CN117247350A - Synthesis method of quinoline-2-xanthate - Google Patents
Synthesis method of quinoline-2-xanthate Download PDFInfo
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- CN117247350A CN117247350A CN202311128863.2A CN202311128863A CN117247350A CN 117247350 A CN117247350 A CN 117247350A CN 202311128863 A CN202311128863 A CN 202311128863A CN 117247350 A CN117247350 A CN 117247350A
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- quinoline
- xanthate
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- -1 quinoline-2-xanthate Chemical compound 0.000 title claims abstract description 42
- 238000001308 synthesis method Methods 0.000 title claims description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 125000001424 substituent group Chemical group 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 10
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 5
- 125000006575 electron-withdrawing group Chemical group 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 239000003208 petroleum Substances 0.000 claims description 11
- 239000003480 eluent Substances 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000011097 chromatography purification Methods 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 239000003125 aqueous solvent Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 3
- 150000001348 alkyl chlorides Chemical class 0.000 claims 1
- 150000001350 alkyl halides Chemical class 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 239000012991 xanthate Substances 0.000 abstract description 13
- 239000003054 catalyst Substances 0.000 abstract description 2
- IRFHMTUHTBSEBK-QGZVFWFLSA-N tert-butyl n-[(2s)-2-(2,5-difluorophenyl)-3-quinolin-3-ylpropyl]carbamate Chemical compound C1([C@H](CC=2C=C3C=CC=CC3=NC=2)CNC(=O)OC(C)(C)C)=CC(F)=CC=C1F IRFHMTUHTBSEBK-QGZVFWFLSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 18
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 16
- 238000004809 thin layer chromatography Methods 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000013543 active substance Substances 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000008367 deionised water Substances 0.000 description 9
- 229910021641 deionized water Inorganic materials 0.000 description 9
- 238000002156 mixing Methods 0.000 description 9
- 238000012544 monitoring process Methods 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 8
- 239000012190 activator Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000003379 elimination reaction Methods 0.000 description 4
- ZOOODBUHSVUZEM-UHFFFAOYSA-N ethoxymethanedithioic acid Chemical group CCOC(S)=S ZOOODBUHSVUZEM-UHFFFAOYSA-N 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
- GIIWGCBLYNDKBO-UHFFFAOYSA-N Quinoline 1-oxide Chemical compound C1=CC=C2[N+]([O-])=CC=CC2=C1 GIIWGCBLYNDKBO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 208000012839 conversion disease Diseases 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 238000007350 electrophilic reaction Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- CIWSCAMXBRAGRP-UHFFFAOYSA-N 1-chloro-2h-quinoxaline Chemical compound C1=CC=C2N(Cl)CC=NC2=C1 CIWSCAMXBRAGRP-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- IFIHYLCUKYCKRH-UHFFFAOYSA-N 6-bromoquinoline Chemical compound N1=CC=CC2=CC(Br)=CC=C21 IFIHYLCUKYCKRH-UHFFFAOYSA-N 0.000 description 1
- HFDLDPJYCIEXJP-UHFFFAOYSA-N 6-methoxyquinoline Chemical compound N1=CC=CC2=CC(OC)=CC=C21 HFDLDPJYCIEXJP-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 150000004832 aryl thioethers Chemical class 0.000 description 1
- 150000001504 aryl thiols Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- OMKVZYFAGQKILB-UHFFFAOYSA-M potassium;butoxymethanedithioate Chemical compound [K+].CCCCOC([S-])=S OMKVZYFAGQKILB-UHFFFAOYSA-M 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
Classifications
-
- 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
- C07D215/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention belongs to the field of organic synthesis, in particular to a method for synthesizing quinoline-2-xanthate, which comprises the steps of preparing raw materials of formula 1) Raw materials [ ]) In the presence of 3-sulfonic anhydride) And carrying out reaction with the assistance of the catalyst to obtain the quinoline-2-xanthate. R is R 8 Phenyl, phenyl with substituent or alkyl substituted by electron withdrawing group; the solvent in the reaction stage is at least one of halogenated alkane, THF, water, acetone and ethyl acetate. The invention can cooperate based on the combination of the formula 3 and the solvent and realize quinoline-2 based on a brand new principleMild and efficient conversion of xanthates.
