CN116924975A - Preparation method of 2-amino-5-fluoropyridine - Google Patents
Preparation method of 2-amino-5-fluoropyridine Download PDFInfo
- Publication number
- CN116924975A CN116924975A CN202311174730.9A CN202311174730A CN116924975A CN 116924975 A CN116924975 A CN 116924975A CN 202311174730 A CN202311174730 A CN 202311174730A CN 116924975 A CN116924975 A CN 116924975A
- Authority
- CN
- China
- Prior art keywords
- reaction
- amino
- fluoropyridine
- preparation
- compound
- 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.)
- Pending
Links
- YJTXQLYMECWULH-UHFFFAOYSA-N 5-fluoropyridin-2-amine Chemical compound NC1=CC=C(F)C=N1 YJTXQLYMECWULH-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 69
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000010438 heat treatment Methods 0.000 claims abstract description 18
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims abstract description 18
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 17
- 239000011737 fluorine Substances 0.000 claims abstract description 17
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- 238000006722 reduction reaction Methods 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 11
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims abstract description 10
- 235000003270 potassium fluoride Nutrition 0.000 claims abstract description 9
- 239000011698 potassium fluoride Substances 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- -1 tetrafluoroborate Chemical compound 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 4
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 4
- 239000011261 inert gas Substances 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical group [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 9
- 239000003444 phase transfer catalyst Substances 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 2
- CGFYNRVHPARGFY-UHFFFAOYSA-N 5-fluoro-2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(F)C=N1 CGFYNRVHPARGFY-UHFFFAOYSA-N 0.000 abstract description 21
- 150000002894 organic compounds Chemical class 0.000 abstract description 2
- 238000013341 scale-up Methods 0.000 abstract description 2
- 238000007039 two-step reaction Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000004537 pulping Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000009286 beneficial effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- ATXXLNCPVSUCNK-UHFFFAOYSA-N 5-bromo-2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Br)C=N1 ATXXLNCPVSUCNK-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- 238000006193 diazotization reaction Methods 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- YUBHMOQVHOODEI-UHFFFAOYSA-N 5-chloro-2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=N1 YUBHMOQVHOODEI-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004176 ammonification Methods 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- MUGXRYIUWFITCP-PGRDOPGGSA-N (1r,2s)-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-2-(3-fluorophenyl)-n-(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide Chemical compound CC1=NC(C)=NC=C1OC[C@]1(C=2C=C(F)C=CC=2)[C@H](C(=O)NC=2N=CC(F)=CC=2)C1 MUGXRYIUWFITCP-PGRDOPGGSA-N 0.000 description 1
- AYCMYBACERJYNY-HIFRSBDPSA-N (2s)-n-(5-fluoro-1-hydroxypyridin-2-ylidene)-1-[(2r)-2-[[formyl(hydroxy)amino]methyl]hexanoyl]pyrrolidine-2-carboxamide Chemical compound CCCC[C@H](CN(O)C=O)C(=O)N1CCC[C@H]1C(=O)N=C1N(O)C=C(F)C=C1 AYCMYBACERJYNY-HIFRSBDPSA-N 0.000 description 1
- YIYIQENCPIISLL-UHFFFAOYSA-N 2,3-dichloro-5-fluoropyridine Chemical compound FC1=CN=C(Cl)C(Cl)=C1 YIYIQENCPIISLL-UHFFFAOYSA-N 0.000 description 1
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 description 1
- 229940127239 5 Hydroxytryptamine receptor antagonist Drugs 0.000 description 1
- CRPBZKKDPLMESO-UHFFFAOYSA-N 5-iodo-2-nitropyridine Chemical compound [O-][N+](=O)C1=NC=C(I)C=C1 CRPBZKKDPLMESO-UHFFFAOYSA-N 0.000 description 1
- QAJYCQZQLVENRZ-UHFFFAOYSA-N 6-chloropyridin-3-amine Chemical compound NC1=CC=C(Cl)N=C1 QAJYCQZQLVENRZ-UHFFFAOYSA-N 0.000 description 1
