CN115557886A - Synthetic method of 3-nitroisonicotinic acid methyl ester - Google Patents
Synthetic method of 3-nitroisonicotinic acid methyl ester Download PDFInfo
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- CN115557886A CN115557886A CN202211227267.5A CN202211227267A CN115557886A CN 115557886 A CN115557886 A CN 115557886A CN 202211227267 A CN202211227267 A CN 202211227267A CN 115557886 A CN115557886 A CN 115557886A
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- chloro
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- nitroisonicotinic
- nitroisonicotinate
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- VFZBLITUPLITGH-UHFFFAOYSA-N methyl 3-nitropyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1[N+]([O-])=O VFZBLITUPLITGH-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000010189 synthetic method Methods 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- YIKBSICAFIIUER-UHFFFAOYSA-N 2-chloro-5-nitropyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC(Cl)=NC=C1[N+]([O-])=O YIKBSICAFIIUER-UHFFFAOYSA-N 0.000 claims abstract description 34
- ADPCJMUNRPBSCO-UHFFFAOYSA-N 353281-15-9 Chemical compound OC(=O)C1=CC=NC(Cl)=C1[N+]([O-])=O ADPCJMUNRPBSCO-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 14
- 230000001590 oxidative effect Effects 0.000 claims abstract description 14
- 239000007800 oxidant agent Substances 0.000 claims abstract description 13
- HWZUMEVIIGNXGM-UHFFFAOYSA-N 2-chloro-4-methyl-5-nitropyridine Chemical compound CC1=CC(Cl)=NC=C1[N+]([O-])=O HWZUMEVIIGNXGM-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 9
- JHARVUVBTAAPLA-UHFFFAOYSA-N 2-chloro-4-methyl-3-nitropyridine Chemical compound CC1=CC=NC(Cl)=C1[N+]([O-])=O JHARVUVBTAAPLA-UHFFFAOYSA-N 0.000 claims abstract description 8
- -1 2-chloro-5-nitroisonicotinic acid ester Chemical class 0.000 claims abstract description 6
- YKPIUHZVTZWEEW-UHFFFAOYSA-N 3-nitroisonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1[N+]([O-])=O YKPIUHZVTZWEEW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 18
- 239000005457 ice water Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 150000007524 organic acids Chemical class 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 239000002244 precipitate Substances 0.000 claims description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 235000011054 acetic acid Nutrition 0.000 claims description 7
- 239000003570 air Substances 0.000 claims description 7
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 235000015165 citric acid Nutrition 0.000 claims description 6
- 230000003472 neutralizing effect Effects 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 235000019260 propionic acid Nutrition 0.000 claims description 5
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 229940011182 cobalt acetate Drugs 0.000 claims description 4
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 239000001630 malic acid Substances 0.000 claims description 3
- 235000011090 malic acid Nutrition 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 3
- 150000003138 primary alcohols Chemical class 0.000 claims description 3
- 229960004889 salicylic acid Drugs 0.000 claims description 3
- 150000003333 secondary alcohols Chemical class 0.000 claims description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- 150000003509 tertiary alcohols Chemical class 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000007792 addition Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- ZWWCURLKEXEFQT-UHFFFAOYSA-N dinitrogen pentaoxide Chemical compound [O-][N+](=O)O[N+]([O-])=O ZWWCURLKEXEFQT-UHFFFAOYSA-N 0.000 description 8
- SBGNWCJYDUUYTN-UHFFFAOYSA-N methyl 2-chloro-5-nitropyridine-4-carboxylate Chemical compound COC(=O)C1=CC(Cl)=NC=C1[N+]([O-])=O SBGNWCJYDUUYTN-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- MGWGWNFMUOTEHG-UHFFFAOYSA-N 4-(3,5-dimethylphenyl)-1,3-thiazol-2-amine Chemical compound CC1=CC(C)=CC(C=2N=C(N)SC=2)=C1 MGWGWNFMUOTEHG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- FJDJVBXSSLDNJB-LNTINUHCSA-N cobalt;(z)-4-hydroxypent-3-en-2-one Chemical compound [Co].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FJDJVBXSSLDNJB-LNTINUHCSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000000382 dechlorinating effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- IKVUHYWOJCHEGA-UHFFFAOYSA-N methyl 2-chloro-3-nitropyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(Cl)=C1[N+]([O-])=O IKVUHYWOJCHEGA-UHFFFAOYSA-N 0.000 description 1
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 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
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a synthetic method of 3-nitroisonicotinic acid methyl ester, which is characterized by comprising the following steps: 1) Dissolving 2-chloro-5-nitro-4-methylpyridine or 2-chloro-3-nitro-4-methylpyridine in a solvent, then adding a first oxidant, and reacting to obtain 2-chloro-5-nitroisonicotinic acid or 2-chloro-3-nitroisonicotinic acid; 2) Adding 2-chloro-5-nitroisonicotinic acid into a chlorinating agent or adding 2-chloro-3-nitroisonicotinic acid into the chlorinating agent, and reacting with alcohol to obtain corresponding 2-chloro-5-nitroisonicotinic acid ester or 2-chloro-3-nitroisonicotinic acid ester; 3) The 3-nitroisonicotinate is obtained by reacting 2-chloro-5-nitroisonicotinate or 2-chloro-3-nitroisonicotinate with a reducing reagent, and the method has the advantages of mild and safe reaction conditions and high yield and is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the field of synthesis of medicine and pesticide intermediates, in particular to a synthesis method of 3-nitroisonicotinic acid methyl ester.
