CN112679494B - Preparation method of pyrazolo [1,5-a ] pyridine derivative - Google Patents
Preparation method of pyrazolo [1,5-a ] pyridine derivative Download PDFInfo
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- DVUBDHRTVYLIPA-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine Chemical class C1=CC=CN2N=CC=C21 DVUBDHRTVYLIPA-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 69
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims abstract description 17
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 44
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- 150000003222 pyridines Chemical class 0.000 claims description 23
- 239000003208 petroleum Substances 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000012046 mixed solvent Substances 0.000 claims description 11
- 239000000741 silica gel Substances 0.000 claims description 11
- 229910002027 silica gel Inorganic materials 0.000 claims description 11
- UCDOJQCUOURTPS-UHFFFAOYSA-N ethyl 2-bromoprop-2-enoate Chemical compound CCOC(=O)C(Br)=C UCDOJQCUOURTPS-UHFFFAOYSA-N 0.000 claims description 6
- OYUNTGBISCIYPW-UHFFFAOYSA-N 2-chloroprop-2-enenitrile Chemical compound ClC(=C)C#N OYUNTGBISCIYPW-UHFFFAOYSA-N 0.000 claims description 3
- OVVAHDSHDPZGMY-UHFFFAOYSA-N ethyl 3-(2-bromophenyl)prop-2-enoate Chemical compound CCOC(=O)C=CC1=CC=CC=C1Br OVVAHDSHDPZGMY-UHFFFAOYSA-N 0.000 claims description 3
- CDZAAIHWZYWBSS-UHFFFAOYSA-N 2-bromoethyl prop-2-enoate Chemical compound BrCCOC(=O)C=C CDZAAIHWZYWBSS-UHFFFAOYSA-N 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 abstract description 12
- 150000001336 alkenes Chemical class 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 7
- 239000003960 organic solvent Substances 0.000 abstract description 7
- 238000006555 catalytic reaction Methods 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 229910052751 metal Inorganic materials 0.000 abstract description 4
- 239000002184 metal Substances 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 239000000654 additive Substances 0.000 abstract description 3
- 238000003541 multi-stage reaction Methods 0.000 abstract description 3
- 239000007800 oxidant agent Substances 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 238000007405 data analysis Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical class C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000003248 quinolines Chemical class 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 229910052801 chlorine Chemical group 0.000 description 2
- 239000000460 chlorine Chemical group 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- -1 alkyl Grignard reagent Chemical class 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229960001271 desloratadine Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention discloses a preparation method of pyrazolo [1,5-a ] pyridine derivatives, and belongs to the field of organic synthesis. Solves the problems that the existing synthesis method of pyrazolo [1,5-a ] pyridine structure needs metal catalysis, limits the range of substrates, has lower total yield of multi-step reaction, and has strict stoichiometric additives, toxic oxidants, anaerobic technology and reaction conditions. The method comprises the following steps: dissolving pyridinium, unsaturated alkene and 2, 3-dichloro-5, 6-dicyanobenzoquinone in an organic solvent, dropwise adding triethylamine for reaction, concentrating by a rotary evaporator to remove the solvent, and separating and purifying by silica gel column chromatography to obtain pyrazolo [1,5-a ] pyridine derivatives.
Description
Technical Field
The invention belongs to the field of organic synthesis.
Background
The pyrazolo [1,5-a ] pyridine core skeleton structure compound has special biological and chemical properties, so that the pyrazolo [1,5-a ] pyridine core skeleton structure compound has important application value in the fields of natural products, pesticides, medicines (compounds 1 and 2), catalysts (compound 3), functional materials and the like. Meanwhile, pyrazolo [1,5-a ] pyridine compounds are widely distributed in nature, are abundant in quantity, are rich in structure type, are remarkable in biological activity and diversified, are attractive in the field of medicine research and development, are continuously and successfully applied to clinic, are huge in market demand and are significant in synthetic research.
Pyrazolo [1,5-a ] pyridine active compounds are widely distributed in natural products and drug molecules, and are common organic molecular building blocks. Pyrazolo [1,5-a ] pyridine core skeleton drugs such as vitamin E, desloratadine and the like have good biological activity in the aspects of treating prostatic cancer, allergic rhinitis and the like. The biochemical property is unique, so that the medicine has wide development prospect and great significance in synthesis research.