- AWCAUUQZTXYMPB-UHFFFAOYSA-N 6-fluoro-1-(5-fluoropyridin-2-yl)-7-(4-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=N1 AWCAUUQZTXYMPB-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229950009869 fandofloxacin Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 229950003528 lemborexant Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000081 peptide deformylase inhibitor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229910001495 sodium tetrafluoroborate Inorganic materials 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- 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
- C07D213/61—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to the technical field of preparation methods of organic compounds, in particular to a preparation method of 2-amino-5-fluoropyridine, which comprises the following steps: s1, under the protection of inert gas, in a first solvent system, carrying out halogen replacement reaction on 2-nitro-5-halopyridine and a fluorine reagent under the heating condition, and obtaining 2-nitro-5-fluoropyridine through post-treatment after the reaction is finished; the fluorine reagent is any one of potassium fluoride, cesium fluoride and tetrafluoroborate. S2, in a second solvent system, under the action of a catalyst, carrying out reduction reaction on the 2-nitro-5-fluoropyridine and a reducing agent hydrogen, and after the reaction is finished, obtaining a target product 2-amino-5-fluoropyridine through post-treatment. The preparation method is simple to operate, the final target product can be obtained only through two-step reaction, the reaction condition in the process is mild, the safety in the preparation process is high, and the industrial scale-up production is facilitated.
Description
Technical Field
The invention relates to a preparation method of 2-amino-5-fluoropyridine, belonging to the technical field of preparation methods of organic compounds.
Background
The 2-amino-5-fluoropyridine can be widely used as an important fluorine-containing medical intermediate for synthesizing various fluorine-containing medicines, such as peptide deformylase inhibitor LBM-415, quinolone antibacterial medicines Fandofloxacin,5-HT receptor antagonists and the like. In the preparation process of a novel insomnia treatment drug Lemborexant approved by the United states Food and Drug Administration (FDA) in 12 months of 2019, 2-amino-5-fluoropyridine is one of important intermediates, so that the 2-amino-5-fluoropyridine has a broad market demand prospect.
In the current published patent literature, the preparation method of 2-amino-5-fluoropyridine mainly comprises the following steps:
chinese patent application CN107759514A discloses a preparation method of 2-amino-5-fluoropyridine, which uses 2-aminopyridine as a starting material to prepare a target product 2-amino-5-fluoropyridine through nitration, aminoacetylation, iron powder reduction, diazotization and hydrolysis, wherein the specific route is as follows. However, the reaction route has longer steps, involves nitrification and diazotization of dangerous reactions, and has a larger safety risk.
。
The target product 2-amino-5-fluoropyridine is prepared by ammonification, oxidation, azide, hydrolysis and denitration by using 2, 3-dichloro-5-fluoropyridine as a starting material reported in the Chinese patent application CN107827887A, wherein the specific reaction route is as follows. However, the reaction steps of the route are longer, wherein the ammonification reaction needs to be carried out for 24 hours at 180 ℃, the reaction conditions are more severe, and sodium azide is used in the process of preparing amino by azide, so that the safety risk is higher.
。
The target product 2-amino-5-fluoropyridine is obtained by diazotizing, fluoro and high-temperature high-pressure ammonolysis of fluoroboric acid by using 2-chloro-5-aminopyridine as a starting material reported by Hand, elli Smakula et al (Synthesis (1989), (12), 905-8), and the specific reaction route is as follows. However, the route involves diazotization reaction, so that the safety risk is high, and the ammonolysis process needs to be carried out for 52 hours under the condition of pressurized 180 ℃ under the condition of strong ammonia water, so that the reaction condition is severe.
。
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a preparation method of 2-amino-5-fluoropyridine, which has the advantages of short reaction route and mild process conditions and is suitable for industrial production.