Background
In general, aromatic substrates are very inert with respect to nucleophilic substitution. However, compounds having strongly electron-withdrawing groups in the ortho-or para-position, which accelerate the dissociationAnd (4) removing. The nitro group, which is not normally lost in aliphatic systems, is a particularly good leaving group in nucleophilic substitution reactions. The nitro group in methyl 3-nitroisonicotinate, since the combination of the pyridyl aromatic system with the stable carbonyl anion to form the ortho group the 3-nitro substituent is a good leaving group. The nitro group in the 3-nitroisonicotinic acid methyl ester can be alkylated in a nucleophilic substitution reaction to generate a new C-C bond and construct more complex carbon skeletons; but also substituted by heteroatoms of oxygen, nitrogen, sulfur and fluoride, yields many new products. Therefore, the 3-nitroisonicotinic acid methyl ester has wide application in organic synthesis. However, few reports on the synthesis of 3-nitromethyl isonicotinate exist, and the prior literature reports that methyl isonicotinate is obtained by nitration with dinitrogen pentoxide, but N is 2 O 5 The pure product is very unstable, is easy to sublimate at room temperature and explodes under the irradiation of sunlight; the crystal has sublimation phenomenon at room temperature, white crystals gradually become light yellow, orange yellow or even tan along with the rise of temperature, the crystal is in liquid state at about 45 ℃ and decomposes to release oxygen, nitrogen dioxide and the like, and if the crystal meets high temperature or flammable substances, the crystal can explode. In view of the danger of dinitrogen pentoxide, the method has the defects that the dinitrogen pentoxide can not be produced in a large scale, can only be used for a small amount of current work in a laboratory, and is easy to cause danger due to high temperature. Therefore, a method for synthesizing 3-nitroisonicotinic acid methyl ester by using dinitrogen pentoxide is avoided, and a new method which is mild and safe in reaction conditions and suitable for industrial large-scale production needs to be found urgently.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a synthesis method of 3-nitroisonicotinic acid methyl ester, which has mild and safe reaction conditions and high yield and is suitable for industrial large-scale production.
The technical scheme adopted by the invention for solving the technical problems is as follows: a synthetic method of 3-nitroisonicotinic acid methyl ester comprises the following steps:
(1) Dissolving 2-chloro-5-nitro-4-methylpyridine or 2-chloro-3-nitro-4-methylpyridine in a solvent, then adding a first oxidant, and reacting to obtain 2-chloro-5-nitroisonicotinic acid or 2-chloro-3-nitroisonicotinic acid;
(2) Adding 2-chloro-5-nitroisonicotinic acid into a chlorinating agent or adding 2-chloro-3-nitroisonicotinic acid into the chlorinating agent, and reacting with alcohol to obtain corresponding 2-chloro-5-nitroisonicotinate or 2-chloro-3-nitroisonicotinate;
(3) Reacting 2-chloro-5-nitroisonicotinate or 2-chloro-3-nitroisonicotinate with a reducing reagent to obtain 3-nitroisonicotinate.
