CN114716367A - Method for preparing 4-mercaptopyridine compound by virtue of micro-flow field reactor technology - Google Patents
Method for preparing 4-mercaptopyridine compound by virtue of micro-flow field reactor technology Download PDFInfo
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- -1 4-mercaptopyridine compound Chemical class 0.000 title claims abstract description 67
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000005516 engineering process Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 125
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 54
- 239000002904 solvent Substances 0.000 claims abstract description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000000654 additive Substances 0.000 claims abstract description 12
- 230000000996 additive effect Effects 0.000 claims abstract description 12
- FHTDDANQIMVWKZ-UHFFFAOYSA-N 1h-pyridine-4-thione Chemical class SC1=CC=NC=C1 FHTDDANQIMVWKZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 238000006467 substitution reaction Methods 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 235000019387 fatty acid methyl ester Nutrition 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000007514 bases Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims 1
- 230000003321 amplification Effects 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 238000010276 construction Methods 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 44
- 238000005086 pumping Methods 0.000 description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 150000001875 compounds Chemical class 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 12
- 238000001514 detection method Methods 0.000 description 11
- 239000003480 eluent Substances 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 11
- 238000010791 quenching Methods 0.000 description 11
- 230000000171 quenching effect Effects 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 11
- 238000004821 distillation Methods 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 238000002156 mixing Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- PTDVPWWJRCOIIO-UHFFFAOYSA-N (4-methoxyphenyl)methanethiol Chemical compound COC1=CC=C(CS)C=C1 PTDVPWWJRCOIIO-UHFFFAOYSA-N 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- 230000003595 spectral effect Effects 0.000 description 6
- FODNGWJBUYRTJP-UHFFFAOYSA-M trifluoromethanesulfonate;triphenyl(pyridin-4-yl)phosphanium Chemical compound [O-]S(=O)(=O)C(F)(F)F.C1=CC=CC=C1[P+](C=1C=CN=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 FODNGWJBUYRTJP-UHFFFAOYSA-M 0.000 description 6
- 238000012986 modification Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- GJTKJPMHCUGCSF-UHFFFAOYSA-N 2-chloro-4-[(4-methoxyphenyl)methylsulfanyl]pyridine Chemical compound C1=CC(OC)=CC=C1CSC1=CC=NC(Cl)=C1 GJTKJPMHCUGCSF-UHFFFAOYSA-N 0.000 description 2
- BRQZYLCBXXUXAY-UHFFFAOYSA-N 4-[(4-methoxyphenyl)methylsulfanyl]pyridine Chemical compound C1=CC(OC)=CC=C1CSC1=CC=NC=C1 BRQZYLCBXXUXAY-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 239000004813 Perfluoroalkoxy alkane Substances 0.000 description 2
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 229920011301 perfluoro alkoxyl alkane Polymers 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- VZXOZSQDJJNBRC-UHFFFAOYSA-N 4-chlorobenzenethiol Chemical compound SC1=CC=C(Cl)C=C1 VZXOZSQDJJNBRC-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical group CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Chemical group COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- PVBRSNZAOAJRKO-UHFFFAOYSA-N ethyl 2-sulfanylacetate Chemical compound CCOC(=O)CS PVBRSNZAOAJRKO-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- LDTLDBDUBGAEDT-UHFFFAOYSA-N methyl 3-sulfanylpropanoate Chemical compound COC(=O)CCS LDTLDBDUBGAEDT-UHFFFAOYSA-N 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Images
Classifications
-
- 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
- C07D213/70—Sulfur atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a method for preparing 4-mercaptopyridine compounds by a micro-flow field reactor technology, which comprises the following steps: reacting a first reaction liquid containing a thiol compound shown in a formula 1, a first solvent and an additive with a second reaction liquid containing a pyridine compound shown in a formula 2 and a second solvent in a micro-flow field reactor, and collecting an effluent reaction liquid, namely the reaction liquid containing the 4-mercaptopyridine compound shown in the formula 3. The reaction of the invention has the advantages of safety, environmental protection, high reaction efficiency, mild reaction conditions, no highly toxic residues, simple construction of a reaction device and industrial amplification prospect.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a method for preparing a 4-mercaptopyridine compound by a micro-flow field reactor technology.