The technical scheme for solving the technical problems is as follows: a preparation method of 2-amino-5-fluoropyridine, which comprises the following steps:
；
x in the compound (iii) is any one of iodine, bromine and chlorine;
the preparation method comprises the following steps:
s1, under the protection of inert gas, in a first solvent system, performing halogen replacement reaction on a compound (iii) and a fluorine reagent under the heating condition, and after the reaction is finished, performing post-treatment to obtain a compound (ii);
s2, in a second solvent system, under the action of a catalyst, carrying out a reduction reaction on the compound (ii) and a reducing agent hydrogen, and obtaining a target product compound (i) through post-treatment after the reaction is finished.
Preferably, in compound (iii) X is bromine or chlorine.
In step S1, the fluorine reagent is any one of potassium fluoride, cesium fluoride, and tetrafluoroborate.
Preferably, in step S1, the fluorine reagent is potassium fluoride.
Further, a phase transfer catalyst is added in the halogen replacement reaction process of the step S1, wherein the phase transfer catalyst is tetramethyl ammonium chloride or tetrabutyl ammonium bromide. The addition of the phase transfer catalyst in the reaction process is more beneficial to the reaction process, and the reaction speed is increased.
Preferably, the phase transfer catalyst is tetramethyl ammonium chloride.
Further, in step S1, the first solvent is selected from any one of N 'N-Dimethylformamide (DMF), N' N-Dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), and sulfolane.
Further, the heating temperature in the step S1 is 120-200 ℃.
Further, the water content in the reaction system of the step S1 is not more than 500ppm.
Further, in step S2, the catalyst is Pd/C or Raney Ni.
Further, in step S2, the second solvent is selected from any one of Tetrahydrofuran (THF), ethanol, methanol and dichloromethane.
Further, in the step S2, the reaction temperature is 20-40 ℃, and the reaction pressure is 0.3-0.5Mpa.
Further, in step S1, the molar ratio of compound (iii) to fluorine reagent is 1: (4-6).
The beneficial effects of the invention are as follows:
the preparation method of the 2-amino-5-fluoropyridine uses commercially available and low-cost 2-nitro-5-halopyridine as a starting material, obtains the 2-nitro-5-fluoropyridine through halogen substitution of a fluorine reagent, and finally prepares the target product 2-amino-5-fluoropyridine through nitro reduction. The preparation method is simple, the final target product can be obtained by two-step reaction, the reaction condition in the process is mild, the safety in the preparation process is high, and the industrial scale-up production is more facilitated.
In the preparation method of the 2-amino-5-fluoropyridine, the 2-amino-5-fluoropyridine product with high yield and high purity can be obtained by controlling the corresponding reaction temperature and pressure and selecting proper fluorine reagent, reducing agent and catalyst.
Detailed Description
The following describes the present invention in detail. The present invention may be embodied in many other forms than described herein and similarly modified by those skilled in the art without departing from the spirit of the invention, so that the invention is not limited to the specific embodiments disclosed.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
A preparation method of 2-amino-5-fluoropyridine, which comprises the following steps:
；
x in the compound (iii) is any one of iodine, bromine and chlorine;
the preparation method comprises the following steps:
s1, under the protection of inert gas, in a first solvent system, performing halogen replacement reaction on a compound (iii) and a fluorine reagent under the heating condition, and after the reaction is finished, performing post-treatment to obtain a compound (ii);
s2, in a second solvent system, under the action of a catalyst, carrying out a reduction reaction on the compound (ii) and a reducing agent hydrogen, and obtaining a target product compound (i) through post-treatment after the reaction is finished.
Specifically, in step S1, the fluorine reagent is any one of potassium fluoride, cesium fluoride, and tetrafluoroborate.
Specifically, a phase transfer catalyst is added in the halogen replacement reaction process of the step S1, wherein the phase transfer catalyst is tetramethyl ammonium chloride or tetrabutyl ammonium bromide. The addition of the phase transfer catalyst can accelerate the reaction rate.
