CN111170933B - Preparation method of 2-chloro-5-nitropyridine - Google Patents
Preparation method of 2-chloro-5-nitropyridine Download PDFInfo
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- CN111170933B CN111170933B CN201811340526.9A CN201811340526A CN111170933B CN 111170933 B CN111170933 B CN 111170933B CN 201811340526 A CN201811340526 A CN 201811340526A CN 111170933 B CN111170933 B CN 111170933B
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- BAZVFQBTJPBRTJ-UHFFFAOYSA-N 2-chloro-5-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1 BAZVFQBTJPBRTJ-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 12
- -1 2-nitroacetaldehyde acetal Chemical class 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 92
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 88
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- 229910021529 ammonia Inorganic materials 0.000 claims description 39
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 36
- 235000019270 ammonium chloride Nutrition 0.000 claims description 27
- 238000007259 addition reaction Methods 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000005977 Ethylene Substances 0.000 claims description 15
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 15
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 14
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 14
- 239000007800 oxidant agent Substances 0.000 claims description 13
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 12
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 238000007363 ring formation reaction Methods 0.000 claims description 10
- 238000000926 separation method Methods 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- 239000012320 chlorinating reagent Substances 0.000 claims description 9
- 230000001590 oxidative effect Effects 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 229960001701 chloroform Drugs 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 5
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical group CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000007530 organic bases Chemical group 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical group CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-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
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- XKWSQIMYNVLGBO-UHFFFAOYSA-N 5-nitro-1h-pyridin-2-one Chemical compound OC1=CC=C([N+]([O-])=O)C=N1 XKWSQIMYNVLGBO-UHFFFAOYSA-N 0.000 abstract description 24
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 abstract description 12
- 238000006396 nitration reaction Methods 0.000 abstract description 8
- 239000002253 acid Substances 0.000 abstract description 6
- 238000006193 diazotization reaction Methods 0.000 abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 6
- 239000002351 wastewater Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 230000035484 reaction time Effects 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000010992 reflux Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 238000004821 distillation Methods 0.000 description 6
- 239000007791 liquid phase Substances 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- DSNXPQCFISEEMR-UHFFFAOYSA-N 1,1-dimethoxy-2-nitroethane Chemical compound COC(OC)C[N+]([O-])=O DSNXPQCFISEEMR-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000003172 aldehyde group Chemical group 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- BPYHGTCRXDWOIQ-UHFFFAOYSA-N 3-nitropyridin-2-amine Chemical compound NC1=NC=CC=C1[N+]([O-])=O BPYHGTCRXDWOIQ-UHFFFAOYSA-N 0.000 description 2
- UGSBCCAHDVCHGI-UHFFFAOYSA-N 5-nitropyridin-2-amine Chemical compound NC1=CC=C([N+]([O-])=O)C=N1 UGSBCCAHDVCHGI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 2
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SIXNEILYIARUKH-UHFFFAOYSA-N 2-nitroethane-1,1-diol Chemical compound OC(O)C[N+]([O-])=O SIXNEILYIARUKH-UHFFFAOYSA-N 0.000 description 1
- OMRRBUOFUHBTGQ-UHFFFAOYSA-N C(CC(=O)O)C(C=O)[N+](=O)[O-] Chemical compound C(CC(=O)O)C(C=O)[N+](=O)[O-] OMRRBUOFUHBTGQ-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- CVUNPKSKGHPMSY-UHFFFAOYSA-N ethyl 2-chloroprop-2-enoate Chemical compound CCOC(=O)C(Cl)=C CVUNPKSKGHPMSY-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- YFYLPWJKCSESGB-UHFFFAOYSA-N pyronaridine Chemical compound C=12NC(OC)=CC=C2NC2=CC(Cl)=CC=C2C=1N=C(C=C(CN1CCCC1)C1=O)C=C1CN1CCCC1 YFYLPWJKCSESGB-UHFFFAOYSA-N 0.000 description 1
- 229950011262 pyronaridine Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- C07D213/61—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention provides a preparation method of 2-chloro-5-nitropyridine. 2-hydroxy-5-nitropyridine is prepared by two methods by taking 2-nitroacetaldehyde acetal as an initial raw material; then 2-hydroxy-5-nitropyridine and chlorinated reagent are subjected to chlorination reaction to prepare 2-chloro-5-nitropyridine. The method has the advantages of cheap and easily obtained raw materials and low cost; diazotization hydrolysis reaction is not involved, and the operation is safe and simple; mixed acid is not used, the waste water generation amount is small, and the environment is protected; meanwhile, the method does not relate to nitration reaction, has high reaction selectivity, less side reaction, simple post-treatment and high product yield and purity, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of 2-chloro-5-nitropyridine, belonging to the technical field of medical chemistry.