At present, the traditional method for constructing pyrazolo [1,5-a ] pyridine structures is mainly realized by reacting pyrazolo [1,5-a ] pyridine derivatives with halogenated aromatic hydrocarbon and alkyl Grignard reagent under the synergistic catalysis of ligands by using a transition metal Pd or copper reagent. And the existing synthesis method comprises the following steps: the substrate range is limited, the total yield of the multi-step reaction is low (the yield is only 40%), the stoichiometric additive (the addition amount is more), the toxic oxidant, the anaerobic technology and the reaction condition are harsh, and the like. Therefore, the synthesis of pyrazolo [1,5-a ] pyridine compounds has important significance. Therefore, the synthesis method of pyrazolo [1,5-a ] pyridine derivatives with mild conditions, simple method and high yield is sought to be solved urgently.
Disclosure of Invention
The invention aims to solve the problems that the existing synthesis method of pyrazolo [1,5-a ] pyridine structure needs metal catalysis, limits the range of substrates, has lower total yield of multi-step reaction, and has harsh stoichiometric additives, toxic oxidants, anaerobic technology and reaction conditions, and provides a preparation method of pyrazolo [1,5-a ] pyridine derivatives.
A preparation method of pyrazolo [1,5-a ] pyridine derivatives is carried out according to the following steps:
at room temperature, dissolving pyridinium, unsaturated alkene and 2, 3-dichloro-5, 6-dicyanobenzoquinone in an organic solvent, dropwise adding triethylamine at a dropwise speed of 4-6 mL/min, reacting for 10-24 h at a temperature of 0-10 ℃ and a stirring speed of 200-400 r/min, concentrating by a rotary evaporator to remove the solvent, and separating and purifying by silica gel column chromatography to obtain pyrazolo [1,5-a ] pyridine derivatives;
the structural general formula of the pyridine salt is
R 1 Is alkyl, alkoxy, halogen, trifluoromethyl or phenyl, and the aromatic ring Ar is pyridine, quinoline, pyridine derivative or quinoline derivative;
the structural general formula of the unsaturated alkene is
R 2 Is hydrogen, alkyl or aryl, R 3 Is cyano, ester, ketone or aldehyde, X is bromine or chlorine;
the molar ratio of the pyridine salt to the unsaturated alkene is 1 (1.5-2); the molar ratio of the pyridine salt to the triethylamine is 1 (2-3); the molar ratio of the pyridine salt to the 2, 3-dichloro-5, 6-dicyanobenzoquinone is 1 (1-1.5); the volume ratio of the molar ratio of the pyridine salt to the organic solvent is 1mmol (8-12) mL.
The beneficial effects of the invention are as follows: the invention provides a preparation method of pyrazolo [1,5-a ] pyridine derivatives, which has potential bioactivity and research value, and can be used as a lead drug for screening, bioactivity test research and the like; the method solves the problems that the existing pyrazolo [1,5-a ] pyridine derivative is subjected to metal catalysis and high-temperature, anhydrous, anaerobic and other harsh reaction conditions are required, and the synthesis route of the pyrazolo [1,5-a ] pyridine derivative is mild in condition, simple in method and high in yield, the yield can reach more than 70%, and the purity of the product is more than 95%.
The invention is used for a preparation method of pyrazolo [1,5-a ] pyridine derivatives.
Drawings
FIG. 1 shows a pyridopyrazole derivative prepared according to example one 1 HNMR spectrogram;
FIG. 2 shows a pyridopyrazole derivative prepared according to example one 13 CNMR spectra.