Background
Compounds having a mercapto (-SH) functional group are collectively referred to as thiol compounds, and the mercapto (-SH) structure has received wide attention from chemists due to its specific properties. Selective modification of thiol compounds has also been extensively studied, such as "thiol-ene" and "thiol-alkyne" reactions. In recent years, studies on thiol compounds as proton transfer intermediates have been advanced, and further, the enthusiasm for studies on thiol compounds has been promoted.
On the other hand, a strategy of achieving heteroaryl functionalization of a target compound by nucleophilic addition using triphenylphosphino-4-pyridinetriflate as a donor of heteroaryl has received great attention in recent years. In 2016, Andrew McNally developed a triphenylphosphino-4-pyridine trifluoromethanesulfonate compound, which can be substituted with alcohol under strong alkaline condition to obtain the corresponding oxopyridine compound (J.Am.chem.Soc.2016,138, 13806-13809). In 2018, the Andrew McNally project group also utilized the reagent to achieve deuterium atom modification of pyridine para position in strongly alkaline conditions and deuterated solvents (J.Am.chem.Soc.2018,140, 1990-1993). The micro-flow field reaction technology is a process enhancement technology with the characteristic scale of reaction in the hundred micron scale. The technology can realize the improvement of the apparent reaction rate by virtue of the advantages of micro-scale effect, continuous flow and the like, and achieves the purposes of shortening the reaction time and improving the reaction selectivity. The reaction technology has the advantages of equipment miniaturization, small real-time online reaction volume, high safety and the like, solves the defects of complex route and complex operation of the traditional batch reaction process, and points out the direction for building a 'desktop factory' for the traditional chemical industry and the green development of the chemical industry. The method for realizing selective modification of thiol compounds by using a micro-flow field reaction technology is still rarely reported in the literature. Referring to the two reactions, the invention intends to utilize triphenylphosphino-4-pyridine trifluoromethanesulfonate compounds and thiol compounds to carry out substitution reaction, and to strengthen the reaction process by means of a micro-flow field reaction technology, thereby overcoming the problems of harsh original reaction conditions and the like. Develops a preparation method of the 4-mercaptopyridine thiopyridine compound with mild reaction conditions, environmental protection and easy amplification.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to solve the technical problem of the prior art and provides a method for preparing a 4-mercaptopyridine compound by a micro-flow field reactor technology.
In order to solve the technical problem, the invention discloses a method for preparing 4-mercaptopyridine compounds by means of a micro-flow field reactor technology (figure 1), which comprises the following steps: respectively pumping a first reaction liquid containing a thiol compound shown in a formula 1, a first solvent and an additive and a second reaction liquid containing a pyridine compound shown in a formula 2 and a second solvent into a micro-flow field reactor at the same time for reaction, and collecting an effluent reaction liquid, namely the reaction liquid containing the 4-mercaptopyridine compound shown in the formula 3;
wherein,
r is selected from phenyl, substituted phenyl or fatty acid methyl ester; the substitution is any one or more of halogen substitution, C1-C6 alkyl substitution and C1-C6 alkoxy substitution; in some embodiments, R is selected from substituted phenyl, or fatty acid methyl ester groups; the substitution is any one or more of halogen substitution, C1-C3 alkyl substitution and C1-C3 alkoxy substitution; in some embodiments, R is selected from 4-methoxybenzyl, 4-chlorobenzyl, methyl acetate, methyl propionate;
R1selected from hydrogen, halogen, alkyl, alkoxy, or phenyl(ii) a In some embodiments, R1Selected from hydrogen, halogen or phenyl; in some embodiments, R1Selected from hydrogen, chlorine or phenyl.
The thiol compounds shown in formula 1 include benzyl mercaptan and derivatives, chain mercaptan, thiophenol and derivatives, cysteine and derivatives, etc.; benzyl mercaptans and chain mercaptans and derivatives thereof are preferred; the pyridine compound shown in the formula 2 is a triphenyl phosphino-4-pyridine trifluoromethanesulfonate compound.
In some embodiments, the first solvent and the second solvent are each independently selected from any one or more combinations of dichloromethane, acetone, ethyl acetate, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, and dimethylsulfoxide; in some embodiments, the first solvent and the second solvent are the same or different; in some embodiments, the first solvent and the second solvent are each independently selected from any one or more combinations of dichloromethane, acetonitrile, and tetrahydrofuran; in some embodiments, the first solvent and the second solvent are each independently selected from tetrahydrofuran.