Background
The 2-chloro-5-nitropyridine is an important medical intermediate, can be used for preparing medicaments such as pyronaridine, sony gebu and the like and other fine chemicals, and has important significance for researching and optimizing the preparation method of the 2-chloro-5-nitropyridine for developing downstream products thereof.
2-chloro-5-nitropyridine (I) with molecular formula C5H3ClN2O2(the English name is 2-Chloro-5-Nitropyridine), the CAS number is 4548-45-2, and the structural formula is as follows:
at present, 2-chloro-5-nitropyridine is synthesized mainly by taking 2-aminopyridine as a raw material and carrying out nitration reaction, diazotization hydrolysis reaction and chlorination reaction.
For example, patent documents CN102040554A and CN105523995A use 2-aminopyridine as a raw material, and perform nitration reaction with mixed acid (concentrated sulfuric acid and fuming nitric acid) to obtain a mixture of 2-amino-5-nitropyridine and 2-amino-3-nitropyridine, and after separation and purification, obtain 2-amino-5-nitropyridine in an aqueous solution of hydrochloric acid, and perform diazotization hydrolysis reaction with sodium nitrite to obtain 2-hydroxy-5-nitropyridine, and perform chlorination reaction between 2-hydroxy-5-nitropyridine and phosphorus oxychloride to obtain 2-chloro-5-nitropyridine. The overall yield was 53.6% based on the starting 2-aminopyridine and the reaction procedure is depicted in scheme 1 below.
Synthesis scheme 1
In the synthetic route 1, 2-aminopyridine generates a large amount of wastewater in the mixed acid nitration treatment process, so that the pollution is great and the green production requirement is not met; meanwhile, more byproducts such as 2-amino-3-nitropyridine (the proportion is up to 15%) are generated in the nitration reaction, and the separation and purification are complicated; the diazotization hydrolysis reaction has poor safety and operability, and is not beneficial to production amplification and safe operation.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of 2-chloro-5-nitropyridine. The method has the advantages of cheap and easily obtained raw materials and low cost; diazotization hydrolysis reaction is not involved, and the operation is safe and simple; mixed acid is not used, the waste water generation amount is small, and the environment is protected; meanwhile, the method does not relate to nitration reaction, has high reaction selectivity, less side reaction, simple post-treatment and high product yield and purity, and is suitable for industrial production.
Description of terms:
a compound of formula II: 2-nitroethanediol;
a compound of formula III: 2-halogenated acrylates;
a compound of formula IV: 2-halo-4-nitro-5-oxopentanoate ketal;
a compound of formula V: 2-hydroxy-5-nitropyridine;
a compound of formula VI: 4-nitro-5-oxopentanoate ketal;
a compound of formula I: 2-chloro-5-nitropyridine.
The compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.
The technical scheme of the invention is as follows:
a preparation method of 2-chloro-5-nitropyridine comprises the following steps:
(1) preparing a compound shown in a formula V by using a compound shown in a formula II as an initial raw material;
wherein in the structural formula of the compound of the formula II, R1、R2Independently selected from the group consisting of carbon number1 to 4 alkyl or R1And R2Combined to ethylene radical-CH2CH2-, trimethylene-CH2CH2CH2-, substituted ethylene radical-CHRCH2-, substituted trimethylene-CHRCH2CH2-or substituted propylene-CH2CHRCH2-, wherein R is selected from alkyl groups having 1 to 4 carbon atoms;
(2) 2-chloro-5-nitropyridine (I) is prepared by chlorination of a compound of formula V and a chlorinating agent.