Further, the specific process of the step (1) is as follows: adding 2-chloro-5-nitro-4-methylpyridine or 2-chloro-3-nitro-4-methylpyridine into a solvent, stirring for dissolving, controlling the temperature to be below T1, slowly adding or introducing a first oxidant, controlling the temperature to be below T2 for reaction, pouring a reaction mixture into ice water after the reaction is completed, controlling the temperature to be not higher than T3 to form a precipitate, filtering, washing and drying the precipitate to obtain the 2-chloro-5-nitroisonicotinic acid or 2-chloro-3-nitroisonicotinic acid.
Further, T1 is more than or equal to 0 ℃ and less than or equal to 100 ℃; t2 is more than or equal to 30 ℃ and less than or equal to 140 ℃; the T3 is more than or equal to 0 ℃ and less than or equal to 40 ℃.
Further, the first oxidant is oxygen, air, sodium dichromate, potassium permanganate or nitric acid; when the oxidant is oxygen or air, a catalyst is added simultaneously, and the catalyst is one or a mixture of cobalt acetate, cobalt acetolactone and cesium carbonate.
Further, the specific process of the step (2) is as follows: adding 2-chloro-5-nitroisonicotinic acid or 2-chloro-3-nitroisonicotinic acid into an aprotic solvent, then controlling the temperature to be below T4, slowly dropwise adding a second chlorinating agent, controlling the temperature to be below T5 for continuous and complete reaction after the addition is finished, slowly dropwise adding alcohol after the reaction is complete and the temperature is reduced to be T6, controlling the temperature to be not higher than T7, and controlling the temperature to be not higher than T7 for continuous reaction for 1 hour after the addition is finished; then pouring into ice water, neutralizing with alkali, extracting with dichloromethane for 3 times, combining organic phases, extracting the organic phases once with saturated salt water, drying with anhydrous sodium sulfate, and desolventizing to obtain 2-chloro-5-nitroisonicotinate or 2-chloro-3-nitroisonicotinate.
Further, T4 is more than or equal to 0 ℃ and less than or equal to 50 ℃; t5 is more than or equal to 30 ℃ and less than or equal to 100 ℃; t6 is more than or equal to minus 10 ℃ and less than or equal to T6 and less than or equal to 20 ℃; the T7 is as follows: t7 is more than or equal to minus 5 ℃ and less than or equal to 25 ℃.
Further, the second chlorinating agent is thionyl chloride, phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, sulfuryl chloride or phenylphosphoryl dichloride; the alcohol is methanol, ethanol, isopropanol, primary alcohol, secondary alcohol or tertiary alcohol.
Further, the specific process of the step (3) is as follows: dissolving 2-chloro-5-nitroisonicotinate or 2-chloro-3-nitroisonicotinate in organic acid at normal temperature, slowly adding copper powder at the temperature of T8, continuously reacting for 15 minutes at the temperature of T8, evaporating the organic acid, pouring the residue into cold water, extracting for 3 times by using ethyl acetate, combining organic phases, washing by using saturated saline water, drying by using anhydrous sodium sulfate, and desolventizing to obtain the 3-nitroisonicotinate methyl ester.
Further, the T8 is more than or equal to 80 ℃ and less than or equal to 200 ℃.
Further, the organic acid is citric acid, malic acid, tartaric acid, acetic acid, propionic acid, succinic acid, oxalic acid, citric acid, acetic acid, benzoic acid or salicylic acid.
Compared with the prior art, the invention has the advantages that: the invention discloses a synthesis method of 3-nitroisonicotinic acid methyl ester, which comprises the steps of taking 2-chloro-5-nitro-4-methylpyridine or 2-chloro-3-nitro-4-methylpyridine as a raw material, oxidizing to obtain 2-chloro-5-nitroisonicotinic acid or 2-chloro-3-nitroisonicotinic acid, esterifying to obtain 2-chloro-5-nitroisonicotinic acid methyl ester or 2-chloro-3-nitroisonicotinic acid methyl ester, and finally, reducing and dechlorinating to obtain the 3-nitroisonicotinic acid methyl ester. The method has the advantages of simple selected process route, mild and safe reaction conditions, suitability for large-scale production, and great implementation value and social and economic benefits.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of methyl 3-nitroisonicotinate synthesized in example 1 of the present invention.