In some embodiments, the additive is a basic compound; in some embodiments, the additive is any one or combination of sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, triethylamine, 4-dimethylaminopyridine, 1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene, N-diisopropylethylamine, N' -tetramethylethylenediamine, and 2, 6-lutidine; in some embodiments, the additive is triethylamine.
In some embodiments, the concentration of the thiol compound represented by formula 1 is 0.05 to 2.0 mmol/mL; in some embodiments, the concentration of the thiol compound represented by formula 1 is 0.05 to 1.0 mmol/mL; in some embodiments, the concentration of the thiol compound represented by formula 1 is 0.05 to 0.5 mmol/mL; in some embodiments, the concentration of the thiol compound of formula 1 is 0.1 mmol/mL.
In some embodiments, the molar ratio of the thiol compound represented by formula 1 to the additive in the first reaction solution is 1 (1-5); in some embodiments, the molar ratio of the thiol compound represented by formula 1 to the additive in the first reaction solution is 1 (1-3); in some embodiments, the molar ratio of the thiol compound represented by formula 1 to the additive in the first reaction solution is 1 (1-1.5).
In some embodiments, the molar ratio of the thiol compound shown in formula 1 to the pyridine compound shown in formula 2 is 1 (1-5); in some embodiments, the molar ratio of the thiol compound shown in the formula 1 to the pyridine compound shown in the formula 2 is 1 (1-3); in some embodiments, the molar ratio of the thiol compound represented by formula 1 to the pyridine compound represented by formula 2 is 1 (1-1.5).
In some embodiments, the concentration of the pyridine compound represented by formula 2 in the second reaction solution is 0.05 to 0.25 mmol/mL; in some embodiments, the concentration of the pyridine compound represented by formula 2 in the second reaction solution is 0.15 mmol/mL.
In some embodiments, the microfluidic field reactor comprises a first feed pump, a second feed pump, a mixer, a microreactor, and a collector; the first feeding pump and the second feeding pump are connected to the mixer in a parallel mode through connecting pipes, the mixer, the microreactor and the receiver are connected in series through pipelines (figure 2), and the feeding pumps pump reaction liquid, the reaction liquid is mixed by the mixer and then flows into the microfluidic reactor for reaction.
In some embodiments, the feed pump is a bagging Leifu Fluid Technology co.ltd, TYD01-01-CE type.
In some embodiments, the mixer is a "Y" or "T" type mixer, or a bayer, etc. mixer; in some embodiments, the mixer is a "Y" type mixer.
In some embodiments, the internal diameter of the mixer is 0.6 mm.
In some embodiments, the microreactor has a channel structure, is made of perfluoroalkoxy alkane (PFA) or Polytetrafluoroethylene (PTFE), and has a size of 0.5-1.0 mm in inner diameter, 5-20 m in length and 1-62.8 mL in volume; in some embodiments, the microreactor has an internal diameter of 0.8mm and a volume of 2 mL.
In some embodiments, the pumping flow rates of the first reaction solution and the second reaction solution are both 0.05-2.0 mL/min; in some embodiments, the pumping flow rates of the first reaction solution and the second reaction solution are both 0.05-0.15 mL/min.
In some embodiments, the temperature of the reaction is 20 to 30 ℃; in some embodiments, the temperature of the reaction is room temperature.
In some embodiments, the residence time of the reaction is 30s to 30 min.
Has the beneficial effects that: compared with the prior art, the invention has the following advantages:
(1) the pyridine compound as the reactant can be prepared by taking cheap triphenylphosphine and pyridine derivatives as raw materials through simple reaction steps.
(2) The invention does not need to add a catalyst and an oxidant, and avoids the problems of cost rise, environmental pollution and the like caused by using the catalyst and the oxidant.
(3) The system provided by the invention has no solid insoluble substances, does not cause the problem of channel blockage, is simple to operate and high in safety, overcomes the defects of the traditional method, and has the advantages of short reaction time, high reaction conversion rate and product yield, continuous preparation, contribution to large-scale production and the like. .
(4) The invention has mild reaction conditions, can realize the generation of products at ambient temperature, and reduces the reaction cost and the energy consumption cost.
(5) The method uses the organic base, is easy to treat and recover after the reaction is finished, and avoids the problems of complex operation and pollution caused by using strong base.
(6) The reaction separation yield of the invention can reach 83-95%.
Drawings
The foregoing and/or other advantages of the invention will become further apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.
