CN112724133A - Preparation method of 6-bromopyrazolo [1,5-a ] pyridine - Google Patents
Preparation method of 6-bromopyrazolo [1,5-a ] pyridine Download PDFInfo
- Publication number
- CN112724133A CN112724133A CN202110033862.4A CN202110033862A CN112724133A CN 112724133 A CN112724133 A CN 112724133A CN 202110033862 A CN202110033862 A CN 202110033862A CN 112724133 A CN112724133 A CN 112724133A
- Authority
- CN
- China
- Prior art keywords
- pyridine
- bromo
- triethylsilyl
- bromopyrazolo
- ethynyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- MJGAKVFFADUFMG-UHFFFAOYSA-N 6-bromopyrazolo[1,5-a]pyridine Chemical compound C1=C(Br)C=CC2=CC=NN21 MJGAKVFFADUFMG-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 28
- ZWOPGUDWTWIICQ-UHFFFAOYSA-N BrC=1C=CC(=NC=1)C#C[Si](CC)(CC)CC Chemical compound BrC=1C=CC(=NC=1)C#C[Si](CC)(CC)CC ZWOPGUDWTWIICQ-UHFFFAOYSA-N 0.000 claims abstract description 23
- RBHNUWFYKMFNEF-UHFFFAOYSA-N NN1C(C=CC(=C1)Br)C#C[Si](CC)(CC)CC Chemical compound NN1C(C=CC(=C1)Br)C#C[Si](CC)(CC)CC RBHNUWFYKMFNEF-UHFFFAOYSA-N 0.000 claims abstract description 23
- HSNBRDZXJMPDGH-UHFFFAOYSA-N 5-bromo-2-iodopyridine Chemical compound BrC1=CC=C(I)N=C1 HSNBRDZXJMPDGH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910001958 silver carbonate Inorganic materials 0.000 claims abstract description 10
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims abstract description 10
- FWSPXZXVNVQHIF-UHFFFAOYSA-N triethyl(ethynyl)silane Chemical group CC[Si](CC)(CC)C#C FWSPXZXVNVQHIF-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000005859 coupling reaction Methods 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 238000005576 amination reaction Methods 0.000 claims abstract description 6
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 8
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 8
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- RRPKGUUYTHFUPN-UHFFFAOYSA-N n-hydroxy-2,4,6-trimethylbenzenesulfonamide Chemical compound CC1=CC(C)=C(S(=O)(=O)NO)C(C)=C1 RRPKGUUYTHFUPN-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003054 catalyst Substances 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 239000002516 radical scavenger Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- BXIBBLZRCAYAGR-UHFFFAOYSA-N S(=O)(=O)=NO.C1(=CC=CC=C1)C Chemical compound S(=O)(=O)=NO.C1(=CC=CC=C1)C BXIBBLZRCAYAGR-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 33
- 239000000047 product Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 150000005229 pyrazolopyridines Chemical class 0.000 description 2
- GVLRTOYGRNLSDW-UHFFFAOYSA-N 1h-pyrazolo[3,4-b]pyridine Chemical class C1=CC=C2C=NNC2=N1 GVLRTOYGRNLSDW-UHFFFAOYSA-N 0.000 description 1
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 description 1
- WCXFPLXZZSWROM-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]pyridine Chemical class C1=NC=C2C=NNC2=C1 WCXFPLXZZSWROM-UHFFFAOYSA-N 0.000 description 1
- 229940124258 Adenosine A1 receptor antagonist Drugs 0.000 description 1
- 108091005471 CRHR1 Proteins 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 239000002598 adenosine A1 receptor antagonist Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003602 anti-herpes Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- XMJJPCJUQLGGND-UHFFFAOYSA-N n-hydroxy-4-methylbenzenesulfonamide Chemical compound CC1=CC=C(S(=O)(=O)NO)C=C1 XMJJPCJUQLGGND-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- DVUBDHRTVYLIPA-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine Chemical class C1=CC=CN2N=CC=C21 DVUBDHRTVYLIPA-UHFFFAOYSA-N 0.000 description 1