Detailed Description
The invention is described in further detail below with reference to the following examples of the drawings.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
A synthetic method of 3-nitroisonicotinic acid methyl ester comprises the following steps:
(1) Dissolving 2-chloro-5-nitro-4-methylpyridine or 2-chloro-3-nitro-4-methylpyridine in a solvent, then adding a first oxidant, and reacting to obtain 2-chloro-5-nitroisonicotinic acid or 2-chloro-3-nitroisonicotinic acid;
(2) Adding 2-chloro-5-nitroisonicotinic acid into a chlorinating agent or adding 2-chloro-3-nitroisonicotinic acid into the chlorinating agent, and reacting with alcohol to obtain corresponding 2-chloro-5-nitroisonicotinate or 2-chloro-3-nitroisonicotinate;
(3) Reacting 2-chloro-5-nitroisonicotinate or 2-chloro-3-nitroisonicotinate with a reducing reagent to obtain 3-nitroisonicotinate, wherein the synthetic route is as follows:
the specific process of the step (1) is as follows: adding 2-chloro-5-nitro-4-methylpyridine or 2-chloro-3-nitro-4-methylpyridine into a solvent, stirring for dissolving, controlling the temperature to be below T1, slowly adding or introducing a first oxidant, controlling the temperature to be below T2 for reaction, pouring a reaction mixture into ice water after the reaction is completed, controlling the temperature to be not higher than T3 to form a precipitate, filtering, washing and drying the precipitate to obtain the 2-chloro-5-nitroisonicotinic acid or 2-chloro-3-nitroisonicotinic acid. Wherein T1 is more than or equal to 0 ℃ and less than or equal to 100 ℃, T2 is more than or equal to 30 ℃ and less than or equal to 140 ℃, and T3 is more than or equal to 0 ℃ and less than or equal to 40 ℃. The first oxidant is oxygen, air, sodium dichromate, potassium permanganate or nitric acid; when the oxidant is oxygen or air, the catalyst is added at the same time, and the catalyst is one or a mixture of cobalt acetate, cobalt acetolactone and cesium carbonate.
The specific process of the step (2) is as follows: adding 2-chloro-5-nitroisonicotinic acid or 2-chloro-3-nitroisonicotinic acid into an aprotic solvent, then controlling the temperature to be below T4, slowly dropping a second chlorinating agent, controlling the temperature to be below T5 for continuous complete reaction after the addition is finished, slowly dropping alcohol after the reaction is finished, controlling the temperature to be not higher than T7, and controlling the temperature to be not higher than T7 for continuous reaction for 1 hour after the addition is finished; then pouring into ice water, neutralizing with alkali, extracting with dichloromethane for 3 times, combining organic phases, extracting the organic phases once with saturated salt water, drying with anhydrous sodium sulfate, and desolventizing to obtain 2-chloro-5-nitroisonicotinate or 2-chloro-3-nitroisonicotinate. Wherein T4 is more than or equal to 0 ℃ and less than or equal to 50 ℃, T5 is more than or equal to 30 ℃ and less than or equal to 100 ℃, T6 is more than or equal to-10 ℃ and less than or equal to 20 ℃, and T7 is more than or equal to-5 ℃ and less than or equal to 25 ℃. The second chlorinating agent is thionyl chloride, phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, sulfuryl chloride or phenyl phosphoryl dichloride; the alcohol is methanol, ethanol, isopropanol, primary alcohol, secondary alcohol or tertiary alcohol.
The specific process of the step (3) is as follows: dissolving 2-chloro-5-nitroisonicotinate or 2-chloro-3-nitroisonicotinate in organic acid at normal temperature, slowly adding copper powder at the temperature of T8, continuously reacting at the temperature of T8 for 15 minutes, evaporating the organic acid, pouring residues into cold water, extracting for 3 times by using ethyl acetate, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, and desolventizing to obtain the 3-nitroisonicotinate methyl ester. Wherein T8 is more than or equal to 80 ℃ and less than or equal to 200 ℃. The organic acid is citric acid, malic acid, tartaric acid, acetic acid, propionic acid, succinic acid, oxalic acid, citric acid, acetic acid, benzoic acid or salicylic acid.
