-o-cyano aryl acrylamide compound, 1.6mmol of difluoroacetic acid and 1.6mmol of iodobenzene acetate are dissolved in 2mL of 2-methyltetrahydrofuran, and are placed under the condition of room temperature and inert (argon) atmosphere for irradiation of a blue LED lamp, and stirred for reaction for 48h.
Under the optimal conditions selected, the preparation method of the difluoro methylated 2, 4-quinolinedione derivative comprises the following specific steps:
n-o-cyano aryl acrylamide compound (0.2 mmol), difluoroacetic acid (1.6 mmol), iodobenzene acetate (1.6 mmol) and 2-methyltetrahydrofuran (2 mL) are sequentially added into a 10mL reaction tube, the tube is vacuumized to remove air, then the tube is placed in argon atmosphere, and the tube is placed under the irradiation of a blue light LED lamp for stirring reaction at room temperature. Then, after 48 hours, the reaction was monitored to be complete by TLC, concentrated directly by rotary evaporator, followed by separation by silica gel column chromatography (ethyl acetate-petroleum ether system) to obtain the objective product.
2. Substrate expansion
Under the optimal condition of screening, preparing corresponding compounds according to the method and the reaction formula; 3- (2, 2-difluoromethyl) -1, 3-dimethylquinoline-2, 4 (1H, 3H) -dione (N- (2-cyanophenyl) -N-methyl methacrylamide as the corresponding raw material N-o-cyanoaryl acrylamide)
3H),2.76–2.63(m,2H),1.46(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ195.6,172.5,143.1,136.6,128.6,123.4,119.4,115.4(t,J＝239.8Hz),115.1,53.2(t,J＝5.2Hz),39.6(t,J＝22.3Hz),30.0,26.9； 19 F NMR(377MHz,CDCl 3 )δ-115.05(dtd,J＝57.1,16.1,4.9Hz).
3- (2, 2-difluoromethyl) -1,3, 6-trimethylquinoline-2, 4 (1H, 3H) -dione (N- (2-cyano-4-methylphenyl) -N-methyl methacrylamide as the corresponding raw material N-o-cyanoaryl acrylamide compound)
2.77–2.63(m,2H),2.36(s,3H),1.46(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ195.8,172.4,141.0,137.4,133.3,128.5,119.3,115.5(t,J＝239.8Hz),115.1,53.2(t,J＝5.3Hz),39.7(t,J＝22.3Hz).,30.0,26.9,20.4； 19 F NMR(377MHz,CDCl 3 ) Delta-115.19 (dtd, j=57.0, 16.0,7.2 hz). 6-chloro-3- (2, 2-difluoromethyl-1, 3-dimethylquinoline-2, 4 (1 h,3 h) -dione (corresponding starting material N-o-cyanoaryl acrylamide is N- (2-cyano-4-chlorophenyl) -N-methyl methacrylamide)
(s,3H),2.72(tdd,J＝16.2,6.0,4.0Hz,2H),1.48(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ194.6,172.2,141.7,136.2,129.4,128.1,120.4,116.7,115.3(t,J＝240.0Hz),53.28(t,J＝5.1Hz),39.65(t,J＝22.3Hz),30.2,26.9； 19 F NMR(377MHz,CDCl 3 ) Delta-115.18 (dt, j=56.9, 15.9 hz). 3- (2, 2-difluoromethyl) -1, 3-dimethyl-6-phenylquinoline-2, 4 (1 h,3 h) -dione (corresponding starting material N-o-cyanoaryl acrylamide is N- (2-cyano-4-phenyl) -N-methyl methacrylamide)
1H),7.30–7.26(m,1H),6.16–5.69(m,1H),3.53(s,3H),2.76(ddt,J＝17.6,14.7,5.4Hz,2H),1.52(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ195.6,172.5,142.3,138.9,136.5,134.9,129.1,128.0,126.8,126.7,119.7,115.7,115.5(t,J＝240.1Hz).,53.3(t,J＝5.2Hz),39.7(t,J＝22.3Hz).,30.1,27.0； 19 F NMR(377MHz,CDCl 3 )δ-114.95–-115.27(m).