FIG. 1 is a schematic reaction scheme.
FIG. 2 is a schematic view of a microfluidic field reaction device.
FIG. 3 is a hydrogen spectrum of compound 4- ((4-methoxybenzyl) thio) pyridine.
FIG. 4 is a carbon spectrum of compound 4- ((4-methoxybenzyl) thio) pyridine.
FIG. 5 is a hydrogen spectrum of compound 2-chloro-4- ((4-methoxybenzyl) thio) pyridine.
FIG. 6 is a carbon spectrum diagram of compound 2-chloro-4- ((4-methoxybenzyl) thio) pyridine.
FIG. 7 is a hydrogen spectrum of compound 2-chloro-4- ((4-chlorobenzyl) thio) pyridine.
FIG. 8 is a carbon spectrum of compound 2-chloro-4- ((4-chlorobenzyl) thio) pyridine.
FIG. 9 is a hydrogen spectrum diagram of compound 4- ((4-methoxybenzyl) thio) -2-phenylpyridine.
FIG. 10 is a carbon spectrum diagram of compound 4- ((4-methoxybenzyl) thio) -2-phenylpyridine.
FIG. 11 is a hydrogen spectrum of compound methyl 2- ((2-phenylpyridin-4-yl) thio) acetate.
FIG. 12 is a carbon spectrum of compound methyl 2- ((2-phenylpyridin-4-yl) thio) acetate.
FIG. 13 is a hydrogen spectrum of compound methyl 3- ((2-phenylpyridin-4-yl) thio) propionate.
FIG. 14 is a carbon spectrum of compound methyl 3- ((2-phenylpyridin-4-yl) thio) propionate.
Detailed Description
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
In the following examples, the flow rates of the first reaction solution and the second reaction solution are the same, and in the following examples, the pumping flow rate is the sum of the total flow rates of the first reaction solution and the second reaction solution.
The reaction described in the examples below was carried out at room temperature.
Example 1
70uL (0.5mmol,1.0equiv) of 4-methoxybenzylthiol was weighed out and dissolved in 5.0mL of dichloromethane, and 104uL (0.75mmol,1.5equiv) of triethylamine was added to prepare a first reaction solution. Then, 0.37g (0.75mmol,1.5equiv) of triphenyl (pyridin-4-yl) phosphonium trifluoromethanesulfonate was weighed and dissolved in 5.0mL of dichloromethane to prepare a second reaction solution. Pumping the reaction liquid by a syringe, pumping the reaction liquid into a Y-shaped mixer by a syringe pump at the same time, fully mixing the reaction liquid and the mixture, and allowing the reaction liquid to flow into a micro-flow field reactor with the inner diameter of 0.8mm for reaction. The length of the pipeline of the micro-flow field reactor is 4m, the volume is 2.0mL, the pumping flow rate of the injection pump is set to be 0.2mL/min, and the reaction residence time is 10.0 minutes. TLC tracing detection reaction, after the reaction is finished, quenching the reaction solution, removing the solvent by reduced pressure distillation, and then obtaining 101.6mg of target 4-mercaptopyridine compound by silica gel column chromatography (eluent is petroleum ether: ethyl acetate), with the yield of 88%. The hydrogen and carbon spectral characterization data of the product are shown below (fig. 3, fig. 4):1H NMR(400MHz,Chloroform-d)δ8.37(d,J＝5.2Hz,2H),7.33–7.27(m,2H),7.11(dd,J＝4.8,1.4Hz,2H),6.90–6.83(m,2H),4.16(s,2H),3.79(s,3H).13C NMR(101MHz,Chloroform-d)δ159.14,149.25,149.21,129.90,127.31,120.81,114.22,55.30,35.17.
example 2
70uL (0.5mmol,1.0equiv) of 4-methoxybenzylthiol was weighed, dissolved in 5.0mL of tetrahydrofuran, and 104uL (0.75mmol,1.5equiv) of triethylamine was added to prepare a first reaction solution. Then, 0.37g (0.75mmol,1.5equiv) of triphenyl (pyridin-4-yl) phosphonium trifluoromethanesulfonate was weighed and dissolved in 5.0mL of tetrahydrofuran to prepare a second reaction solution. Pumping the reaction liquid by a syringe, pumping the reaction liquid into a Y-shaped mixer by a syringe pump at the same time, fully mixing the reaction liquid and the mixture, and allowing the reaction liquid to flow into a micro-flow field reactor with the inner diameter of 0.8mm for reaction. The length of the pipeline of the micro-flow field reactor is 4m, the volume is 2.0mL, the pumping flow rate of the injection pump is set to be 0.2mL/min, and the reaction residence time is 10.0 minutes. TLC tracking detection reaction, after the reaction is finished, quenching the reaction solution, removing the solvent by reduced pressure distillation, and then obtaining 103.9mg of the target 4-mercaptopyridine compound by silica gel column chromatography (eluent is petroleum ether: ethyl acetate), wherein the yield is 90%.