Example 1
1. Synthesis of 2-chloro-5-nitroisonicotinic acid
Adding 60ml of concentrated sulfuric acid into a 250ml reaction bottle, starting stirring, cooling to below 10 ℃ in an ice bath, slowly adding 10g of 2-chloro-5-nitro-4-methylpyridine into the concentrated sulfuric acid, stirring for 30 minutes, then adding 21g of sodium dichromate into the reaction bottle in batches, controlling the temperature to be not higher than 25 ℃, stirring at room temperature after the addition is finished, naturally heating to room temperature after removing the ice bath, and then reacting for 1 hour. The reaction mixture was poured into 200ml of ice water to form a precipitate. Filtration, washing with ice water and drying gave 11g of white solid in 94% yield.
2. Synthesis of 2-chloro-5-nitroisonicotinic acid methyl ester
Adding 2L of dichloromethane into a 3L reaction bottle, adding 200g of 2-chloro-5-nitroisonicotinic acid under stirring, then adding 150mL of thionyl chloride, heating to reflux reaction, dissolving clear after 4 hours, and continuing the reflux reaction for 1 hour. Cooling the reaction mixed solution to 5 ℃ by using an ice water bath, dropwise adding 400Ml of methanol into the reaction solution, controlling the temperature to be not higher than 25 ℃, finishing the dropwise adding reaction at the temperature of below 25 ℃, continuing to react for 1 hour, then pouring the reaction mixed solution into 2L of ice water, neutralizing by using solid potassium carbonate, separating an organic phase, and extracting the water phase by using dichloromethane for 2 times; the organic phases were combined, dried over anhydrous sodium sulfate and the dichloromethane was evaporated under reduced pressure to give 210g of a white solid in 98% yield.
3. Synthesis of methyl 3-nitroisonicotinate
100ml of glacial acetic acid is added into a 250ml reaction bottle, 20g of 2-chloro-5-nitroisonicotinic acid methyl ester is added under stirring, the temperature is raised to 100 ℃, then 8g of copper powder is slowly added, and after the addition is finished, the reflux reaction is carried out for 15 minutes. The acetic acid was evaporated under reduced pressure, the residue was poured into cold water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and desolventized to give 12g of a colorless liquid with a yield of 71%. The nuclear magnetic resonance spectrum is shown in figure 1.
Example 2
1. Synthesis of 2-chloro-5-nitroisonicotinic acid
Adding 120ml of concentrated sulfuric acid into a 500ml reaction bottle, starting stirring, cooling to below 10 ℃ in an ice bath, slowly adding 20g of 2-chloro-5-nitro-4-methylpyridine into the concentrated sulfuric acid, stirring for 30 minutes, then adding 42g of sodium dichromate into the reaction bottle in batches, controlling the temperature to be not higher than 60 ℃, after the addition is finished, controlling the temperature to be 60 ℃, and then keeping the temperature for reaction for 1 hour; then, it was cooled to room temperature, and the reaction mixture was poured into 400ml of ice water to form a precipitate. Filtration, washing with ice water and drying gave 20g of white solid in 86% yield.
2. Synthesis of 2-chloro-5-nitroisonicotinic acid methyl ester
Adding 2L of dichloromethane into a 3L reaction bottle, adding 200g of 2-chloro-5-nitroisonicotinic acid under stirring, then adding 200g of oxalyl chloride, heating to reflux reaction, dissolving clear after 4 hours, and continuing the reflux reaction for 1 hour. Cooling the reaction mixed solution to 5 ℃ by using an ice water bath, dropwise adding 400Ml of methanol into the reaction solution, controlling the temperature to be not higher than 25 ℃, finishing the dropwise adding reaction at the temperature of below 25 ℃, continuing to react for 1 hour, then pouring the reaction mixed solution into 2L of ice water, neutralizing by using solid potassium carbonate, separating an organic phase, and extracting the water phase by using dichloromethane for 2 times; the organic phases were combined, dried over anhydrous sodium sulfate and the dichloromethane was evaporated under reduced pressure to give 200g of a white solid in 93% yield.
3. Synthesis of methyl 3-nitroisonicotinate
100ml of propionic acid was added to a 250ml reaction flask, and 20g of methyl 2-chloro-5-nitroisonicotinate was added while stirring, and the temperature was raised to 100 ℃ and then 8g of copper powder was slowly added, and after the addition, the reaction was carried out at 120 ℃ for 15 minutes. The solvent was evaporated under reduced pressure, the residue was poured into cold water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and desolventized to give 11g of a colorless liquid with a yield of 65%.