Description
Technical Field
The invention belongs to the field of organic synthesis, and relates to a method for synthesizing quinoline-2-xanthate.
Background
Xanthates are widely used in the fields of pharmaceutical molecules, agriculture, polymer chemistry, environmental chemistry, and the like. Among them, aryl xanthates are an important class of organic synthesis intermediates that can be efficiently converted into aryl thiols, thioethers and sulfur-containing heterocyclic compounds. The traditional method for synthesizing aryl xanthate is mainly realized by the reaction of aryl diazonium salt and potassium ethylxanthate, however, the aryl diazonium salt is unstable and has potential explosiveness, and the industrial application of the reaction is limited. In recent years, transition metal catalyzed carbon-halogen cross-coupling reactions of aryl halides with potassium ethylxanthate have also been reported. However, most aryl xanthates exhibit very low stability at higher temperatures and in the presence of a base, and are readily further converted to the corresponding aryl thioether compounds. In 2022, the university of south China Wang Qingmin group developed a method for synthesizing arylxanthates from dibenzothiophenium salts and potassium ethylxanthate in the absence of a catalyst (org. Lett.,2022,24,8895-8900). Recently, dmitry i.bugaenko and colleagues reported a novel process for the preparation of various aryl xanthates by reacting potassium xanthate with diarylthium salts in the absence of transition metals (org.lett., 2023,25,272-276). Despite these favorable achievements, however, both dibenzothiophenium salts and diarylthio salts are not readily available and require multiple complicated synthetic procedures. Most importantly, all reported aryl xanthates are mainly limited to functionalized phenyl xanthates, and the synthesis method of heterocyclic substituted xanthates is rarely reported.
Quinoline is an important nitrogenous heterocyclic compound and has good anti-tumor, antibacterial, anti-tuberculosis, antimalarial, antioxidant, anti-HIV and other biological activities. If active xanthate fragments can be introduced into the quinoline skeleton to prepare a series of quinoline derivatives, it is very likely that some novel highly active drug molecules will be obtained. Therefore, the development of a technical method for introducing xanthate fragments into quinoline heterocycles and the preparation of various xanthate compounds containing quinoline heterocycles meet the requirements of new drug creation, which are one of the hot spots and the key points of the research in the field at present, are the motive power of the completion of the invention.
Disclosure of Invention
Aiming at the problem of lack of the existing quinoline-2-xanthate synthesis means, the invention aims to provide a mild and high-conversion-rate quinoline-2-xanthate synthesis method.
The present invention provides the following solutions to the problem that quinoline-C2-H has low activity and is difficult to directly nucleophilic couple with xanthates, especially under mild conditions:
the quinoline-2-xanthate synthesis method comprises the steps of reacting a raw material of a formula 1 and a raw material of a formula 2 with the assistance of sulfonic anhydride of a formula 3 to prepare a product of a formula 4;
said R is 1 ～R 6 Independently H, halogen, C 1 ～C 10 Alkyl, C of (2) 1 ～C 10 Alkoxy, phenyl, cyano, C with substituents 1 ～C 10 Alkyl of (a); or wherein adjacent groups are cyclized to form a ring structure;
said R is 7 Independently C 1 ～C 10 Alkyl, phenyl, C with substituents 1 ～C 10 Alkyl or substituted formyl;
m is H, na, K or NH 4 ；
R 8 Phenyl, phenyl with substituent or alkyl substituted by electron withdrawing group;
the substituent is at least one of alkyl, alkoxy, phenyl, cyclic group, trifluoromethyl, nitro, ester group, amide group and aminoacyl;
the solvent in the reaction stage is at least one of halogenated alkane, THF, water, acetone and ethyl acetate.