Example 3
70uL (0.5mmol,1.0equiv) of 4-methoxybenzylthiol was weighed, dissolved in 5.0mL of acetonitrile, and 104uL (0.75mmol,1.5equiv) of triethylamine was added to prepare a first reaction solution. Then, 0.37g (0.75mmol,1.5equiv) of triphenyl (pyridin-4-yl) phosphonium trifluoromethanesulfonate was weighed and dissolved in 5.0mL of acetonitrile to prepare a second reaction solution. Pumping the reaction liquid by a syringe, pumping the reaction liquid into a Y-shaped mixer by a syringe pump at the same time, fully mixing the reaction liquid and the mixture, and allowing the reaction liquid to flow into a micro-flow field reactor with the inner diameter of 0.8mm for reaction. The length of the pipeline of the micro-flow field reactor is 4m, the volume is 2.0mL, the pumping flow rate of the injection pump is set to be 0.2mL/min, and the reaction residence time is 10.0 minutes. TLC tracking detection reaction, after the reaction is finished, quenching the reaction solution, removing the solvent by reduced pressure distillation, and then obtaining the target 4-mercaptopyridine compound 98.2mg with the yield of 85% by silica gel column chromatography (the eluent is petroleum ether: ethyl acetate).
Example 4
70uL (0.5mmol,1.0equiv) of 4-methoxybenzylthiol was weighed, dissolved in 5.0mL of tetrahydrofuran, and 104uL (0.75mmol,1.5equiv) of triethylamine was added to prepare a first reaction solution. Then, 0.37g (0.75mmol,1.5equiv) of triphenyl (pyridin-4-yl) phosphonium trifluoromethanesulfonate was weighed and dissolved in 5.0mL of tetrahydrofuran to prepare a second reaction solution. Pumping the reaction liquid by a syringe, pumping the reaction liquid into a Y-shaped mixer by a syringe pump at the same time, fully mixing the reaction liquid and the mixture, and allowing the reaction liquid to flow into a micro-flow field reactor with the inner diameter of 0.8mm for reaction. The length of the pipeline of the micro-flow field reactor is 4m, the volume is 2.0mL, the pumping flow rate of the injection pump is set to be 0.1mL/min, and the reaction residence time is 20.0 minutes. TLC tracing detection reaction, after the reaction is finished, quenching the reaction solution, removing the solvent by reduced pressure distillation, and then obtaining 109.7mg of target 4-mercaptopyridine compound by silica gel column chromatography (eluent is petroleum ether: ethyl acetate), with the yield of 95%.
Example 5
70uL (0.5mmol,1.0equiv) of 4-methoxybenzylthiol was weighed, dissolved in 5.0mL of tetrahydrofuran, and 104uL (0.75mmol,1.5equiv) of triethylamine was added to prepare a first reaction solution. Then, 0.37g (0.75mmol,1.5equiv) of triphenyl (pyridin-4-yl) phosphonium trifluoromethanesulfonate was weighed and dissolved in 5.0mL of tetrahydrofuran to prepare a second reaction solution. Pumping the reaction liquid by a syringe, pumping the reaction liquid into a Y-shaped mixer by a syringe pump at the same time, fully mixing the reaction liquid and the mixture, and allowing the reaction liquid to flow into a micro-flow field reactor with the inner diameter of 0.8mm for reaction. The length of the pipeline of the micro-flow field reactor is 4m, the volume is 2.0mL, the pumping flow rate of the injection pump is set to be 0.3mL/min, and the reaction residence time is 6.7 minutes. TLC tracing detection reaction, after the reaction is finished, quenching the reaction solution, removing the solvent by reduced pressure distillation, and then obtaining 95.8mg of target 4-mercaptopyridine compound by silica gel column chromatography (eluent is petroleum ether: ethyl acetate), wherein the yield is 83%.