Example 3
1. Synthesis of 2-chloro-5-nitroisonicotinic acid
Adding 1.2L of methanol, 200g of 2-chloro-5-nitro-4-methylpyridine, 0.02g of cobalt acetate, 0.02g of cobalt acetylacetonate, 20g of cesium carbonate and 75g of sodium hydroxide into a 2L pressure kettle, replacing air in the kettle with nitrogen for 2 times, stirring, introducing oxygen for reaction, keeping the temperature at 80 ℃ under the pressure of 0.5MPa for 20 hours. After the reaction, the mixture was filtered, methanol was evaporated under reduced pressure, 800mL of water was added to the residue, and the mixture was stirred, and the pH of the residue was adjusted to 3 with 10% hydrochloric acid to form a precipitate, which was filtered and dried to obtain 208g of a white solid with a yield of 89%.
2. Synthesis of 2-chloro-5-nitroisonicotinic acid methyl ester
Adding 2L of dichloromethane into a 3L reaction bottle, adding 200g of 2-chloro-5-nitroisonicotinic acid under stirring, then adding 120-thionyl chloride, heating to reflux reaction, dissolving clear after 4 hours, and continuing the reflux reaction for 1 hour. Cooling the reaction mixed solution to 5 ℃ by using an ice water bath, dropwise adding 400Ml of methanol into the reaction solution, controlling the temperature to be not higher than 25 ℃, finishing the dropwise adding reaction, continuously reacting for 1 hour at the temperature of below 25 ℃, then pouring the reaction mixed solution into 2L of ice water, neutralizing by using solid potassium carbonate, separating out an organic phase, and extracting the water phase by using dichloromethane for 2 times; the organic phases were combined, dried over anhydrous sodium sulfate and the dichloromethane was evaporated under reduced pressure to give 189g of a white solid in 88% yield.
3. Synthesis of methyl 3-nitroisonicotinate
150ml of propionic acid was added to a 250ml reaction flask, 30g of methyl 2-chloro-5-nitroisonicotinate was added with stirring, the temperature was raised to 120 ℃, then 20g of copper powder was slowly added, and the reaction was carried out at 140 ℃ for 15 minutes. The solvent was evaporated under reduced pressure, the residue was poured into cold water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and desolventized to give 16g of a colorless liquid with a yield of 64%.
The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Those skilled in the art should also appreciate that they may make various changes, modifications, additions and substitutions within the spirit and scope of the invention.
Claims (10)
1. A synthetic method of 3-nitroisonicotinic acid methyl ester is characterized by comprising the following steps:
(1) Dissolving 2-chloro-5-nitro-4-methylpyridine or 2-chloro-3-nitro-4-methylpyridine in a solvent, then adding a first oxidant, and reacting to obtain 2-chloro-5-nitroisonicotinic acid or 2-chloro-3-nitroisonicotinic acid;
(2) Adding 2-chloro-5-nitroisonicotinic acid into a chlorinating agent or adding 2-chloro-3-nitroisonicotinic acid into the chlorinating agent, and reacting with alcohol to obtain corresponding 2-chloro-5-nitroisonicotinate or 2-chloro-3-nitroisonicotinate;
(3) Reacting 2-chloro-5-nitroisonicotinate or 2-chloro-3-nitroisonicotinate with a reducing reagent to obtain 3-nitroisonicotinate.
2. The method for synthesizing 3-nitroisonicotinic acid methyl ester according to claim 1, characterized in that: the specific process of the step (1) is as follows: adding 2-chloro-5-nitro-4-methylpyridine or 2-chloro-3-nitro-4-methylpyridine into a solvent, stirring for dissolving, slowly adding or introducing a first oxidant under the condition that the temperature is controlled to be T1, reacting under the condition that the temperature is controlled to be T2, pouring a reaction mixture into ice water after the reaction is completed, controlling the temperature to be not higher than T3 to form a precipitate, filtering, washing and drying the precipitate to obtain the 2-chloro-5-nitroisonicotinic acid or 2-chloro-3-nitroisonicotinic acid.