- -1 pyrazolopyridine compound Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a preparation method of 6-bromopyrazolo [1,5-a ] pyridine, which comprises the following steps: dissolving 5-bromo-2-iodopyridine to obtain a solution A, and then adding triethylsilyl acetylene into the solution A to perform a coupling reaction to obtain 5-bromo-2- ((triethylsilyl) ethynyl) pyridine; dissolving 5-bromo-2- ((triethylsilyl) ethynyl) pyridine to obtain a solution B, and adding a nitrogen aminating agent into the solution B to perform nitrogen amination reaction to obtain 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine; dissolving 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine to obtain a solution C, and adding silver carbonate into the solution C to perform cyclization reaction to obtain 6-bromopyrazolo [1,5-a ] pyridine. The invention uses low-cost raw materials, is easy to control reaction conditions, has high reaction selectivity, few byproducts and simpler product post-treatment, obtains a more ideal product and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of organic matter preparation and synthesis, and particularly relates to a preparation method of 6-bromopyrazolo [1,5-a ] pyridine.
Background
In recent years, due to the remarkable physiological activity of fused heterocyclic compounds, the attention of wide medicine and pesticide researchers is attracted, wherein pyrazolopyridine compounds are paid more and more attention due to the similarity and difference of indole or purine structures, and the fused heterocyclic compounds are researched more and more. Pyrazolopyridines have conjugated pi-electron systems and can serve as isoelectric substances for similar compounds present in the body; meanwhile, the aromatic pentacyclic hexacyclic system has larger dipole moment and a certain number of nitrogen atoms, can be used as an auxiliary structure of a medicament to enhance the combination of the medicament and organisms and shows certain selectivity. The fused ring type of pyrazolopyridine compound can be classified into the following groups: the most studied isomers of pyrazolo [3,4-b ] pyridine, pyrazolo [4,3-c ] pyridine and pyrazolo [1,5-a ] pyridine have very high biological activity. The current research on such compounds is mainly in terms of the biological activity of their derivatives, including: 1. adenosine a1 receptor antagonists; a CRF1 receptor inhibitor; inhibitors of P38 kinase; 4. anti-herpes inhibitory activity.
According to various documents and patents, compounds having a pyrazolopyridine basic structure have very important roles in pharmacological research. Pharmacological research shows that the compounds have various activities such as sterilization, weeding, antifungal, anti-inflammatory, antiallergic, antimalarial, anxiolytic, antithrombotic, hypotensive, antibacterial, analgesic and antiplatelet activities, and are compounds with high research value.
6-bromopyrazolo [1,5-A]The pyridine being pyrazolo [1,5-a ]]An important class of compounds in the group of bipyridines has the following structural formula:
molecular formula C7H5BrN2CAS number 1264193-11-4. At present, few relevant documents report about the synthesis method of the compound.
Disclosure of Invention
Aiming at the defects and problems of the prior art, the invention provides a preparation method of 6-bromopyrazolo [1,5-a ] pyridine, aiming at solving the technical problems that: provides a preparation method of 6-bromopyrazolo [1,5-a ] pyridine, which has low raw material price, easily controlled reaction conditions, less by-products and is suitable for industrial amplification production.
In order to achieve the purpose, the invention adopts the following technical means:
a process for the preparation of 6-bromopyrazolo [1,5-a ] pyridine comprising the steps of:
s1, dissolving 5-bromo-2-iodopyridine to obtain a solution A, and then adding triethylsilyl acetylene to the solution A to perform a coupling reaction to obtain 5-bromo-2- ((triethylsilyl) ethynyl) pyridine;
s2, dissolving 5-bromo-2- ((triethylsilyl) ethynyl) pyridine to obtain a solution B, and adding a nitrogen aminating agent into the solution B to perform nitrogen amination reaction to obtain 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine;
s3, dissolving 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine to obtain a solution C, and adding silver carbonate into the solution C to perform cyclization reaction to obtain 6-bromopyrazolo [1,5-a ] pyridine.