Example 6
70uL (0.5mmol,1.0equiv) of 4-methoxybenzylthiol was weighed, dissolved in 5.0mL of tetrahydrofuran, and 104uL (0.75mmol,1.5equiv) of triethylamine was added to prepare a first reaction solution. Then, 0.39g (0.75mmol,1.5equiv) of (2-chloropyridin-4-yl) triphenylphosphonium trifluoromethanesulfonate was weighed out and dissolved in 5.0mL of tetrahydrofuran to prepare a second reaction solution. Pumping the reaction liquid by a syringe, pumping the reaction liquid into a Y-shaped mixer by a syringe pump at the same time, fully mixing the reaction liquid and the mixture, and allowing the reaction liquid to flow into a micro-flow field reactor with the inner diameter of 0.8mm for reaction. The length of the pipeline of the micro-flow field reactor is 4m, the volume is 2.0mL, the pumping flow rate of the injection pump is set to be 0.1mL/min, and the reaction residence time is 20.0 minutes. TLC tracing detection reaction, after the reaction is finished, quenching the reaction solution, removing the solvent by reduced pressure distillation, and then obtaining 113.9mg of the target 4-mercaptopyridine compound by silica gel column chromatography (eluent is petroleum ether: ethyl acetate), wherein the yield is 86%. The hydrogen and carbon spectral characterization data of the product are shown below (fig. 5, 6): 1H NMR (400MHz, Chloroform-d) δ 8.07(d, J ═ 5.4Hz,1H), 7.26-7.20 (m,2H),7.07(d, J ═ 1.5Hz,1H),6.94(dd, J ═ 5.4,1.7Hz,1H), 6.83-6.77 (m,2H),4.10(s,2H),3.73(s,3H).13C NMR (101MHz, Chloroform-d) δ 158.25,151.54,150.61,147.75,128.91,125.54,119.18,118.43,113.28,54.29,34.26.
Example 7
66uL (0.5mmol,1.0equiv) of 4-chlorobenzenethiol was weighed, dissolved in 5.0mL of tetrahydrofuran, and 104uL (0.75mmol,1.5equiv) of triethylamine was added to prepare a first reaction solution. Then, 0.39g (0.75mmol,1.5equiv) of (2-chloropyridin-4-yl) triphenylphosphonium trifluoromethanesulfonate was weighed out and dissolved in 5.0mL of tetrahydrofuran to prepare a second reaction solution. Pumping the reaction liquid by a syringe, pumping the reaction liquid into a Y-shaped mixer by a syringe pump at the same time, fully mixing the reaction liquid and the mixture, and allowing the reaction liquid to flow into a micro-flow field reactor with the inner diameter of 0.8mm for reaction. The length of the pipeline of the micro-flow field reactor is 4m, the volume is 2.0mL, the pumping flow rate of the injection pump is set to be 0.1mL/min, and the reaction residence time is 20.0 minutes. TLC tracing detection reaction, after the reaction is finished, quenching the reaction solution, removing the solvent by reduced pressure distillation, and then obtaining 111.6mg of target 4-mercaptopyridine compound by silica gel column chromatography (eluent is petroleum ether: ethyl acetate), wherein the yield is 83%. The hydrogen and carbon spectral characterization data of the product are shown below (fig. 7, 8): 1H NMR (400MHz, Chloroform-d) δ 8.15(d, J ═ 5.4Hz,1H),7.32(s,4H),7.12(d, J ═ 1.5Hz,1H),7.00(dd, J ═ 5.4,1.7Hz,1H),4.18(s,2H), 13C NMR (101MHz, Chloroform-d) δ 151.82,151.75,148.93,133.87,133.43,130.05,129.13,120.32,119.49,35.14.