Detailed Description
The first embodiment is as follows: the preparation method of the pyrazolo [1,5-a ] pyridine derivative comprises the following steps:
at room temperature, dissolving pyridinium, unsaturated alkene and 2, 3-dichloro-5, 6-dicyanobenzoquinone in an organic solvent, dropwise adding triethylamine at a dropwise speed of 4-6 mL/min, reacting for 10-24 h at a temperature of 0-10 ℃ and a stirring speed of 200-400 r/min, concentrating by a rotary evaporator to remove the solvent, and separating and purifying by silica gel column chromatography to obtain pyrazolo [1,5-a ] pyridine derivatives;
the structural general formula of the pyridine salt is
R 1 Is alkyl, alkoxy, halogen, trifluoromethyl or phenyl, and the aromatic ring Ar is pyridine, quinoline, pyridine derivative or quinoline derivative;
the structural general formula of the unsaturated alkene is
R 2 Is hydrogen, alkyl or aryl, R 3 Is cyano, ester, ketone or aldehyde, X is bromine or chlorine;
the molar ratio of the pyridine salt to the unsaturated alkene is 1 (1.5-2); the molar ratio of the pyridine salt to the triethylamine is 1 (2-3); the molar ratio of the pyridine salt to the 2, 3-dichloro-5, 6-dicyanobenzoquinone is 1 (1-1.5); the volume ratio of the molar ratio of the pyridine salt to the organic solvent is 1mmol (8-12) mL.
The structural general formula of the pyrazolo [1,5-a ] pyridine derivative prepared by the specific embodiment is as follows:
R 1 is alkyl, alkoxy, halogen, trifluoromethyl or phenyl, R 2 Is hydrogen, alkyl or aryl, R 3 Is cyano, ester, ketone or aldehyde, and the aromatic ring Ar is pyridine, quinoline, pyridine derivative or quinoline derivative.
This embodiment R 3 Is an electron withdrawing group.
The reaction route of the specific embodiment is as follows:
The beneficial effects of this concrete implementation are: the specific embodiment provides a preparation method of pyrazolo [1,5-a ] pyridine derivatives, which have potential biological activity and research value, and can be used as a lead drug for screening, biological activity test research and the like; the method solves the problems that the existing pyrazolo [1,5-a ] pyridine derivative needs metal catalysis and needs harsh reaction conditions such as high temperature, no water and no oxygen, and the like, and the synthetic route of the pyrazolo [1,5-a ] pyridine derivative is mild in condition, simple in method and high in yield, the yield can reach more than 70%, and the purity of the product is more than 95%.
The second embodiment is as follows: the first difference between this embodiment and the specific embodiment is that: the organic solvent is acetonitrile, toluene, N-dimethylformamide or dimethyl sulfoxide. The other is the same as in the first embodiment.
And a third specific embodiment: this embodiment differs from one or both of the embodiments in that: the solvent used for separating and purifying the silica gel column is a mixed solvent of petroleum ether and ethyl acetate. The other is the same as the first or second embodiment.
The specific embodiment IV is as follows: this embodiment differs from one of the first to third embodiments in that: the volume ratio of petroleum ether to ethyl acetate is (50-20): 1. The other embodiments are the same as those of the first to third embodiments.
Fifth embodiment: this embodiment differs from one to four embodiments in that: and dripping triethylamine with the dripping speed of 5-6 mL/min. The other embodiments are the same as those of the first to fourth embodiments.
Specific embodiment six: this embodiment differs from one of the first to fifth embodiments in that: reacting for 12-24 h under the conditions of the temperature of 0-10 ℃ and the stirring speed of 300-400 r/min. The other embodiments are the same as those of the first to fifth embodiments.
Seventh embodiment: this embodiment differs from one of the first to sixth embodiments in that: the molar ratio of the pyridine salt to the unsaturated alkene is 1:1.5. The other embodiments are the same as those of the first to sixth embodiments.
Eighth embodiment: this embodiment differs from one of the first to seventh embodiments in that: the molar ratio of the pyridine salt to the triethylamine is 1:2. The other is the same as in embodiments one to seven.
Detailed description nine: this embodiment differs from one to eight of the embodiments in that: the molar ratio of the pyridine salt to the 2, 3-dichloro-5, 6-dicyanobenzoquinone is 1 (1-1.1). The others are the same as in embodiments one to eight.
Detailed description ten: this embodiment differs from one of the embodiments one to nine in that: the volume ratio of the molar ratio of the pyridine salt to the organic solvent is 1mmol (10-12) mL. The others are the same as in embodiments one to nine.