Specifically, in step S1, the first solvent is selected from any one of N 'N-dimethylformamide, N' N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and sulfolane.
Specifically, the heating temperature in the step S1 is 120-200 ℃.
Specifically, the water content in the reaction system of the step S1 is not higher than 500ppm. If the water content in the reaction system is too high, more side reactions are generated in the reaction process, and finally the yield and purity of the product are affected.
Specifically, in step S2, the catalyst is Pd/C or Raney Ni.
Specifically, in step S2, the second solvent is selected from any one of tetrahydrofuran, ethanol, methanol and dichloromethane.
Specifically, in the step S2, the reaction temperature is 20-40 ℃, and the reaction pressure is 0.3-0.5Mpa.
Specifically, in step S1, the molar ratio of compound (iii) to fluorine reagent is 1: (4-6).
Example 1
S1, adding 600mL of NMP subjected to water removal treatment, 100g of 2-nitro-5-bromopyridine (0.49 mol), 142.3g of potassium fluoride (2.45 mol) and 5.48g of tetramethyl ammonium chloride (0.05 mol) into a reaction bottle, measuring the water content of the system to be less than 500ppm, heating to 180 ℃ under the protection of nitrogen, reacting for 10 hours, detecting no raw materials remained by HPLC, pouring the reaction system into water to separate out solids, and then carrying out suction filtration and drying to obtain 68.2g of crude 2-nitro-5-fluoropyridine, wherein the crude 2-nitro-5-fluoropyridine is directly fed back without purification.
S2, adding a 2-nitro-5-fluoropyridine crude product into a high-pressure reaction kettle, adding 600mL of tetrahydrofuran, adding 0.6g of catalyst Pd/C, introducing hydrogen after nitrogen replacement, introducing 0.3Mpa, heating to 40 ℃, reacting for 2 hours, detecting no raw materials remained by HPLC, filtering a reaction liquid to remove the catalyst, evaporating the solvent, adding methanol for pulping, and finally carrying out suction filtration to obtain a target product 2-amino-5-fluoropyridine, wherein the purity of the HPLC product is 99.3%, and the yield is 95.3%.
Example 2
S1, adding 500mL of DMA (direct memory access), 100g of 2-nitro-5-chloropyridine (0.63 mol), 183.0g of potassium fluoride (3.15 mol) and 6.58g of tetramethyl ammonium chloride (0.06 mol) subjected to water removal treatment into a reaction bottle, measuring the water content of the system to be less than 500ppm, heating to 160 ℃ under the protection of nitrogen, reacting for 20h, and detecting that no raw material remains by HPLC (high performance liquid chromatography). Pouring the reaction system into water to separate out solid, and then carrying out suction filtration and drying to obtain 87.0g of crude 2-nitro-5-fluoropyridine product, wherein the crude 2-nitro-5-fluoropyridine product is directly fed backwards without purification.
S2, adding a 2-nitro-5-fluoropyridine crude product into a high-pressure reaction kettle, adding 600mL of ethanol, adding 0.8g of Raney Ni catalyst, introducing hydrogen after nitrogen replacement, heating to 20 ℃ under the pressure of 0.5Mpa, reacting for 1.5h, detecting that no raw materials remain by HPLC, filtering a reaction liquid to remove the catalyst, evaporating the solvent, adding methanol for pulping, and finally carrying out suction filtration to obtain a target product 2-amino-5-fluoropyridine, wherein the purity of the HPLC product is 99.2%, and the total yield is 94.8%.
Example 3
S1, adding 500mL of sulfolane subjected to water removal treatment, 100g of 2-nitro-5-chloropyridine (0.63 mol), 183.0g of potassium fluoride (3.15 mol) and 16.12g of tetrabutylammonium bromide (0.05 mol) into a reaction bottle, measuring the water content of the system to be less than 500ppm, heating to 200 ℃ under the protection of nitrogen, reacting for 14h, and detecting that no raw material remains by HPLC. Pouring the reaction system into water to separate out solid, and then carrying out suction filtration and drying to obtain 87.2g of crude 2-nitro-5-fluoropyridine product, wherein the crude 2-nitro-5-fluoropyridine product is directly fed backwards without purification.