Preferably, the solvent in the solution A is toluene, tetrahydrofuran or N, N-dimethylformamide.
Preferably, the catalyst used for the coupling reaction comprises cuprous iodide, cuprous bromide or cuprous chloride.
Preferably, the solution A also comprises an acid binding agent.
Preferably, the acid scavenger comprises diisopropylethylamine.
Preferably, the base used in the coupling reaction is triethylamine, diisopropylethylamine or potassium carbonate.
Preferably, the equivalent ratio of the 5-bromo-2-iodopyridine to the base is 1: 1.5-3.
Preferably, the mass ratio of the 5-bromo-2-iodopyridine to the cuprous iodide is 1: 0.05-0.15.
Preferably, the catalyst further comprises bis (triphenylphosphine) palladium dichloride.
Preferably, the mass ratio of the 5-bromo-2-iodopyridine to the bis (triphenylphosphine) palladium dichloride is 1: 0.01-0.03.
Preferably, the equivalent ratio of the 5-bromo-2-iodopyridine to the triethylsilyl acetylene is 1: 1-2.
Preferably, the nitrogen amination agent comprises 2,4, 6-trimethylbenzenesulfonylhydroxylamine or p-methylbenzenesulfonylhydroxylamine.
Preferably, the equivalent ratio of the 5-bromo-2- ((triethylsilyl) ethynyl) pyridine to the nitrogen aminating agent is 1:1.2 to 1.7.
Preferably, the equivalent ratio of the 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine to the silver carbonate is 1: 1.8-2.5.
Compared with the prior art, the invention has the following technical effects:
the invention uses low-cost raw materials, is easy to control reaction conditions, has high reaction selectivity, few byproducts and simpler product post-treatment, obtains a more ideal product and is suitable for large-scale industrial production.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The synthetic route of the invention is as follows:
the preparation method comprises the following steps:
synthesis of S1, 5-bromo-2- ((triethylsilyl) ethynyl) pyridine: 5-bromo-2- ((triethylsilyl) ethynyl) pyridine is obtained by coupling reaction of a 5-bromo-2-iodopyridine raw material and triethylsilyl acetylene under the condition of a proper solvent.
Synthesis of S2, 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine: and carrying out nitrogen amination reaction on the 5-bromo-2- ((triethylsilyl) ethynyl) pyridine under the condition of a proper solvent to obtain the 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine.
Synthesis of S3, 6-bromopyrazolo [1,5-a ] pyridine: reacting 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine under the catalysis of silver carbonate to obtain 6-bromopyrazolo [1,5-a ] pyridine.
The technical solution of the present invention is illustrated by the following specific examples:
example 1
Step one, synthesis of 5-bromo-2- ((triethylsilyl) ethynyl) pyridine
Under the protection of nitrogen, 800ml of N, N-dimethylformamide was added as a solvent, 284g of 5-bromo-2-iodopyridine, 19g of cuprous iodide, 258g of diisopropylethylamine and 14g of bis (triphenylphosphine) palladium dichloride were added, and stirring was carried out at room temperature for 5 hours, 168g of triethylsilylacetylene was added, and the mixture was left to stand and stirred for 24 hours. The reaction mixture was diluted with 700ml of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to give 251.6g of 5-bromo-2- ((triethylsilyl) ethynyl) pyridine, yield 84.9%.