The following examples are used to verify the benefits of the present invention:
embodiment one:
402.0mg (0.1 mmol) of pyridine salt, 198mg (0.15 mmol) of 2-chloroacrylonitrile and 250mg (0.11 mmol) of 2, 3-dichloro-5, 6-dicyanobenzoquinone are dissolved in 1.2mL of acetonitrile at room temperature, 202mg (0.2 mmol) of triethylamine is dropwise added at a dropping speed of 5mL/min, the mixture is reacted for 15h at a temperature of 0-10 ℃ and a stirring speed of 300r/min, the solvent is removed by concentration through a rotary evaporator, and then the mixture is separated and purified through silica gel column chromatography to obtain the corresponding pyrazolo [1,5-a ] pyridine derivative;
the solvent used for separating and purifying the silica gel column is a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate is 20:1.
The reaction formula is as follows:
wherein 2, 3-dichloro-5, 6-dicyanobenzoquinone is DDQ and triethylamine is Et 3 N。
The purity of the product was 97% and the yield was 80%.
FIG. 1 shows a pyridopyrazole derivative prepared according to example one 1 HNMR spectrogram; FIG. 2 shows a pyridopyrazole derivative prepared according to example one 13 CNMR spectrogram; the nuclear magnetic data analysis is: 1 HNMR(400MHz，CDCl 3 )：δ H 8.33(s，1H)，8.13(s，1H)，6.75(s，1H)，4.04(s，3H)。
13 CNMR(101MHz，CDCl 3 )：δ C 150.8，145.4，135.0，123.0，113.7，109.1，108.2，83.0，56.8。
embodiment two:
294.0mg (0.1 mmol) of pyridinium, 269mg (0.15 mmol) of ethyl 2-bromoacrylate and 250mg (0.11 mmol) of 2, 3-dichloro-5, 6-dicyanobenzoquinone are dissolved in 1.2mL of acetonitrile at a dropping speed of 5mL/min, 202mg (0.2 mmol) of triethylamine is added dropwise, the mixture is reacted for 12h at a temperature of 0-10 ℃ and a stirring speed of 300r/min, the solvent is removed by concentration through a rotary evaporator, and then the mixture is separated and purified through silica gel column chromatography to obtain the corresponding pyrazolo [1,5-a ] pyridine derivative;
the solvent used for separating and purifying the silica gel column is a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate is 20:1.
The reaction formula is as follows:
wherein 2, 3-dichloro-5, 6-dicyanobenzoquinone is DDQ and triethylamine is Et 3 N。
The purity of the product was 95% and the yield was 71%.
The nuclear magnetic data analysis is: 1 HNMR(400MHz，CDCl 3 )：δ H 8.42(d，J＝7.0Hz，1H)，8.30(s，1H)，8.10(d，J＝9.0Hz，1H)，7.30(t，J＝8.0Hz，1H)，6.86(t，J＝6.5Hz，1H)，4.31(q，J＝7.0Hz，2H)，1.33(t，J＝7.0Hz，3H)。
13 CNMR(101MHz，CDCl 3 )：δ C 163.4，144.6，140.7，129.1，127.1，119.1，113.4，103.9，59.7，14.4。
embodiment III:
372.0mg (0.1 mmol) of pyridinium, 269mg (0.15 mmol) of ethyl 2-bromoacrylate and 250mg (0.11 mmol) of 2, 3-dichloro-5, 6-dicyanobenzoquinone are dissolved in 1.2mL of acetonitrile at a dropping speed of 5mL/min, 202mg (0.2 mmol) of triethylamine is added dropwise, the mixture is reacted for 12h at a temperature of 0-10 ℃ and a stirring speed of 300r/min, the solvent is removed by concentration through a rotary evaporator, and then the mixture is separated and purified through silica gel column chromatography to obtain the corresponding pyrazolo [1,5-a ] pyridine derivative;
the solvent used for separating and purifying the silica gel column is a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate is 20:1.
The reaction formula is as follows:
wherein 2, 3-dichloro-5, 6-dicyanobenzoquinone is DDQ and triethylamine is Et 3 N。
The purity of the product was 97% and the yield was 88%.