S2, adding a 2-nitro-5-fluoropyridine crude product into a high-pressure reaction kettle, adding 600mL of methanol, adding 0.8g of Raney Ni catalyst, introducing hydrogen after nitrogen replacement, heating to 30 ℃ under the pressure of 0.4Mpa, reacting for 2 hours, detecting no raw materials remained by HPLC, filtering a reaction liquid to remove the catalyst, evaporating the solvent, adding methanol for pulping, and finally carrying out suction filtration to obtain a target product 2-amino-5-fluoropyridine, wherein the purity of the HPLC product is 99.0%, and the total yield is 95.0%.
Example 4
S1, 700mL of DMSO subjected to water removal treatment, 100g of 2-nitro-5-bromopyridine (0.49 mol), 372.2g of cesium fluoride (2.45 mol) and 10.96g of tetramethylammonium chloride (0.1 mol) are added into a reaction bottle, the water content of the system is measured to be less than 500ppm, the temperature is raised to 120 ℃ under the protection of nitrogen, the reaction is carried out for 24 hours, and no raw material remains by HPLC detection. Pouring the reaction system into water to separate out solid, and then carrying out suction filtration and drying to obtain 68.6g of crude 2-nitro-5-fluoropyridine product, wherein the crude 2-nitro-5-fluoropyridine product is directly fed back without purification.
S2, adding a 2-nitro-5-fluoropyridine crude product into a high-pressure reaction kettle, adding 600mL of dichloromethane, adding 0.6g of catalyst Pd/C, introducing hydrogen after nitrogen replacement, introducing 0.5Mpa of pressure, heating to 30 ℃, reacting for 1.5h, detecting no raw materials remained by HPLC, filtering a reaction liquid to remove the catalyst, evaporating the solvent, adding methanol for pulping, and finally carrying out suction filtration to obtain a target product 2-amino-5-fluoropyridine, wherein the purity of the HPLC product is 99.0%, and the total yield is 95.5%.
Example 5
S1, adding 600mL of DMF (dimethyl formamide) subjected to water removal, 100g of 2-nitro-5-iodopyridine (0.20 mol), 109.0g of sodium tetrafluoroborate (1.0 mol) and 5.48g of tetramethylammonium chloride (0.05 mol) into a reaction bottle, measuring the water content of the system to be less than 500ppm, heating to 140 ℃ under the protection of nitrogen, reacting for 12h, detecting no raw materials left by HPLC, pouring the reaction system into water to separate out solids, and then carrying out suction filtration and drying to obtain 27.6g of crude 2-nitro-5-fluoropyridine, wherein the crude 2-nitro-5-fluoropyridine is directly fed backwards without purification.
S2, adding a 2-nitro-5-fluoropyridine crude product into a high-pressure reaction kettle, adding 500mL of tetrahydrofuran, adding 0.3g of catalyst Pd/C, introducing hydrogen after nitrogen replacement, introducing 0.5Mpa of pressure, heating to 30 ℃, reacting for 1.5h, detecting no raw material residue by HPLC, filtering a reaction liquid to remove the catalyst, evaporating the solvent, adding methanol for pulping, and finally carrying out suction filtration to obtain a target product 2-amino-5-fluoropyridine, wherein the purity of the HPLC product is 99.2%, and the yield is 95.1%.