Step two, synthesis of 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine
850ml of methylene chloride was added as a solvent to a reaction flask, 286g of 5-bromo-2- ((triethylsilyl) ethynyl) pyridine was added, 322g of 2,4, 6-trimethylbenzenesulfonylhydroxylamine was dissolved in 800ml of a methylene chloride solution, and the solution was slowly added dropwise to the reaction flask. After stirring the reaction for 20 hours, the reaction mixture was concentrated to give a solid, and the resulting solid was washed with methyl t-butyl ether, then filtered and dried under vacuum at 60 ℃ for 8 hours to give 255.1g of 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine with a yield of 81.8%.
Step three, synthesis of 6-bromopyrazolo [1,5-a ] pyridine
312g of 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine, 552g of silver carbonate and 1000ml of N, N-dimethylformamide were charged into a reaction flask, the reaction was stirred at room temperature for 6 hours, the progress of the reaction was monitored by HPLC, and after the completion of the reaction, the reaction mixture was extracted 3 times with 300ml of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. The crude product obtained was purified by column chromatography (hexane: ethyl acetate ═ 10:1) to give 167.8g of 6-bromopyrazolo [1,5-a ] pyridine in 85.2% yield.
Example 2
Step one, synthesis of 5-bromo-2- ((triethylsilyl) ethynyl) pyridine
Under the protection of nitrogen, 800ml of N, N-dimethylformamide was added as a solvent, 284g of 5-bromo-2-iodopyridine, 19g of cuprous iodide and 14g of bis (triphenylphosphine) palladium dichloride were further added, and stirring was carried out at room temperature for 5 hours, and 168g of triethylsilylacetylene was further added, and the mixture was left to stand and stirred for 24 hours. The reaction mixture was diluted with 700ml of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to give 251.6g of 5-bromo-2- ((triethylsilyl) ethynyl) pyridine, yield 84.9%.
Step two, synthesis of 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine
850ml of methylene chloride was added as a solvent to a reaction flask, 286g of 5-bromo-2- ((triethylsilyl) ethynyl) pyridine was added, 322g of 2,4, 6-trimethylbenzenesulfonylhydroxylamine was dissolved in 800ml of a methylene chloride solution, and the solution was slowly added dropwise to the reaction flask. After stirring the reaction for 20 hours, the reaction mixture was concentrated to give a solid, and the resulting solid was washed with methyl t-butyl ether, then filtered and dried under vacuum at 60 ℃ for 8 hours to give 255.1g of 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine with a yield of 81.8%.
Step three, synthesis of 6-bromopyrazolo [1,5-a ] pyridine
312g of 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine, 552g of silver carbonate and 1000ml of N, N-dimethylformamide were charged into a reaction flask, the reaction was stirred at room temperature for 6 hours, the progress of the reaction was monitored by HPLC, and after the completion of the reaction, the reaction mixture was extracted 3 times with 300ml of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. The crude product obtained was purified by column chromatography (hexane: ethyl acetate ═ 10:1) to give 160.5g of 6-bromopyrazolo [1,5-a ] pyridine in 81.5% yield.
Example 3
Step one, synthesis of 5-bromo-2- ((triethylsilyl) ethynyl) pyridine
Under the protection of nitrogen, 800ml of N, N-dimethylformamide was added as a solvent, 284g of 5-bromo-2-iodopyridine, 19g of cuprous iodide, 258g of diisopropylethylamine and 14g of bis (triphenylphosphine) palladium dichloride were added, and stirring was carried out at room temperature for 5 hours, 168g of triethylsilylacetylene was added, and the mixture was left to stand and stirred for 24 hours. The reaction mixture was diluted with 700ml of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to give 251.6g of 5-bromo-2- ((triethylsilyl) ethynyl) pyridine, yield 84.9%.
Step two, synthesis of 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine
850ml of methylene chloride was added as a solvent to a reaction flask, 286g of 5-bromo-2- ((triethylsilyl) ethynyl) pyridine was added, 322g of 2,4, 6-trimethylbenzenesulfonylhydroxylamine was dissolved in 800ml of a methylene chloride solution, and the solution was slowly added dropwise to the reaction flask. After stirring the reaction for 20 hours, the reaction mixture was concentrated to give a solid, and the resulting solid was washed with methyl t-butyl ether, then filtered and dried under vacuum at 60 ℃ for 8 hours to give 255.1g of 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine with a yield of 81.8%.