3. The method for synthesizing 3-nitroisonicotinic acid methyl ester according to claim 2, characterized in that: t1 is more than or equal to 0 ℃ and less than or equal to 100 ℃; t2 is more than or equal to 30 ℃ and less than or equal to 140 ℃; the T3 is more than or equal to 0 ℃ and less than or equal to 40 ℃.
4. The method for synthesizing 3-nitroisonicotinic acid methyl ester according to claim 2, characterized in that: the first oxidant is oxygen, air, sodium dichromate, potassium permanganate or nitric acid; when the oxidant is oxygen or air, a catalyst is added simultaneously, and the catalyst is one or a mixture of cobalt acetate, cobalt acetolactone and cesium carbonate.
5. The method for synthesizing 3-nitroisonicotinic acid methyl ester according to claim 1, characterized in that: the specific process of the step (2) is as follows: adding 2-chloro-5-nitroisonicotinic acid or 2-chloro-3-nitroisonicotinic acid into an aprotic solvent, then controlling the temperature to be below T4, slowly dropwise adding a second chlorinating agent, controlling the temperature to be below T5 for continuous and complete reaction after the addition is finished, slowly dropwise adding alcohol after the reaction is complete and the temperature is reduced to be T6, controlling the temperature to be not higher than T7, and controlling the temperature to be not higher than T7 for continuous reaction for 1 hour after the addition is finished; then pouring into ice water, neutralizing with alkali, extracting with dichloromethane for 3 times, combining organic phases, extracting the organic phases once with saturated salt water, drying with anhydrous sodium sulfate, and desolventizing to obtain 2-chloro-5-nitroisonicotinate or 2-chloro-3-nitroisonicotinate.
6. The method for synthesizing 3-nitroisonicotinic acid methyl ester according to claim 6, characterized in that: t4 is more than or equal to 0 ℃ and less than or equal to 50 ℃; t5 is more than or equal to 30 ℃ and less than or equal to 100 ℃; t6 is more than or equal to minus 10 ℃ and less than or equal to T6 and less than or equal to 20 ℃; the T7 is as follows: t7 is more than or equal to minus 5 ℃ and less than or equal to 25 ℃.
7. The method for synthesizing 3-nitroisonicotinic acid methyl ester according to claim 6, characterized in that: the second chlorinating agent is thionyl chloride, phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, sulfonyl chloride or phenyl phosphoryl dichloride; the alcohol is methanol, ethanol, isopropanol, primary alcohol, secondary alcohol or tertiary alcohol.
8. The method for synthesizing 3-nitroisonicotinic acid methyl ester according to claim 1, characterized in that: the specific process of the step (3) is as follows: dissolving 2-chloro-5-nitroisonicotinate or 2-chloro-3-nitroisonicotinate in organic acid at normal temperature, slowly adding copper powder at the temperature of T8, continuously reacting for 15 minutes at the temperature of T8, evaporating the organic acid, pouring the residue into cold water, extracting for 3 times by using ethyl acetate, combining organic phases, washing by using saturated saline water, drying by using anhydrous sodium sulfate, and desolventizing to obtain the 3-nitroisonicotinate methyl ester.
9. The method for synthesizing 3-nitroisonicotinic acid methyl ester according to claim 8, characterized in that: t8 is more than or equal to 80 ℃ and less than or equal to 200 ℃.
10. The method for synthesizing 3-nitroisonicotinic acid methyl ester according to claim 8, characterized in that: the organic acid is citric acid, malic acid, tartaric acid, acetic acid, propionic acid, succinic acid, oxalic acid, citric acid, acetic acid, benzoic acid or salicylic acid.
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| CN102321016A (en) * | 2011-07-29 | 2012-01-18 | 山东轻工业学院 | Synthesis method of 5-bromo-2-methyl 4-hydroxypyridinecarboxylate |
| CN113929622A (en) * | 2021-11-22 | 2022-01-14 | 山西永津集团有限公司 | Synthetic method of 2,5, 6-trichloro-cyanic acid |
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| CN102321016A (en) * | 2011-07-29 | 2012-01-18 | 山东轻工业学院 | Synthesis method of 5-bromo-2-methyl 4-hydroxypyridinecarboxylate |
| CN113929622A (en) * | 2021-11-22 | 2022-01-14 | 山西永津集团有限公司 | Synthetic method of 2,5, 6-trichloro-cyanic acid |
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