Example 8
70uL (0.5mmol,1.0equiv) of 4-methoxybenzylthiol was weighed, dissolved in 5.0mL of tetrahydrofuran, and 104uL (0.75mmol,1.5equiv) of triethylamine was added to prepare a first reaction solution. Then, 0.42g (0.75mmol,1.5equiv) of triphenyl (2-phenylpyridin-4-yl) phosphonium trifluoromethanesulfonate was weighed and dissolved in 5.0mL of tetrahydrofuran to prepare a second reaction solution. Pumping the reaction liquid by a syringe, pumping the reaction liquid into a Y-shaped mixer by a syringe pump at the same time, fully mixing the reaction liquid and the mixture, and allowing the reaction liquid to flow into a micro-flow field reactor with the inner diameter of 0.8mm for reaction. The length of the pipeline of the micro-flow field reactor is 4m, the volume is 2.0mL, the pumping flow rate of the injection pump is set to be 0.1mL/min, and the reaction residence time is 20.0 minutes. TLC tracking detection reaction, after the reaction is finished, quenching the reaction solution, removing the solvent by reduced pressure distillation, and then obtaining the target 4-mercaptopyridine compound 130.5mg with the yield of 85% by silica gel column chromatography (the eluent is petroleum ether: ethyl acetate). The hydrogen and carbon spectral characterization data of the product are shown below (fig. 9, 10): 1H NMR (400MHz, Chloroform-d) δ 8.39(d, J ═ 5.3Hz,1H), 7.87-7.81 (m,2H),7.47(d, J ═ 1.3Hz,1H), 7.41-7.33 (m,3H), 7.29-7.24 (m,2H),7.00(dd, J ═ 5.3,1.8Hz,1H), 6.84-6.78 (m,2H),4.16(s,2H),3.73(s,3H), 13C NMR (101MHz, Chloroform-d) δ 159.15,157.28,149.69,149.19,139.14,129.94,129.13,128.75,127.51,126.99,119.29,117.94,114.24,55.33,35.42.
Example 9
Ethylthioglycolate (45 uL) (0.5mmol,1.0equiv) was weighed, dissolved in 5.0mL of tetrahydrofuran, and triethylamine (104 uL) (0.75mmol,1.5equiv) was added to prepare a first reaction solution. 0.42g (0.75mmol,1.5equiv) of triphenyl (2-phenylpyridin-4-yl) phosphonium trifluoromethanesulfonate was weighed and dissolved in 5.0mL of tetrahydrofuran to prepare a second reaction solution. Pumping the reaction liquid by a syringe, pumping the reaction liquid into a Y-shaped mixer by a syringe pump at the same time, fully mixing the reaction liquid and the mixture, and allowing the reaction liquid to flow into a micro-flow field reactor with the inner diameter of 0.8mm for reaction. The length of the pipeline of the micro-flow field reactor is 4m, the volume is 2.0mL, the pumping flow rate of the injection pump is set to be 0.1mL/min, and the reaction residence time is 20.0 minutes. TLC tracing detection reaction, after the reaction is finished, quenching the reaction solution, removing the solvent by reduced pressure distillation, and then obtaining the target 4-mercaptopyridine compound 120.4mg with 93% yield by silica gel column chromatography (eluent is petroleum ether: ethyl acetate). The hydrogen and carbon spectral characterization data of the product are shown below (fig. 11, 12): 1H NMR (400MHz, Chloroform-d) δ 8.42(d, J ═ 5.3Hz,1H),7.87(d, J ═ 7.1Hz,2H),7.53(s,1H), 7.41-7.30 (m,3H),7.01(dt, J ═ 5.2,1.8Hz,1H),3.69(d, J ═ 2.0Hz,2H),3.68(d, J ═ 2.2Hz,3H), 13C NMR (101MHz, Chloroform-d) δ 168.25,156.45,148.35,146.86,137.82,128.22,127.75,125.93,117.89,116.57,51.94,32.18.
Example 10
55uL (0.5mmol,1.0equiv) of methyl 3-mercaptopropionate was weighed, dissolved in 5.0mL of tetrahydrofuran, and 104uL (0.75mmol,1.5equiv) of triethylamine was added to prepare a first reaction solution. 0.42g (0.75mmol,1.5equiv) of triphenyl (2-phenylpyridin-4-yl) phosphonium trifluoromethanesulfonate was weighed and dissolved in 5.0mL of tetrahydrofuran to prepare a second reaction solution. Pumping the reaction liquid by a syringe, pumping the reaction liquid into a Y-shaped mixer by a syringe pump at the same time, fully mixing the reaction liquid and the mixture, and allowing the reaction liquid to flow into a micro-flow field reactor with the inner diameter of 0.8mm for reaction. The length of the pipeline of the micro-flow field reactor is 4m, the volume is 2.0mL, the pumping flow rate of the injection pump is set to be 0.1mL/min, and the reaction residence time is 20.0 minutes. TLC (thin layer chromatography) tracking detection reaction, quenching the reaction solution after the reaction is finished, distilling under reduced pressure to remove the solvent, and performing silica gel column chromatography (eluent is petroleum ether: ethyl acetate) to obtain 122.9mg of the target 4-mercaptopyridine compound with the yield of 90%. The hydrogen and carbon spectral characterization data of the product are shown below (fig. 13, 14): 1H NMR (400MHz, Chloroform-d) δ 8.51(d, J ═ 5.3Hz,1H), 7.97-7.93 (m,2H),7.55(d, J ═ 1.3Hz,1H),7.44(dtd, J ═ 12.9,7.3,6.7,2.8Hz,3H),7.08(dd, J ═ 5.3,1.8Hz,1H),3.73(s,3H),3.32(t, J ═ 7.4Hz,2H),2.76(t, J ═ 7.3Hz,2H), 13C NMR (101MHz, Chloroform-d) δ 171.73,157.52,149.36,148.57,138.98,129.25,128.80,127.03,119.17,118.00,52.10,33.52,25.85.