The invention provides a quinoline-2-xanthate synthesis idea of electrophilic activation-nucleophilic addition-elimination, which innovatively uses a compound with a structure shown in a formula 3 as a catalytic activator to perform electrophilic reaction on N-O on a quinoline ring shown in the formula 1 in advance, so that the activity of C2-H is improved, the selective nucleophilic attack of the formula 2 on the C2-H is facilitated, and the elimination of the formula 3 is synchronously realized. The method disclosed by the invention does not need to adopt special metal coordination raw materials, and is mild in reaction condition, high in reaction selectivity and high in conversion rate.
In the present invention, the formula 1 may be any quinoline N-oxide having H at the 2-position. In view of the availability of cost, for example, in the formula 1, R 1 ～R 6 Independently H, halogen, C 1 ～C 6 Alkyl or C of (2) 1 ～C 6 Alkoxy groups of (a).
In the present invention, the formula 2 may be any desired xanthogen and salts thereof, for example, in the formula 2, R 7 Independently C 1 ～C 6 Or C with substituents 1 ～C 6 Is a hydrocarbon group. The substituent may be C 1 ～C 6 At least one of an alkoxy group, a trifluoromethyl group, a halogen group, a three-to six-membered cycloalkyl group, a three-to six-membered heterocyclic cycloalkyl group, a five-membered heterocyclic aryl group, a phenyl group, and a six-membered heterocyclic aryl group.
In the present invention, the raw material of formula 2 may be appropriately in excess, and for example, the molar ratio of the raw material of formula 1 to the raw material of formula 2 is 1:1 to 2.5, preferably 1:1.1 to 1.8, in view of cost.
In the invention, the coordination of the activator of the formula 3 and the solvent in the reaction stage is the key for realizing the synergy and improving the quinoline-2-xanthate. Research shows that in the formula 3, R of aromatic or electron-withdrawing type 8 Compared with anhydrides and acyl chlorides of other structures, the constructed sulfonic anhydride can unexpectedly show excellent activity and can unexpectedly realize the efficient conversion of quinoline-2-xanthate.
Preferably, said R 8 Is trifluoromethyl, phenyl or substituted phenyl;
preferably, the substituted phenyl is a substituted phenyl with C 1 ～C 6 Alkyl, C 1 ～C 6 Phenyl of at least one substituent selected from alkoxy, nitro, halogen and trifluoromethyl.
In the present invention, the molar ratio of the raw material of formula 1 to the sulfonic anhydride of formula 3 is 1:1 to 2.5, preferably 1:1.1 to 1.8.
According to the invention, the solvent and the formula 3 can be matched to realize unexpected synergy, so that the activity of C2-H can be unexpectedly improved, nucleophilic attack and dissociation of the formula 3 are facilitated, and the conversion rate of quinoline-2-xanthate can be unexpectedly improved.
The halogenated alkane in the solvent is more than two chloro-substituted C1-C3 chlorinated alkane;
preferably, the solvent is at least one of dichloromethane, dichloroethane and THF, and more preferably THF. In the present invention, THF is used as a solvent, which surprisingly further cooperates with formula 3 to improve the reaction conversion.
In the present invention, the temperature of the reaction stage is not particularly limited, and for example, the temperature of the reaction stage may be 10℃or higher, and further may be 15 to 50℃and may be room temperature directly in view of the easiness of the process.
In the present invention, the reaction time can be measured by a known central control detection means, for example, the reaction materials and the conversion of the product can be monitored by TLC or HPLC. It has been found through experimentation that the process of the present invention can be carried out for a period of substantially 60 minutes (e.g., from 10 to 60 minutes).
In the present invention, after the completion of the reaction, the quinoline-2-xanthate can be obtained from the reaction system based on known principles and operations. For example, after the reaction is completed, the crude quinoline-2-xanthate is obtained by extraction with a non-aqueous solvent and concentration. The non-water soluble solvent can be dichloromethane, dichloroethane, ethyl acetate, etc.
In the present invention, a fine product can be obtained by refining a crude product by a known method. For example, performing chromatographic purification treatment on the crude quinoline-2-xanthate to obtain refined quinoline-2-xanthate;
in the present invention, as a typical example, the eluent in the chromatographic purification stage is a petroleum ether/ethyl acetate mixed solvent having a volume ratio of 6 to 15:1.