Step three, synthesis of 6-bromopyrazolo [1,5-a ] pyridine
312g of 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine, 600g of silver carbonate and 1000ml of N, N-dimethylformamide were charged into a reaction flask, the reaction was stirred at room temperature for 6 hours, the progress of the reaction was monitored by HPLC, and after the completion of the reaction, the reaction mixture was extracted 3 times with 300ml of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. The crude product obtained was purified by column chromatography (hexane: ethyl acetate ═ 10:1) to give 143.8g of 6-bromopyrazolo [1,5-a ] pyridine in 73.0% yield.
Example 4
Step one, synthesis of 5-bromo-2- ((triethylsilyl) ethynyl) pyridine
Under the protection of nitrogen, 800ml of N, N-dimethylformamide was added as a solvent, 284g of 5-bromo-2-iodopyridine, 19g of cuprous iodide, 258g of diisopropylethylamine and 14g of bis (triphenylphosphine) palladium dichloride were added, and stirring was carried out at room temperature for 5 hours, 168g of triethylsilylacetylene was added, and the mixture was left to stand and stirred for 24 hours. The reaction mixture was diluted with 700ml of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to give 251.6g of 5-bromo-2- ((triethylsilyl) ethynyl) pyridine, yield 84.9%.
Step two, synthesis of 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine
850ml of methylene chloride was added as a solvent to a reaction flask, 286g of 5-bromo-2- ((triethylsilyl) ethynyl) pyridine was added, 322g of 2,4, 6-trimethylbenzenesulfonylhydroxylamine was dissolved in 800ml of a methylene chloride solution, and the solution was slowly added dropwise to the reaction flask. After stirring the reaction for 20 hours, the reaction mixture was concentrated to give a solid, and the resulting solid was washed with methyl t-butyl ether, then filtered and dried under vacuum at 60 ℃ for 8 hours to give 255.1g of 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine with a yield of 81.8%.
Step three, synthesis of 6-bromopyrazolo [1,5-a ] pyridine
312g of 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine, 500g of silver carbonate and 1000ml of N, N-dimethylformamide were charged into a reaction flask, the reaction was stirred at room temperature for 6 hours, the progress of the reaction was monitored by HPLC, and after the completion of the reaction, the reaction mixture was extracted 3 times with 300ml of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. The crude product obtained was purified by column chromatography (hexane: ethyl acetate ═ 10:1) to give 153.6g of 6-bromopyrazolo [1,5-a ] pyridine in 77.9% yield.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
- A process for the preparation of 1, 5-a-pyridine, which comprises the steps of:s1, dissolving 5-bromo-2-iodopyridine to obtain a solution A, and then adding triethylsilyl acetylene to the solution A to perform a coupling reaction to obtain 5-bromo-2- ((triethylsilyl) ethynyl) pyridine;s2, dissolving 5-bromo-2- ((triethylsilyl) ethynyl) pyridine to obtain a solution B, and adding a nitrogen aminating agent into the solution B to perform nitrogen amination reaction to obtain 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine;s3, dissolving 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine to obtain a solution C, and adding silver carbonate into the solution C to perform cyclization reaction to obtain 6-bromopyrazolo [1,5-a ] pyridine.
- 2. A process for the preparation of 6-bromopyrazolo [1,5-a ] pyridine as claimed in claim 1, wherein:the solvent in the solution A is toluene, tetrahydrofuran or N, N-dimethylformamide;the catalyst adopted by the coupling reaction comprises cuprous iodide, cuprous bromide or cuprous chloride;the solution A also comprises an acid binding agent;the acid scavenger comprises diisopropylethylamine.