Preferred processes for preparing the compound of formula V in step (1) starting from the compound of formula II are route 1 or route 2, respectively, wherein,
route 1 comprises the steps of:
in a solvent A and under the action of a catalyst B, a compound shown in a formula II and a compound shown in a formula III are subjected to addition reaction to prepare a compound shown in a formula IV; directly carrying out cyclization reaction on the compound of the formula IV and ammonia without separation to prepare a compound of a formula V;
wherein, in the structural formula of the compound shown in the formula III, X is Cl or Br, R3Selected from alkyl groups having a carbon number of 1 to 4; in the structural formula of the compound of the formula IV, X, R3According to formula III of X, R3Are as defined above, R1、R2Independently selected from alkyl with carbon number of 1 to 4 or R1And R2Combined to ethylene radical-CH2CH2-, trimethylene-CH2CH2CH2-, substituted ethylene radical-CHRCH2-, substituted trimethylene-CHRCH2CH2-or substituted propylene-CH2CHRCH2-, wherein R is selected from alkyl groups having 1 to 4 carbon atoms;
route 2 comprises the steps of:
in a solvent C and under the action of a catalyst D, a compound shown in a formula II and acrylic ester are subjected to addition reaction to prepare a compound shown in a formula VI; the compound shown in the formula VI reacts with ammonia and an oxidant in sequence without separation to prepare a compound shown in the formula V;
wherein in the structural formula of the compound shown in the formula VI, R1、R2Independently selected from alkyl with carbon number of 1 to 4 or R1And R2Combined to ethylene radical-CH2CH2-, trimethylene-CH2CH2CH2-, substituted ethylene radical-CHRCH2-, substituted trimethylene-CHRCH2CH2-or substituted propylene-CH2CHRCH2-, wherein R is selected from alkyl groups having 1 to 4 carbon atoms; r3Selected from alkyl groups having a carbon number of 1 to 4.
Preferably, in route 1 of the method for preparing the compound of formula v using the compound of formula ii as the starting material, the solvent a is one or a combination of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, 1, 2-dichloroethane, dichloromethane or chloroform; the mass ratio of the solvent A to the compound of the formula II is (5-15): 1.
Preferably, in route 1 of the process for preparing a compound of formula V starting from a compound of formula II, said catalyst B is an organic base catalyst, more preferably piperidine, 4-dimethylaminopyridine, tri-n-butylamine or 1, 8-diazabicycloundecen-7-ene (DBU); the mass of the catalyst B is 0.5-5.0% of that of the compound of the formula II.
Preferably, in route 1 of the process for preparing the compound of formula V starting from the compound of formula II, the molar ratio of the compound of formula II to the compound of formula III is 1 (1.0-1.2).
Preferably, in route 1 of the process for preparing the compound of formula V starting from the compound of formula II, the addition reaction temperature is 20-80 ℃; further preferably, the addition reaction temperature is 40 to 60 ℃. The addition reaction time is 1-8 hours; further preferably, the addition reaction time is 2 to 4 hours.
Preferably, in route 1 of the method for preparing the compound of formula v using the compound of formula ii as the starting material, the ammonia is one or a combination of two or more selected from ammonia gas, ammonium chloride, ammonia water or ammonia alcohol solution; further preferably, the ammonia is ammonium chloride, a combination of ammonium chloride and ammonia gas, a combination of ammonium chloride and aqueous ammonia, or a combination of ammonium chloride and an ammonia alcohol solution; the molar ratio of ammonia to the compound of formula II is (2.0-10.0) 1; further preferably, the molar ratio of ammonia to the compound of formula II is (4.0-7.0): 1.
Preferably, in route 1 of the process for preparing the compound of formula V starting from the compound of formula II, the ring-closure reaction temperature is 0-100 ℃; further preferably, the cyclization reaction temperature is 30-60 ℃. The cyclization reaction time is 2-10 hours; more preferably, the cyclization reaction time is 3 to 5 hours.
Preferably, in route 2 of the method for preparing the compound of formula v using the compound of formula ii as the starting material, the solvent C is one or a combination of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, 1, 2-dichloroethane, dichloromethane or chloroform; the mass ratio of the solvent C to the compound of the formula II is (5-15): 1.