In the present invention, the atmosphere of the reaction is not particularly limited, and may be an air atmosphere in view of the simplicity of the process.
The beneficial effects are that:
the invention provides a quinoline-2-xanthate synthesis idea of electrophilic activation-nucleophilic addition-elimination, which innovatively uses a compound with a structure shown in a formula 3 as a catalytic activator to perform electrophilic reaction on N-O on a quinoline ring shown in the formula 1 in advance, so that the activity of C2-H is improved, the selective nucleophilic attack of the formula 2 on the C2-H is facilitated, and the elimination of the formula 3 is synchronously realized. The method disclosed by the invention does not need to adopt special metal coordination raw materials, and is mild in reaction condition, high in reaction selectivity and high in conversion rate.
According to the invention, the Ts2O is adopted as an activator, and THF is adopted as a solvent, so that a better synergistic effect can be unexpectedly shown, and the conversion effect of quinoline-2-xanthate under mild conditions can be further improved.
Drawings
FIG. 1 is a diagram of the product of example 1 1 H-NMR chart;
FIG. 2 is a diagram of the product of example 1 13 C-NMR chart;
the specific embodiment is as follows:
according to the quinoline-2-xanthate synthesis method, a quinoline N-oxide raw material of the formula 1, a xanthate raw material of the formula 2 and a salt raw material thereof and a sulfonic anhydride of the formula 3 are dispersed in a solvent to react to prepare a product of the formula 4;
in the invention, the combination of the activator of the formula 3 and the solvent can realize the mild conversion of the quinoline-2-xanthate based on a brand new principle unexpectedly:
as a typical example, the reaction principle of the present invention is, for example:
in the following cases, the room temperature was 20 to 35℃unless specifically stated.
Example 1:
room temperatureNext, quinoline oxynitride (0.3 mmol), potassium ethylxanthate (0.45 mmol), tetrahydrofuran (solvent, 3 mL) and p-toluenesulfonic anhydride (activator, ts) were sequentially added to a 10mL reaction tube equipped with a magnetic stirrer 2 O,0.45 mmol), stirring at normal temperature for about 30min, monitoring by TLC (thin layer chromatography) plate, adding dichloromethane (10 mL) and deionized water (10 mL) into the reaction solution after the reaction is completed, mixing uniformly, extracting an organic phase, extracting an aqueous phase with dichloromethane twice (2X 10 mL), combining the organic phases, removing the organic solvent by a rotary evaporator, purifying the residue by silica gel column chromatography, wherein the silica gel specification is 200-300 meshes, the eluent is petroleum ether/ethyl acetate (10:1 v/v), and obtaining the target product 62.0mg with the yield of 83%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,CDCl 3 )δ8.18(d,J＝8.5Hz,1H),8.12(d,J＝8.5Hz,1H),7.85(d,J＝8.1Hz,1H),7.75(t,J＝7.6Hz,1H),7.69(d,J＝8.5Hz,1H),7.61(t,J＝7.5Hz,1H),4.63(q,J＝7.1Hz,2H),1.32(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ210.5,153.0,148.3,137.0,130.2,129.5,127.8,127.6,127.3,127.2,70.3,13.5；HRMS(ESI):m/z[M+H] + calcd for C 12 H 12 NOS 2 :250.0355；found:250.0358.
based on example 1, the following controls were made for formula 3 and the solvent during the treatment, and the results were:
a conditions are as follows: 1a (0.1 mmol,1 equiv.), 2a (0.15 mmol,1.5 equiv.), active agent (activator, 0.15mmol,1.5 equiv.), solvent (1 mL), r.t.,0.5h. b Yield of 3aa by 1 H NMR determination. PyBroP, tripyrrolidinyl phosphonium bromide hexafluorophosphate.
As can be seen from the above table, by adopting the combination of Ts2O and THF, a better synergistic effect can be obtained unexpectedly, which is helpful for further improving the reaction conversion rate of quinoline-2-xanthate under mild conditions.