- 3. A process for the preparation of 6-bromopyrazolo [1,5-a ] pyridine as claimed in claim 1, wherein:the base adopted in the coupling reaction is triethylamine, diisopropylethylamine or potassium carbonate.
- 4. A process for the preparation of 6-bromopyrazolo [1,5-a ] pyridine as claimed in claim 3, wherein:the equivalent ratio of the 5-bromo-2-iodopyridine to the base is 1: 1.5-3.
- 5. The process for the preparation of 6-bromopyrazolo [1,5-a ] pyridine according to claim 2, wherein:the mass ratio of the 5-bromo-2-iodopyridine to the cuprous iodide is 1: 0.05-0.15.
- 6. The process for the preparation of 6-bromopyrazolo [1,5-a ] pyridine according to claim 2, wherein:the catalyst also comprises bis (triphenylphosphine) palladium dichloride.The mass ratio of the 5-bromo-2-iodopyridine to the bis (triphenylphosphine) palladium dichloride is 1: 0.01-0.03.
- 7. A process for the preparation of 6-bromopyrazolo [1,5-a ] pyridine as claimed in claim 1, wherein:the equivalent ratio of the 5-bromo-2-iodopyridine to the triethylsilyl acetylene is 1: 1-2.
- 8. A process for the preparation of 6-bromopyrazolo [1,5-a ] pyridine as claimed in claim 1, wherein:the nitrogen amination agent comprises 2,4, 6-trimethyl benzene sulfonyl hydroxylamine or p-methyl benzene sulfonyl hydroxylamine.
- 9. A process for the preparation of 6-bromopyrazolo [1,5-a ] pyridine as claimed in claim 1, wherein:the equivalent ratio of the 5-bromo-2- ((triethylsilyl) ethynyl) pyridine to the aminating agent is 1: 1.2-1.7.
- 10. A process for the preparation of 6-bromopyrazolo [1,5-a ] pyridine as claimed in claim 1, wherein:the equivalent ratio of the 1-amino-5-bromo-2- ((triethylsilyl) ethynyl) pyridine to the silver carbonate is 1: 1.8-2.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110033862.4A CN112724133B (en) | 2021-01-12 | 2021-01-12 | Preparation method of 6-bromopyrazolo [1,5-a ] pyridine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110033862.4A CN112724133B (en) | 2021-01-12 | 2021-01-12 | Preparation method of 6-bromopyrazolo [1,5-a ] pyridine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112724133A true CN112724133A (en) | 2021-04-30 |
| CN112724133B CN112724133B (en) | 2022-03-25 |
Family
ID=75590453
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110033862.4A Active CN112724133B (en) | 2021-01-12 | 2021-01-12 | Preparation method of 6-bromopyrazolo [1,5-a ] pyridine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112724133B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5948648A (en) * | 1998-05-29 | 1999-09-07 | Khan; Shaheer H. | Nucleotide compounds including a rigid linker |
| WO2000021974A1 (en) * | 1998-10-14 | 2000-04-20 | The Perkin-Elmer Corporation | Nucleotide compounds including a rigid linker |
| CN102712658A (en) * | 2009-10-29 | 2012-10-03 | 帕劳制药股份有限公司 | N-containing heteroaryl derivatives as jak3 kinase inhibitors |
| WO2020163193A1 (en) * | 2019-02-04 | 2020-08-13 | Biogen Ma Inc. | Bicyclic ether o-glycoprotein-2-acetamido-2-deoxy-3-d-glucopyranosidase inhibitors |
-
2021
- 2021-01-12 CN CN202110033862.4A patent/CN112724133B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5948648A (en) * | 1998-05-29 | 1999-09-07 | Khan; Shaheer H. | Nucleotide compounds including a rigid linker |
| WO2000021974A1 (en) * | 1998-10-14 | 2000-04-20 | The Perkin-Elmer Corporation | Nucleotide compounds including a rigid linker |