The nuclear magnetic data analysis is: 1 HNMR(400MHz，CDCl 3 )：δ H 8.52(s，1H)，8.20(dd，J＝8.1，2.0Hz，1H)，7.34-7.26(m，2H)，4.42(q，J＝7.1Hz，2H)，1.43(t，J＝7.1Hz，3H)。
13 CNMR(101MHz，CDCl 3 )：δ C 163.3，144.6，142.7，127.6，119.9，118.2，118.2，106.0，60.4，14.5。
embodiment four:
448.0mg (0.1 mmol) of pyridinium, 269mg (0.15 mmol) of ethyl 2-bromoacrylate and 250mg (0.11 mmol) of 2, 3-dichloro-5, 6-dicyanobenzoquinone are dissolved in 1.2mL of acetonitrile at a dropping speed of 5mL/min, 202mg (0.2 mmol) of triethylamine is added dropwise, the mixture is reacted for 12h at a temperature of 0-10 ℃ and a stirring speed of 300r/min, the solvent is removed by concentration through a rotary evaporator, and then the mixture is separated and purified through silica gel column chromatography to obtain the corresponding pyrazolo [1,5-a ] pyridine derivative;
the solvent used for separating and purifying the silica gel column is a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate is 20:1.
The reaction formula is as follows:
wherein 2, 3-dichloro-5, 6-dicyanobenzoquinone is DDQ and triethylamine is Et 3 N。
The purity of the product was 96% and the yield was 83%.
The nuclear magnetic data analysis is: 1 HNMR(400MHz，CDCl3)：δ H 8.40(s，1H)，7.90-7.96(m，1H)，7.36(d，J＝1.8Hz，1H)，4.37(q，J＝7.1Hz，2H)，2.72(q，J＝7.5，2H)，1.41(t，J＝7.1Hz，3H)，1.31(t，J＝7.6Hz，3H)。
13 CNMR(101MHz，CDCl3)：δ C 163.9，145.3，144.4，141.8，127.2，116.4，105.4，92.2，60.3，28.2，14.6，14.5。
fifth embodiment:
294.0mg (0.1 mmol) of pyridinium, 383 (0.15 mmol) of ethyl 2-bromocinnamate and 250mg (0.11 mmol) of 2, 3-dichloro-5, 6-dicyanobenzoquinone are dissolved in 1.2mL of acetonitrile at room temperature, 202mg (0.2 mmol) of triethylamine is dropwise added at a dropping speed of 5mL/min, the mixture is reacted for 12h at a temperature of 0-10 ℃ and a stirring speed of 300r/min, the solvent is removed by concentration through a rotary evaporator, and then the mixture is separated and purified through silica gel column chromatography to obtain the corresponding pyrazolo [1,5-a ] pyridine derivative;
the solvent used for separating and purifying the silica gel column is a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate is 20:1.
The reaction formula is as follows:
wherein 2, 3-dichloro-5, 6-dicyanobenzoquinone is DDQ and triethylamine is Et 3 N。
The purity of the product was 98% and the yield was 82%.
The nuclear magnetic data analysis is: 1 HNMR(400MHz，CDCl 3 )：δ H 8.55(d，J＝7.0Hz，1H)，8.24(d，J＝9.0Hz，1H)，7.80(q，J＝7.5Hz，2H)，7.46-7.40(m，4H)，6.98(t，J＝7.0Hz，1H)，4.33(q，J＝7.5Hz，2H)，1.31(t，J＝7.0Hz，3H)。
13 CNMR(101MHz，CDCl 3 )：δ C 163.6，129.8，128.9，127.7，127.2，119.6，113.9，59.8，14.2。
Claims (5)
1. a preparation method of pyrazolo [1,5-a ] pyridine derivatives is characterized by comprising the following steps:
dissolving 0.1mmol of pyridinium, 0.15mmol of 2-chloroacrylonitrile and 0.11mmol of 2, 3-dichloro-5, 6-dicyanobenzoquinone in 1.2mL of acetonitrile at room temperature, dropwise adding 0.2mmol of triethylamine at a dropwise speed of 5mL/min, reacting for 15h at a temperature of 0-10 ℃ and a stirring speed of 300r/min, concentrating by a rotary evaporator to remove the solvent, and separating and purifying by silica gel column chromatography to obtain pyrazolo [1,5-a ] pyridine derivatives;
the solvent used for separating and purifying the silica gel column is a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of the petroleum ether to the ethyl acetate is 20:1;
the structural formula of the pyridinium is
The structural formula of the 2-chloroacrylonitrile is
The pyrazolo [1,5-a ]]The pyridine derivative has the structural formula
The purity was 97% and the yield was 80%.