Example 2:
6-bromoquinoline oxynitride (0.3 mmol), potassium ethylxanthate (0.45 mmol), tetrahydrofuran (solvent, 3 mL) and Ts were added sequentially to a 10mL reaction tube equipped with a magnetic stirrer at room temperature 2 O (active agent, 0.45 mmol), stirring at normal temperature for about 30min, monitoring by TLC (thin layer chromatography) plate, adding dichloromethane (10 mL) and deionized water (10 mL) into the reaction solution after the reaction is completed, mixing uniformly, extracting an organic phase, extracting an aqueous phase with dichloromethane twice (2X 10 mL), combining the organic phases, removing the organic solvent by a rotary evaporator, purifying the residue by silica gel column chromatography, wherein the silica gel specification is 200-300 meshes, the eluent is petroleum ether/ethyl acetate (10:1v/v), and obtaining 72.6mg of a target product with the yield of 74%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,CDCl 3 )δ8.09(d,J＝8.3Hz,1H),7.98(d,J＝14.2Hz,2H),7.80(d,J＝8.8Hz,1H),7.71(d,J＝8.3Hz,1H),4.63(q,J＝6.4Hz,2H),1.33(t,J＝6.6Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ210.0,153.7,146.8,135.8,133.7,131.2,129.6,128.3,128.0,121.9,70.5,13.5；HRMS(ESI):m/z[M+H] + calcd for C 12 H 11 BrNOS 2 :327.9460；found:327.9461.
example 3:
6-Methoxyquinoline oxynitride (0.3 mmol), potassium ethylxanthate (0.45 mmol), tetrahydrofuran (solvent, 3 mL) and Ts were sequentially added to a 10mL reaction tube equipped with a magnetic stirrer at room temperature 2 O (active agent, 0.45 mmol), stirring at normal temperature for about 30min, monitoring by TLC plate, and after the reaction is completedDichloromethane (10 mL) and deionized water (10 mL) were added to the reaction solution, mixed uniformly, an organic phase was extracted, an aqueous phase was extracted twice with dichloromethane (2×10 mL), the organic phases were combined, and the organic solvent was removed by a rotary evaporator, and the residue was purified by silica gel column chromatography with a silica gel size of 200 to 300 mesh, an eluent of petroleum ether/ethyl acetate (4:1 v/v), to give 61.1mg of the objective product in 73% yield.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,CDCl 3 )δ8.06(d,J＝8.5Hz,1H),8.00(d,J＝9.2Hz,1H),7.61(d,J＝8.5Hz,1H),7.38(dd,J＝9.2,2.3Hz,1H),7.07(d,J＝2.1Hz,1H),4.61(q,J＝7.1Hz,2H),3.92(s,3H),1.30(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ211.2,158.8,149.7,144.5,135.7,131.0,128.6,127.7,122.9,104.9,70.3,55.6,13.5；HRMS(ESI):m/z[M+H] + calcd for C 13 H 14 NO 2 2S 2 :280.0460；found:280.0463.
example 4:
to a 10mL reaction tube equipped with a magnetic stirrer, 4-chloroquinoxaline oxynitride (0.3 mmol), potassium ethylxanthate (0.45 mmol), tetrahydrofuran (solvent, 3 mL) and Ts were sequentially added at room temperature 2 O (active agent, 0.45 mmol), stirring at normal temperature for about 30min, monitoring by TLC (thin layer chromatography) plate, adding dichloromethane (10 mL) and deionized water (10 mL) into the reaction solution after the reaction is completed, mixing uniformly, extracting an organic phase, extracting an aqueous phase with dichloromethane twice (2X 10 mL), combining the organic phases, removing the organic solvent by a rotary evaporator, purifying the residue by silica gel column chromatography, wherein the silica gel specification is 200-300 meshes, the eluent is petroleum ether/ethyl acetate (4:1v/v), and obtaining 57.7mg of a target product with the yield of 68%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,CDCl 3 )δ8.22(d,J＝8.4Hz,1H),8.12(d,J＝8.4Hz,1H),7.84–7.75(m,2H),7.69(t,J＝7.6Hz,1H),4.64(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ209.3,152.8,148.7,142.9,131.0,129.8,128.7,126.7,125.5,124.0,70.5,13.5；HRMS(ESI):m/z[M+H] + calcd for C 12 H 11 ClNOS 2 :283.9965；found:283.9968.