| CN102712658A (en) * | 2009-10-29 | 2012-10-03 | 帕劳制药股份有限公司 | N-containing heteroaryl derivatives as jak3 kinase inhibitors |
| WO2020163193A1 (en) * | 2019-02-04 | 2020-08-13 | Biogen Ma Inc. | Bicyclic ether o-glycoprotein-2-acetamido-2-deoxy-3-d-glucopyranosidase inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112724133B (en) | 2022-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK2872515T3 (en) | MACROCYCLIC PURINES FOR TREATING VIRUS INFECTIONS | |
| CN107556317B (en) | Imidazole pyrazinamine phenyl derivative and application thereof | |
| CA3075968C (en) | Process for the preparation of 7-(4,7-diazaspiro[2,5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one derivatives | |
| Beaulieu et al. | Synthesis and biological evaluation of 4-amino derivatives of benzimidazoquinoxaline, benzimidazoquinoline, and benzopyrazoloquinazoline as potent IKK inhibitors | |
| CN112679420A (en) | Preparation method of 2,5-dibromopyridine | |
| Martin-Encinas et al. | Fused chromeno and quinolino [1, 8] naphthyridines: Synthesis and biological evaluation as topoisomerase I inhibitors and antiproliferative agents | |
| CN111690947A (en) | Electrochemical synthesis method of trifluoromethylated aryl amide derivative | |
| CN112724133B (en) | Preparation method of 6-bromopyrazolo [1,5-a ] pyridine | |
| Meshram et al. | Bismuthtriflate-catalyzed Reaction of N-Alkylisatins with Allyltrimethylsilane | |
| CN103172637B (en) | Pyrimido [1, 2-a] benzimidazole compound and method for preparing same | |
| CN107759596A (en) | A kind of synthesis Pa Boxini method | |
| CN103483339A (en) | Simple synthesis method of 9H-pyridino-[2, 3-b] indole | |
| CN109081840B (en) | Preparation method of 5-bromo-7-azaindole | |
| Tang et al. | Synthesis of 8-Bromo-7-chloro [1, 2, 4] triazolo [4, 3-c] pyrimidines, Their Ring Rearrangement to [1, 5-c] Analogues, and Further Diversification | |
| EP4215521A1 (en) | Fused ring diimide derivative, preparation method therefor and use thereof | |
| CN101397302A (en) | 9-substituted homocamptothecins compounds and its use as medicaments | |
| CN104045643A (en) | Method for preparing pyrazolo [1, 5-c] quinazoline skeleton compounds by copper catalysis in water phase | |
| US9353109B2 (en) | Flindersia alkaloids, derivatives and analogs: compositions and methods for producing the same | |
| CN108484617B (en) | Novel benzofuran azanaphthalene dione derivative and preparation method thereof | |
| DE60209029T2 (en) | POLYCYCLIC COMPOUNDS WITH ANTITUMOR EFFECT | |
| CN114773340B (en) | N-heteroatom multi-ring indolizine and derivative as well as synthesis process and application thereof | |
| Ferlin et al. | Synthesis and characterization of some N‐mannich bases of [1, 2, 3] triazoloquinolines | |
| CN115215803B (en) | Preparation method of 4-halogenated-1- (difluoromethyl) -1H-imidazole | |
| CN115322120B (en) | Small molecule compound and application thereof in preparation of medicine for treating DHODH-mediated diseases | |
| CN105541865B (en) | Imidazoles [1,2 c] thiophene [2,3 e] pyrimidine 7 of 2,3,5 substitutions（8H）Ketone heterocyclic compound and its synthetic method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation method of 6-bromopyrazolo [1,5-a] pyridine Granted publication date: 20220325 Pledgee: Agricultural Bank of China Xiangtan County Branch Pledgor: Hunan Furui Biomedical Technology Co.,Ltd. Registration number: Y2024980000042 |