Comparative example 1
A dry, stirred Schlenk reaction tube was charged with 70uL (0.5mmol,1.0equiv) of 4-methoxybenzylmercaptan, 104uL (0.75mmol,1.5equiv) of triethylamine, and 5.0mL of tetrahydrofuran, in that order, under an argon atmosphere. The reaction tube was then placed in an ice bath at 0 deg.C and 0.03g of sodium hydride (0.75mmol,1.5equiv) was added, followed by the addition of 0.37g (0.75mmol,1.5equiv) of triphenyl (pyridin-4-yl) phosphonium triflate. After the argon gas was replaced three times, the reaction was stirred at room temperature for 12 hours. TLC tracking detection reaction, after the reaction is finished, quenching the reaction solution, removing the solvent by reduced pressure distillation, and then obtaining the target 4-mercaptopyridine compound 92.3mg with the yield of 80% by silica gel column chromatography (the eluent is petroleum ether: ethyl acetate).
The present invention provides a method and a concept for synthesizing thiopyridines using a microchannel reactor, and a method and a way for implementing the method and the concept are numerous, and the above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, a plurality of modifications and embellishments can be made without departing from the principle of the present invention, and these modifications and embellishments should also be regarded as the protection scope of the present invention. All the components not specified in the present embodiment can be realized by the prior art.
Claims (10)
1. A method for preparing 4-mercaptopyridine compounds by a micro-flow field reactor technology is characterized by comprising the following steps: reacting a first reaction liquid containing a thiol compound shown in a formula 1, a first solvent and an additive with a second reaction liquid containing a pyridine compound shown in a formula 2 and a second solvent in a micro-flow field reactor, and collecting an effluent reaction liquid, namely the reaction liquid containing the 4-mercaptopyridine compound shown in the formula 3;
wherein,
r is selected from phenyl, substituted phenyl or fatty acid methyl ester; the substitution is any one or more of halogen substitution, C1-C6 alkyl substitution and C1-C6 alkoxy substitution;
R1selected from hydrogen, halogen, alkyl, alkoxy, or phenyl.
2. The method according to claim 1, wherein the first solvent and the second solvent are each independently selected from the group consisting of dichloromethane, acetone, ethyl acetate, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, and dimethylsulfoxide, or a combination thereof.
3. The method of claim 1, wherein the additive is a basic compound.
4. The method according to claim 1 or 3, wherein the additive is any one or more of sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, triethylamine, 4-dimethylaminopyridine, 1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene, N, N-diisopropylethylamine, N, N, N ', N' -tetramethylethylenediamine and 2, 6-lutidine.
5. The method according to claim 1, wherein the concentration of the thiol compound represented by formula 1 in the first reaction solution is 0.05 to 2.0 mmol/mL.
6. The method according to claim 1, wherein the molar ratio of the thiol compound represented by formula 1 to the additive in the first reaction solution is 1 (1-5).
7. The method according to claim 1, wherein the molar ratio of the thiol compound represented by formula 1 to the pyridine compound represented by formula 2 is 1 (1-5).
8. The method according to claim 1, wherein the concentration of the pyridine compound represented by formula 2 in the second reaction solution is 0.05 to 0.25 mmol/mL.
9. The method according to claim 1, wherein the reaction temperature is 20 to 30 ℃.
10. The process according to claim 1, wherein the residence time of the reaction is 30s to 30 min.
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