Example 6
S1, adding 600mL of DMA (direct memory access), 100g of 2-nitro-5-bromopyridine (0.49 mol), 170.8g of potassium fluoride (2.94 mol) and 5.48g of tetramethyl ammonium chloride (0.05 mol) into a reaction bottle after water removal treatment, measuring the water content of the system to be less than 500ppm, heating to 160 ℃ under the protection of nitrogen, reacting for 12h, detecting that no raw materials remain by HPLC, pouring the reaction system into water to separate out solids, and then carrying out suction filtration and drying to obtain 68.3g of crude 2-nitro-5-fluoropyridine product, wherein the crude 2-nitro-5-fluoropyridine product is directly fed back without purification.
S2, adding a 2-nitro-5-fluoropyridine crude product into a high-pressure reaction kettle, adding 500mL of tetrahydrofuran, adding 0.5g of Raney Ni catalyst, introducing hydrogen after nitrogen replacement, introducing 0.3Mpa, heating to 30 ℃, reacting for 2 hours, detecting no raw materials remained by HPLC, filtering a reaction liquid to remove the catalyst, evaporating the solvent, adding methanol for pulping, and finally carrying out suction filtration to obtain a target product 2-amino-5-fluoropyridine, wherein the purity of the HPLC product is 99.0%, and the yield is 95.5%.
Comparative example 1
2-amino-5-fluoropyridine was produced by the same method as in example 3 except that the reaction temperature in step S1 was set to 220 ℃ (higher than the temperature conditions defined in the present invention). The purity of the 2-amino-5-fluoropyridine obtained in comparative example 1 was 95.0% and the yield was 85.6%.
From comparison of experimental data of comparative example 1 and example 3, it can be seen that if the reaction temperature of step S1 is increased, the purity and yield of the 2-amino-5-fluoropyridine product are decreased. Since 2-nitro-5-halopyridine is fluorinated in step S1, nitro groups are easily substituted with fluorine when the reaction temperature is too high, and this side reaction eventually results in a decrease in the product yield.
Comparative example 2
2-amino-5-fluoropyridine was produced by the same method as in example 4 except that the reaction temperature in step S1 was set to 100 ℃ (lower than the temperature conditions defined in the present invention). The purity of the 2-amino-5-fluoropyridine obtained in comparative example 2 was 92.3% and the yield was 68.0%.
As can be seen from comparison of the experimental data of comparative example 2 and example 4, when the reaction temperature is lowered, the yield of the product is significantly lowered, because the reaction temperature is too low, which may result in low reactivity and incomplete reaction. As can be seen from the results of comparative examples 1 and 2, the reaction temperature defined by the present invention is more advantageous for obtaining a high-yield, high-purity product.
Comparative example 3
The same procedure as in example 1 was used to prepare 2-amino-5-fluoropyridine except that the reaction pressure in step S2 was 0.6MPa (higher than the pressure conditions defined in the present invention). The purity of the 2-amino-5-fluoropyridine obtained in comparative example 3 was 95.2% and the yield was 82.5%.
As can be seen from comparison of the experimental data of comparative example 3 and example 1, when the pressure during the reduction reaction is too high, the problem of F-peeling in the 2-amino-5-fluoropyridine structure is caused, and finally the product yield is reduced.
Comparative example 4
The same procedure as in example 1 was used to prepare 2-amino-5-fluoropyridine except that the reaction temperature in step S2 was 50deg.C (above the temperature conditions defined in the present invention). The purity of the 2-amino-5-fluoropyridine obtained in comparative example 4 was 96.0% and the yield was 84.0%.
As can be seen from comparison of the experimental data of comparative example 4 and example 1, when the temperature increases during the reduction reaction, side reactions occur in the system, F in 2-amino-5-fluoropyridine is easily removed, and finally the product yield is also reduced. As can be seen from the experimental data of comparative examples 3 and 4, the reduction reaction is carried out under the temperature and pressure conditions defined by the invention, which is more beneficial to obtaining the products with high yield and high purity.
In addition, the reduction reaction process of the preparation method adopts hydrogen reduction, the hydrogen reduction is more beneficial to environmental protection and product yield improvement, if the conventional iron powder reduction is adopted, a large amount of solid waste is generated, the environmental protection requirement of industrial production is not facilitated, and in addition, experiments show that if the iron powder reduction is adopted, the post-treatment process is more complicated, so that the product is seriously lost in the post-treatment process, and finally the product yield is influenced.