3- (2, 2-difluoromethyl) -5-fluoro-1, 3-dimethylquinoline-2, 4 (1H, 3H) -dione (N- (2-cyano-3-fluorophenyl) -N-methyl methacrylamide as the corresponding raw material N-o-cyanoaryl acrylamide)
2.58(m,2H),1.49(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ193.0,172.0,162.5(d,J＝266.7Hz),144.2(d,J＝3.2Hz),136.7(d,J＝11.8Hz),115.4(t,J＝239.9Hz),111.7(d,J＝21.7Hz),110.9(d,J＝3.6Hz),109.5(d,J＝9.2Hz),54.4(t,J＝5.2Hz),38.9(t,J＝22.6Hz),30.9,26.0； 19 F NMR(377MHz,CDCl 3 )δ-109.99(dd,J＝10.3,5.9Hz),-114.87(ddt,J＝156.6,57.3,15.9Hz).
7-bromo-3- (2, 2-difluoromethyl) -1, 3-dimethylquinoline-2, 4 (1H, 3H) -dione (N- (2-cyano-5-bromophenyl) -N-methyl methacrylamide as the corresponding starting material N-o-cyanoaryl acrylamide)
3.46(s,3H),2.81–2.64(m,2H),1.47(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ194.7,172.5,144.0,131.7,130.0,126.7,118.4,118.1,115.3(t,J＝238.5Hz),53.3(t,J＝5.1Hz),39.7(t,J＝22.3Hz),30.2,26.9； 19 F NMR(377MHz,CDCl 3 )δ-115.17(dt,J＝56.9,16.0Hz).
From the structural characterization, the target product can be obtained by the method provided by the application.
Although embodiments of the present invention have been disclosed above, it is not limited to the details and embodiments shown, it is well suited to various fields of use for which the invention is suited, and further modifications may be readily made by one skilled in the art, and the invention is therefore not to be limited to the particular details and examples shown and described herein, without departing from the general concepts defined by the claims and the equivalents thereof.
Claims (8)
1. The preparation method of the difluoro methylation 2, 4-quinoline dione derivative is characterized in that difluoro acetic acid, iodobenzene acetate and N-o-cyano aryl acrylamide compounds are taken as reaction raw materials in an organic solvent, inert gas atmosphere and visible light irradiation are adopted, and stirring reaction is carried out at room temperature to obtain the difluoro methylation 2, 4-quinoline dione derivative; the reaction formula is as follows:
wherein R is 1 Represents any one of a hydrogen group, a methyl group, a halogenated group and a phenyl group attached to a benzene ring; r is R 2 Represents one of substituents such as methyl and benzyl; r is R 3 Represents one of substituents such as methyl, benzyl, aryl, ester, sulfinyl, etc.
2. The process for preparing difluoromethylated 2, 4-quinolinedione derivatives as claimed in claim 1, wherein the inert gas is argon.
3. The process for the preparation of difluoromethylated 2, 4-quinolinedione derivatives as claimed in claim 1, wherein the organic solvent is tetrahydrofuran, acetonitrile, 1,4-dioxane, 1,3-dioxolane, 2-methyltetrahydrofuran, dichloromethane, dimethyl sulfoxide or N, N-dimethylformamide.
4. The method for preparing difluoromethylated 2, 4-quinolindione derivatives as in claim 1, wherein the irradiation condition of visible light is specifically blue LED lamp irradiation.
5. The process for preparing difluoromethylated 2, 4-quinolinedione derivatives as claimed in claim 1, wherein the feed ratio of N-o-cyanoaryl acrylamide compound to difluoroacetic acid is 1:8.
6. The process for preparing difluoromethylated 2, 4-quinolinedione derivatives as claimed in claim 1, wherein the feed ratio of N-o-cyanoaryl acrylamide compound to iodobenzene acetate is 1:8.
7. The process for the preparation of difluoromethylated 2, 4-quinolinedione derivatives as claimed in claim 1, characterized by specifically comprising: sequentially adding N-o-cyano aryl acrylamide compounds, difluoroacetic acid and iodobenzene acetate into an organic solvent in a reaction tube, degassing, placing the mixture under the irradiation of visible light in an inert gas atmosphere at room temperature, stirring and reacting for 48 hours, concentrating the mixture by a rotary evaporator, and separating the mixture by silica gel column chromatography to obtain the difluoromethylated 2, 4-quinolinedione derivative.
8. The process for preparing difluoromethylated 2, 4-quinolinedione derivatives as claimed in claim 7, wherein an eluent of ethyl acetate-petroleum ether system is used in the separation by silica gel column chromatography.
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