Preferably, in route 2 of the process for preparing a compound of formula V starting from a compound of formula II, said catalyst D is an organic base catalyst, more preferably piperidine, 4-dimethylaminopyridine, tri-n-butylamine or 1, 8-diazabicycloundecen-7-ene (DBU); the mass of the catalyst D is 0.5-5.0% of that of the compound of the formula II.
Preferably, in route 2 of the process for preparing the compound of formula V starting from a compound of formula II, the molar ratio of the compound of formula II to the acrylate is 1 (1.0-1.2).
Preferably, in route 2 of the process for preparing the compound of formula V starting from the compound of formula II, the addition reaction temperature is 20-80 ℃; further preferably, the addition reaction temperature is 40 to 60 ℃. The addition reaction time is 1-8 hours; further preferably, the addition reaction time is 2 to 4 hours.
Preferably, in route 2 of the method for preparing the compound of formula v using the compound of formula ii as the starting material, the ammonia is one or a combination of two or more selected from ammonia gas, ammonium chloride, ammonia water or ammonia alcohol solution; further preferably, the ammonia is ammonium chloride, a combination of ammonium chloride and ammonia gas, a combination of ammonium chloride and aqueous ammonia, or a combination of ammonium chloride and an ammonia alcohol solution; the molar ratio of ammonia to the compound of formula II is (2.0-10.0) 1; further preferably, the molar ratio of ammonia to the compound of formula II is (4.0-7.0): 1.
Preferably, in route 2 of the process for preparing the compound of formula V starting from the compound of formula II, the reaction temperature of said compound of formula VI with ammonia is from 0 to 100 ℃; it is further preferred that the reaction temperature of the compound of formula VI with ammonia is from 30 to 60 ℃. The reaction time of the compound of formula VI and ammonia is 2-10 hours; it is further preferred that the reaction time of the compound of formula VI with ammonia is from 3 to 5 hours.
Preferably, in the route 2 of the method for preparing the compound of the formula V by using the compound of the formula II as the initial raw material, the oxidant is tert-butyl hydroperoxide, hydrogen peroxide, 3-chloroperoxybenzoic acid, sodium hypochlorite or nitric acid; the molar ratio of the oxidant to the compound of formula II is (1.0-2.0): 1; further preferably, the molar ratio of the oxidizing agent to the compound of formula II is (1.1-1.5): 1.
Preferably, in route 2 of the process for preparing the compound of formula V starting from the compound of formula II, the oxidation reaction temperature with the oxidizing agent is 10-80 ℃; further preferably, the oxidation reaction temperature is 30 to 50 ℃. The oxidation reaction time is 1-5 hours; further preferably, the oxidation reaction time is 2 to 4 hours.
Preferably, according to the invention, in step (2), the chlorination of the compound of formula V and the chlorinating agent is carried out in solvent E.
Preferably, the solvent E is one or a combination of more than two of dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, N-dimethylformamide, chlorobenzene, thionyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, diphosgene or triphosgene; the mass ratio of the solvent E to the compound of the formula V is (5-10): 1.
Preferably, the chlorinating reagent is one or a combination of more than two of thionyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, diphosgene and triphosgene; the mol ratio of the chlorinated reagent to the compound of the formula V is (0.5-20) to 1; more preferably, the molar ratio of the chlorinating reagent to the compound of formula V is (1-10): 1. The chlorinating agent may be used in excess, and when in excess, the chlorinating agent may act as a solvent.
Preferably, the chlorination reaction temperature is 40-160 ℃; further preferably, the chlorination reaction temperature is 60-120 ℃. The chlorination reaction time is 1-10 hours; further preferably, the chlorination reaction time is 2 to 8 hours.
The work-up of the products obtained in the various steps of the process according to the invention can be carried out with reference to the state of the art. The invention preferably provides a method for the work-up of the product obtained, comprising the steps of:
(1) in route 1 or route 2 of the method for preparing the compound of formula V by using the compound of formula II as an initial raw material, water is added into a reaction liquid obtained after the reaction is finished, the organic solvent is recovered under slightly reduced pressure, the remainder is cooled to 20-25 ℃, the filtration is carried out, and a filter cake is washed by water and dried to obtain the compound of formula V.