2. A preparation method of pyrazolo [1,5-a ] pyridine derivatives is characterized by comprising the following steps:
dissolving 0.1mmol of pyridinium, 0.15mmol of ethyl 2-bromoacrylate and 0.11mmol of 2, 3-dichloro-5, 6-dicyanobenzoquinone in 1.2mL of acetonitrile at a dropping speed of 5mL/min, dropwise adding 0.2mmol of triethylamine, reacting for 12h at a temperature of 0-10 ℃ and a stirring speed of 300r/min, concentrating by a rotary evaporator to remove the solvent, and separating and purifying by silica gel column chromatography to obtain pyrazolo [1,5-a ] pyridine derivatives;
the solvent used for separating and purifying the silica gel column is a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of the petroleum ether to the ethyl acetate is 20:1;
the structural formula of the pyridinium is
The structural formula of the 2-bromoethyl acrylate is
The pyrazolo [1,5-a ]]The pyridine derivative has the structural formula
Purity was 95% and yield was 71%.
3. A preparation method of pyrazolo [1,5-a ] pyridine derivatives is characterized by comprising the following steps:
dissolving 0.1mmol of pyridinium, 0.15mmol of ethyl 2-bromoacrylate and 0.11mmol of 2, 3-dichloro-5, 6-dicyanobenzoquinone in 1.2mL of acetonitrile at a dropping speed of 5mL/min, dropwise adding 0.2mmol of triethylamine, reacting for 12h at a temperature of 0-10 ℃ and a stirring speed of 300r/min, concentrating by a rotary evaporator to remove the solvent, and separating and purifying by silica gel column chromatography to obtain pyrazolo [1,5-a ] pyridine derivatives;
the solvent used for separating and purifying the silica gel column is a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of the petroleum ether to the ethyl acetate is 20:1;
the structural formula of the pyridinium is
The structural formula of the 2-bromoethyl acrylate is
The pyrazolo [1,5-a ]]The pyridine derivative has the structural formula
The purity was 97% and the yield was 88%.
4. A preparation method of pyrazolo [1,5-a ] pyridine derivatives is characterized by comprising the following steps:
dissolving 0.1mmol of pyridinium, 0.15mmol of ethyl 2-bromoacrylate and 0.11mmol of 2, 3-dichloro-5, 6-dicyanobenzoquinone in 1.2mL of acetonitrile at a dropping speed of 5mL/min, dropwise adding 0.2mmol of triethylamine, reacting for 12h at a temperature of 0-10 ℃ and a stirring speed of 300r/min, concentrating by a rotary evaporator to remove the solvent, and separating and purifying by silica gel column chromatography to obtain pyrazolo [1,5-a ] pyridine derivatives;
the solvent used for separating and purifying the silica gel column is a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of the petroleum ether to the ethyl acetate is 20:1;
the structural formula of the pyridinium is
The structural formula of the 2-bromoethyl acrylate is
The pyrazolo [1,5-a ]]The pyridine derivative has the structural formula
The purity was 96% and the yield was 83%.
5. A preparation method of pyrazolo [1,5-a ] pyridine derivatives is characterized by comprising the following steps:
dissolving 0.1mmol of pyridinium, 0.15mmol of ethyl 2-bromocinnamate and 0.11mmol of 2, 3-dichloro-5, 6-dicyanobenzoquinone in 1.2mL of acetonitrile at a dropping speed of 5mL/min, dropwise adding 0.2mmol of triethylamine, reacting for 12h at a temperature of 0-10 ℃ and a stirring speed of 300r/min, concentrating by a rotary evaporator to remove the solvent, and separating and purifying by silica gel column chromatography to obtain pyrazolo [1,5-a ] pyridine derivatives;
the solvent used for separating and purifying the silica gel column is a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of the petroleum ether to the ethyl acetate is 20:1;
the structural formula of the pyridinium is
The structural formula of the 2-bromocinnamic acid ethyl ester is
The pyrazolo [1,5-a ]]The pyridine derivative has the structural formula
Purity was 98% and yield was 82%. />
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