The technical features of the above-described embodiments may be arbitrarily combined, and in order to simplify the description, all possible combinations of the technical features in the above-described embodiments are not exhaustive, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the invention as defined in the appended claims.
Claims (10)
1. The preparation method of the 2-amino-5-fluoropyridine is characterized by comprising the following steps:
；
x in the compound (iii) is any one of iodine, bromine and chlorine;
the preparation method comprises the following steps:
s1, under the protection of inert gas, in a first solvent system, performing halogen replacement reaction on a compound (iii) and a fluorine reagent under the heating condition, and after the reaction is finished, performing post-treatment to obtain a compound (ii);
s2, in a second solvent system, under the action of a catalyst, carrying out a reduction reaction on the compound (ii) and a reducing agent hydrogen, and obtaining a target product compound (i) through post-treatment after the reaction is finished.
2. The method for producing 2-amino-5-fluoropyridine according to claim 1, wherein in step S1, the fluorine reagent is any one of potassium fluoride, cesium fluoride, and tetrafluoroborate.
3. The method for preparing 2-amino-5-fluoropyridine according to claim 1, wherein a phase transfer catalyst is added in the halogen substitution reaction process of step S1, and the phase transfer catalyst is tetramethyl ammonium chloride or tetrabutyl ammonium bromide.
4. The method for producing 2-amino-5-fluoropyridine according to claim 1, wherein in step S1, said first solvent is selected from any one of N 'N-dimethylformamide, N' N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and sulfolane.
5. The method for preparing 2-amino-5-fluoropyridine according to claim 1, wherein the heating temperature in step S1 is 120 ℃ to 200 ℃.
6. The process for producing 2-amino-5-fluoropyridine according to claim 1, wherein the water content in the reaction system of step S1 is not more than 500ppm.
7. The method for preparing 2-amino-5-fluoropyridine according to claim 1, wherein in step S2, the catalyst is Pd/C or Raney Ni.
8. The method for preparing 2-amino-5-fluoropyridine according to claim 1, wherein in step S2, said second solvent is selected from any one of tetrahydrofuran, ethanol, methanol and dichloromethane.
9. The process for preparing 2-amino-5-fluoropyridine according to claim 1, wherein in step S2, the reaction temperature is 20 to 40 ℃ and the reaction pressure is 0.3 to 0.5Mpa.
10. The process for the preparation of 2-amino-5-fluoropyridine according to claim 1, wherein in step S1, the molar ratio of compound (iii) to fluorine reagent is 1: (4-6).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311174730.9A CN116924975A (en) | 2023-09-13 | 2023-09-13 | Preparation method of 2-amino-5-fluoropyridine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311174730.9A CN116924975A (en) | 2023-09-13 | 2023-09-13 | Preparation method of 2-amino-5-fluoropyridine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116924975A true CN116924975A (en) | 2023-10-24 |
Family
ID=88382815
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311174730.9A Pending CN116924975A (en) | 2023-09-13 | 2023-09-13 | Preparation method of 2-amino-5-fluoropyridine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116924975A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106414440A (en) * | 2013-12-05 | 2017-02-15 | 拜耳制药股份公司 | Aryl- and hetaryl-substituted imidazo[1,2-a]pyridine-3-carboxamides and use thereof |
| CN106800493A (en) * | 2017-01-16 | 2017-06-06 | 三峡大学 | A kind of method that fragrant nitro is reduced to arylamine |