(2) And (3) after the reaction in the step (2) is finished, distilling the obtained reaction liquid under reduced pressure to recover the organic solvent, slowly pouring the residues into ice water, fully stirring, neutralizing the system with a sodium hydroxide aqueous solution until the pH value is 8-9, layering, extracting the water layer with the organic solvent for three times, combining organic phases, washing the obtained organic phases with saturated saline solution, drying with anhydrous sodium sulfate, distilling to recover the organic solvent, and drying to obtain the organic solvent.
The process of the present invention is depicted as scheme 2 below:
the synthetic route for the compounds of formula v is as follows, route 1 or 2:
route 1
Or pathway 2
The synthetic route for the preparation of 2-chloro-5-nitropyridine (I) from the compound of formula V is as follows:
synthesis scheme 2
In scheme 2 above, R1、R2Independently selected from alkyl with carbon number of 1 to 4 or R1And R2Combined to ethylene radical-CH2CH2-, trimethylene-CH2CH2CH2-, substituted ethylene radical-CHRCH2-, substituted trimethylene-CHRCH2CH2-or substituted propylene-CH2CHRCH2-, wherein R is selected from alkyl groups having 1 to 4 carbon atoms; r3Selected from alkyl groups having a carbon number of 1 to 4; and X is Cl or Br.
The invention has the technical characteristics and beneficial effects that:
1. the invention provides a novel preparation method of 2-chloro-5-nitropyridine, which comprises the steps of preparing 2-hydroxy-5-nitropyridine by using a compound shown in a formula II as an initial raw material through a way 1 or a way 2, and further preparing the 2-chloro-5-nitropyridine. In the method 1, 2-nitroacetaldehyde acetal and 2-halogenated acrylate are subjected to addition reaction to prepare 2-halo-4-nitro-5-oxopentanoate acetal, and directly cyclized with ammonia without separation to prepare 2-hydroxy-5-nitropyridine; the method 2 prepares 4-nitro-5-oxo-valerate acetal by performing addition reaction on 2-nitroacetaldehyde acetal and acrylate, and sequentially reacts with ammonia and an oxidant without separation to prepare 2-hydroxy-5-nitropyridine; then 2-hydroxy-5-nitropyridine and chlorinated reagent are subjected to chlorination reaction to prepare 2-chloro-5-nitropyridine.
2. The invention does not use the 2-aminopyridine with higher price, and the used raw materials are cheap and easy to obtain and have low cost; the diazotization hydrolysis reaction is avoided, the process operation is safe and simple, and the reaction condition is mild; the nitration reaction is avoided by using mixed acid, the amount of wastewater in the process is small, and the method is green and environment-friendly; the invention does not relate to nitration reaction, has high reaction selectivity, less by-products, simple separation and purification and high yield and purity of target products, and is suitable for industrial production.
3. The 2-halo-4-nitro-5-oxo-valerate acetal or 4-nitro-5-oxo-valerate acetal is prepared by 2-nitroacetaldehyde acetal and 2-haloacrylate or acrylate through an addition reaction, the carbon-hydrogen bond at the nitro-ortho position of the 2-nitroacetaldehyde acetal is relatively active, under the action of a catalyst, formed carbanions are easy to perform designed addition reaction, the reaction is specific, the stability of an intermediate is good, aldehyde groups dissociated from the acetal in a reaction system are easy to react with ammonia to generate imine, and then the imine and the pyridine ring or a dihydropyridine ring are generated through cyclization. The dihydropyridine ring is easy to react with an oxidizing agent to generate a pyridine ring with more stable thermodynamics, thereby promoting the reaction to be completely carried out. The reactions involved in the route of the invention have reaction specificity and appropriate reaction activity, and high reaction selectivity, and ensure high yield and high purity of the target product.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples are all commercially available products.
In the examples, "%" is given by weight unless otherwise specified.
The yields in the examples are all molar yields.