example 5:
quinoline oxynitride (0.3 mmol), butyl potassium xanthate (0.45 mmol), tetrahydrofuran (solvent, 3 mL) and Ts were added sequentially to a 10mL reaction tube equipped with a magnetic stirrer at room temperature 2 O (active agent, 0.45 mmol), stirring at normal temperature for about 30min, monitoring by TLC (thin layer chromatography) plate, adding dichloromethane (10 mL) and deionized water (10 mL) into the reaction solution after the reaction is completed, mixing uniformly, extracting an organic phase, extracting an aqueous phase with dichloromethane twice (2X 10 mL), combining the organic phases, removing the organic solvent by a rotary evaporator, purifying the residue by silica gel column chromatography, wherein the silica gel specification is 200-300 meshes, the eluent is petroleum ether/ethyl acetate (10:1v/v), and obtaining the target product of 60.7mg with the yield of 73%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,CDCl 3 )δ8.16(d,J＝8.5Hz,1H),8.10(d,J＝8.5Hz,1H),7.82(d,J＝8.1Hz,1H),7.73(t,J＝7.7Hz,1H),7.66(d,J＝8.5Hz,1H),7.58(t,J＝7.5Hz,1H),4.53(t,J＝6.5Hz,2H),1.66–1.58(m,2H),1.29–1.18(m,2H),0.79(t,J＝7.4Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ210.3,152.8,148.2,136.9,130.1,129.4,127.7,127.5,127.2,127.0,74.1,29.8,18.8,13.4；HRMS(ESI):m/z[M+H] + calcd for C 14 H 16 NOS 2 :278.0668；found:278.0671.
example 6:
at room temperature, facingA10 mL reaction tube with a magnetic stirrer was charged with quinoline oxynitride (0.3 mmol), (2-ethoxy) -ethyl potassium xanthate (0.45 mmol), tetrahydrofuran (solvent, 3 mL) and Ts in this order 2 O (active agent, 0.45 mmol), stirring at normal temperature for about 30min, monitoring by TLC (thin layer chromatography) plate, adding dichloromethane (10 mL) and deionized water (10 mL) into the reaction solution after the reaction is completed, mixing uniformly, extracting an organic phase, extracting an aqueous phase with dichloromethane twice (2X 10 mL), combining the organic phases, removing the organic solvent by a rotary evaporator, purifying the residue by silica gel column chromatography, wherein the silica gel specification is 200-300 meshes, the eluent is petroleum ether/ethyl acetate (6:1v/v), and 58.9mg of target product is obtained, and the yield is 67%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,CDCl 3 )δ8.16(d,J＝8.5Hz,1H),8.11(d,J＝8.5Hz,1H),7.83(d,J＝8.1Hz,1H),7.80–7.69(m,2H),7.60(t,J＝7.5Hz,1H),4.77–4.61(m,2H),3.72–3.59(m,2H),3.36(q,J＝7.0Hz,2H),1.08(t,J＝7.0Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ210.4,153.1,148.2,136.9,130.1,129.5,127.8,127.5,127.3,127.1,73.1,67.3,66.6,15.0；HRMS(ESI):m/z[M+H] + calcd for C 14 H 16 NO 2 S 2 :294.0617；found:294.0622.