| US20170355648A1 (en) * | 2016-04-26 | 2017-12-14 | The University Of Chicago | Synthesis of meta-substituted [18f]-3-fluoro-4-aminopyridines by direct radiofluorination of pyridine n-oxides |
| CN113527020A (en) * | 2021-07-06 | 2021-10-22 | 浙江大学 | Method for continuous fluorination in pipeline by using fluorine salt as fluorine source |
-
2023
- 2023-09-13 CN CN202311174730.9A patent/CN116924975A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106414440A (en) * | 2013-12-05 | 2017-02-15 | 拜耳制药股份公司 | Aryl- and hetaryl-substituted imidazo[1,2-a]pyridine-3-carboxamides and use thereof |
| US20170355648A1 (en) * | 2016-04-26 | 2017-12-14 | The University Of Chicago | Synthesis of meta-substituted [18f]-3-fluoro-4-aminopyridines by direct radiofluorination of pyridine n-oxides |
| CN106800493A (en) * | 2017-01-16 | 2017-06-06 | 三峡大学 | A kind of method that fragrant nitro is reduced to arylamine |
| CN113527020A (en) * | 2021-07-06 | 2021-10-22 | 浙江大学 | Method for continuous fluorination in pipeline by using fluorine salt as fluorine source |
Non-Patent Citations (3)
| Title |
|---|
| ALLAN WISSNER等: ""Syntheses and EGFR kinase inhibitory activity of 6-substituted-4-anilino[1, 7] and [1, 8] naphthyridine-3-carbonitriles"", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 14, pages 1411 - 1416, XP002399928, DOI: 10.1016/j.bmcl.2004.01.034 * |
| 张青山: "《有机合成反应基础》", vol. 1, 高等教育出版社, pages: 42 * |
| 柴民军: ""2-氨基-5-氟吡啶合成工艺的改进"", 《中国优秀硕士学位论文全文数据库 工程科技I辑》, no. 09, pages 016 - 39 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112851563A (en) | Synthesis process of N-amino-3-azabicyclo [3,3,0] octane hydrochloride | |
| CN110950765A (en) | Preparation method of terbutaline sulfate | |
| CN114605308B (en) | Preparation method of azabicyclo medicine intermediate of Pa Luo Weide and intermediate | |
| US11981616B2 (en) | Method for preparing 3,3′-diaminobenzidine | |
| CN107778223A (en) | A kind of preparation method of maleic acid betrixaban | |
| CN113636973B (en) | Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester | |
| CN116924975A (en) | Preparation method of 2-amino-5-fluoropyridine | |
| CN110003206A (en) | A kind of preparation method of Eliquis | |
| CN111285821A (en) | Method for continuously preparing febuxostat | |
| CN114409524A (en) | Preparation method of 2, 6-dichlorophenylacetic acid | |
| CN111018782B (en) | Preparation method of 9-aminoacridine and derivatives thereof | |
| CN109678741B (en) | Preparation method of 4-amino-3-fluorobenzoic acid | |
| CN103833660B (en) | The preparation method of lamotrigine and intermediate thereof | |
| CN1258519C (en) | Method for coproducing 3-chloro-4-fluoroaniline and 2,6-dichlorofluobenzene | |
| CN115536610B (en) | Preparation method of vothixetine | |
| CN115677561B (en) | 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone and synthesis method thereof | |
| CN114163362B (en) | Preparation method of N-benzenesulfonyl-4-halo-2-nitroaniline | |
| CN111004141B (en) | New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide | |
| CN102173993A (en) | Method for synthesizing 4,6-diamino resorcinol dihydrochloride (DAR) | |
| WO2022126388A1 (en) | Method for synthesizing 5-bromo-1h-3-amino-1,2,4-triazole | |
| CN113912554A (en) | Erlotinib hydrochloride synthesis and refining process | |
| CN117551003A (en) | Method for preparing Fmoc-Thr (tBu) -OH by catalytic hydrogen transfer | |
| CN114292227A (en) | Method for preparing 2-chloro-3-trifluoromethylpyridine | |
| CN115231992A (en) | Preparation method of (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone | |
| CN116621813A (en) | Preparation and purification method of voronoi fumarate |
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 |