example 7:
into a 10mL reaction tube equipped with a magnetic stirrer, quinoline oxynitride (0.3 mmol), (2-trifluoromethyl) -ethyl potassium xanthate (0.45 mmol), tetrahydrofuran (solvent, 3 mL) and Ts were sequentially added at room temperature 2 O (active agent, 0.45 mmol), stirring at room temperature for about 30min, monitoring by TLC plate, adding dichloromethane (10 mL) and deionized water (10 mL) into the reaction solution after the reaction, mixing, extracting organic phase, extracting aqueous phase with dichloromethane twice (2×10 mL), mixing organic phases, removing organic solvent by rotary evaporator, purifying residue by silica gel column chromatography with silica gel specification of 200-300 mesh, eluting with petroleum etherEthyl acetate (8:1 v/v) gave the desired product 68.5mg, 72% yield.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,CDCl 3 )δ8.20(d,J＝8.5Hz,1H),8.13(d,J＝8.5Hz,1H),7.86(d,J＝8.1Hz,1H),7.77(t,J＝7.7Hz,1H),7.68(d,J＝8.5Hz,1H),7.62(t,J＝7.5Hz,1H),4.76(t,J＝6.2Hz,2H),2.52(qt,J＝10.7,6.3Hz,2H)； 13 C NMR(100MHz,CDCl3)δ210.2,152.2,148.4,137.3,130.3,129.5,128.0,127.6,127.4,127.1,125.3(q,J C-F ＝275.2Hz),65.9(q,J C-F ＝3.5Hz),32.8(q,J C-F ＝29.6Hz)； 19 FNMR(376MHz,CDCl 3 )δ-64.93；HRMS(ESI):m/z[M+H] + calcd for C 13 H 11 F 3 NOS 2 :318.0229；found:318.0236.
example 8:
quinoline oxynitride (0.3 mmol), potassium cyclobutylxanthate (0.45 mmol), tetrahydrofuran (solvent, 3 mL) and Ts were added sequentially to a 10mL reaction tube equipped with a magnetic stirrer at room temperature 2 O (active agent, 0.45 mmol), stirring at normal temperature for about 30min, monitoring by TLC (thin layer chromatography) plate, adding dichloromethane (10 mL) and deionized water (10 mL) into the reaction solution after the reaction is completed, mixing uniformly, extracting an organic phase, extracting an aqueous phase with dichloromethane twice (2X 10 mL), combining the organic phases, removing the organic solvent by a rotary evaporator, purifying the residue by silica gel column chromatography, wherein the silica gel specification is 200-300 meshes, the eluent is petroleum ether/ethyl acetate (8:1v/v), and obtaining the target product of 60.2mg with the yield of 73%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,CDCl 3 )δ8.18(d,J＝8.5Hz,1H),8.12(d,J＝8.5Hz,1H),7.84(d,J＝8.1Hz,1H),7.77–7.66(m,2H),7.60(t,J＝7.5Hz,1H),5.55–5.46(m,1H),2.47–2.36(m,2H),5.55–5.46(m,2H),1.85–1.74(m,1H),1.66–1.55(m,1H)； 13 C NMR(100MHz,CDCl 3 )δ208.8,153.2,148.2,136.9,130.1,129.5,127.8,127.5,127.2,127.1,77.8,29.9,13.5；HRMS(ESI):m/z[M+H] + calcd for C 14 H 14 NOS 2 :276.0511；found:276.0506.
example 9:
to a 10mL reaction tube equipped with a magnetic stirrer, quinoline oxynitride (0.3 mmol), (2-thienyl) -methylxanthate potassium (0.45 mmol), tetrahydrofuran (solvent, 3 mL) and Ts were sequentially added at room temperature 2 O (active agent, 0.45 mmol), stirring at normal temperature for about 30min, monitoring by TLC (thin layer chromatography) plate, adding dichloromethane (10 mL) and deionized water (10 mL) into the reaction solution after the reaction is completed, mixing uniformly, extracting an organic phase, extracting an aqueous phase with dichloromethane twice (2X 10 mL), combining the organic phases, removing the organic solvent by a rotary evaporator, purifying the residue by silica gel column chromatography, wherein the silica gel specification is 200-300 meshes, the eluent is petroleum ether/ethyl acetate (8:1v/v), and obtaining the target product 71.3mg with the yield of 75%.
The nuclear magnetic spectrum data of the obtained product are:
1 H NMR(400MHz,CDCl 3 )δ8.19(d,J＝8.5Hz,1H),8.10(d,J＝8.5Hz,1H),7.85(d,J＝8.1Hz,1H),7.75(t,J＝8.0Hz,2H),7.60(t,J＝7.5Hz,1H),7.20(d,J＝5.1Hz,1H),6.99(s,1H),6.91(t,J＝4.1Hz,1H),4.47(s,2H)； 13 C NMR(100MHz,CDCl 3 )δ186.9,151.3,148.5,138.6,137.2,130.3,129.4,127.8,127.6,127.5,127.3,127.0,126.4,125.7,29.7；HRMS(ESI):m/z[M+H] + calcd for C 15 H 12 NOS 3 :318.0076；found:318.0079。
Claims (10)
1. a quinoline-2-xanthate synthesis method is characterized in that a raw material of a formula 1 and a raw material of a formula 2 react with the assistance of sulfonic anhydride of a formula 3 to prepare a product of a formula 4;
said R is 1 ～R 6 Independently H, halogen, C 1 ～C 10 Alkyl, C of (2) 1 ～C 10 Alkoxy, phenyl, cyano, C with substituents 1 ～C 10 Alkyl of (a); or wherein adjacent groups are cyclized to form a ring structure;
said R is 7 Independently C 1 ～C 10 Alkyl, phenyl, C with substituents 1 ～C 10 Alkyl or substituted formyl;
m is H, na, K or NH 4 ；
R 8 Phenyl, phenyl with substituent or alkyl substituted by electron withdrawing group;
the substituent is at least one of alkyl, alkoxy, phenyl, cyclic group, trifluoromethyl, nitro, ester group, amide group and aminoacyl;
the solvent in the reaction stage is at least one of halogenated alkane, THF, water, acetone and ethyl acetate.
2. The method for synthesizing quinoline-2-xanthate according to claim 1, wherein R is 1 ～R 6 Independently H, halogen, C 1 ～C 6 Alkyl or C of (2) 1 ～C 6 Alkoxy groups of (a).
3. The method for synthesizing quinoline-2-xanthate according to claim 1, wherein in formula 2, said R 7 Independently C 1 ～C 6 Or C with substituents 1 ～C 6 Alkyl of (a);
the substituent is C 1 ～C 6 At least one of an alkoxy group, a trifluoromethyl group, a halogen group, a three-to six-membered cycloalkyl group, a three-to six-membered heterocyclic cycloalkyl group, a five-membered heterocyclic aryl group, a phenyl group, and a six-membered heterocyclic aryl group.
4. A process according to any one of claims 1 to 3, wherein the molar ratio of starting materials of formula 1 to starting materials of formula 2 is from 1:1 to 2.5, preferably from 1:1.1 to 1.8.
5. The method for synthesizing quinoline-2-xanthate according to claim 1, wherein R is 8 Is trifluoromethyl, phenyl or substituted phenyl;
preferably, the substituted phenyl is a substituted phenyl with C 1 ～C 6 Alkyl, C 1 ～C 6 Phenyl of at least one substituent selected from alkoxy, nitro, halogen and trifluoromethyl.
6. The process for the synthesis of quinoline-2-xanthate according to claim 1 or 5, characterized in that the molar ratio of starting material of formula 1 to sulphonic anhydride of formula 3 is comprised between 1:1 and 2.5, preferably between 1:1.1 and 1.8.
7. The method for synthesizing quinoline-2-xanthate according to claim 1, wherein the haloalkane in the solvent is a chloro-substituted C1-C3 chloroalkane with two or more chlorine substitutions;
preferably, the solvent is at least one of dichloromethane, dichloroethane and THF, and more preferably THF.
8. The process for the synthesis of quinoline-2-xanthate according to claim 1, characterized in that the temperature of the reaction stage is above 10 ℃, preferably between 15 and 50 ℃.
9. The method for synthesizing quinoline-2-xanthate according to claim 1, wherein after the reaction is finished, the crude quinoline-2-xanthate is obtained by extraction with a non-aqueous solvent and concentration.
10. The method for synthesizing quinoline-2-xanthate according to claim 9, wherein the crude quinoline-2-xanthate is subjected to chromatographic purification treatment to obtain a refined quinoline-2-xanthate;
preferably, the eluent in the chromatographic purification stage is petroleum ether/ethyl acetate mixed solvent with the volume ratio of 6-15:1.
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