Example 1: preparation of 2-hydroxy-5-nitropyridine (V) (route 1 of step (1))
A500 ml four-neck flask which is connected with a stirring thermometer and a reflux condenser is added with 200 g of dichloromethane, 27.0 g (0.2 mol) of 2-nitroacetaldehyde dimethyl acetal (II 1), 0.5 g of piperidine and 25.3 g (0.21 mol) of 2-methyl chloroacrylate (III 1), stirred and reacted at 40-45 ℃ for 3 hours, the reaction liquid is cooled to 25 ℃, 5.0 g of ammonium chloride and 100 g of 17% ammonia water are added, and stirred and reacted at 35-40 ℃ for 5 hours. 100 g of water is added, dichloromethane is recovered under slight reduced pressure, the mixture is cooled to 20-25 ℃, filtered, washed for 1 time by 20 g of water and dried to obtain 25.8 g of 2-hydroxy-5-nitropyridine with the liquid phase purity of 99.6 percent and the yield of 92.1 percent.
Example 2: preparation of 2-hydroxy-5-nitropyridine (V) (route 1 of step (1))
200 g of tetrahydrofuran, 26.6 g (0.2 mol) of 2-nitroaldehyde ethylene glycol (II 2), 0.5 g of DBU, 34.7 g (0.21 mol) of 2-bromomethyl acrylate (III 2) are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and reflux condenser, the mixture is stirred and reacted for 3 hours at the temperature of 40-45 ℃, the reaction solution is cooled to 25 ℃, 3.5 g of ammonium chloride and 100 g of 17 percent ammonia methanol solution are added, and the mixture is stirred and reacted for 3 hours at the temperature of 50-55 ℃. Adding 150 g of water, slightly decompressing and recovering tetrahydrofuran and methanol, cooling to 20-25 ℃, filtering, washing for 1 time by 20 g of water, and drying to obtain 26.2 g of 2-hydroxy-5-nitropyridine with the liquid phase purity of 99.5 percent and the yield of 93.6 percent.
Example 3: preparation of 2-hydroxy-5-nitropyridine (V) (route 1 of step (1))
A500 ml four-neck flask which is connected with a stirring thermometer and a reflux condenser is added with 200 g of 1, 2-dichloroethane, 27.0 g (0.2 mol) of 2-nitroacetaldehyde dimethyl acetal (II 1), 0.5 g of piperidine and 28.2 g (0.21 mol) of 2-chloroacrylic acid ethyl ester (III 3), stirred and reacted for 2 hours at the temperature of 55-60 ℃, the reaction liquid is cooled to 25 ℃, 3.5 g of ammonium chloride and 100 g of 17% ammonia water are added, and stirred and reacted for 3 hours at the temperature of 50-55 ℃. 100 g of water is added, 1, 2-dichloroethane is recovered under slight reduced pressure, the mixture is cooled to 20-25 ℃, filtered, washed for 1 time by 20 g of water and dried to obtain 25.3 g of 2-hydroxy-5-nitropyridine with the liquid phase purity of 99.2 percent and the yield of 90.4 percent.
Example 4: preparation of 2-hydroxy-5-nitropyridine (V) (route 2 of step (1))
A500 ml four-neck flask equipped with a stirrer, a thermometer and a reflux condenser was charged with 200 g of methylene chloride, 27.0 g (0.2 mol) of 2-nitroacetaldehyde dimethyl acetal (II 1), 0.5 g of piperidine, 18.9 g (0.22 mol) of methyl acrylate, and stirred at 40-45 ℃ for reaction for 3 hours, the reaction mixture was cooled to 25 ℃, 10.0 g of ammonium chloride and 90 g of 17% ammonia water were added, and stirred at 45-50 ℃ for reaction for 4 hours. Then 28.5 g (0.25 mol) of 30 wt% hydrogen peroxide is added, and the mixture is stirred and reacted for 3 hours at the temperature of 40-45 ℃. 100 g of water is added, dichloromethane is recovered under slight reduced pressure, the mixture is cooled to 20-25 ℃, filtered, washed for 1 time by 20 g of water and dried to obtain 25.1 g of 2-hydroxy-5-nitropyridine with the liquid phase purity of 99.3 percent and the yield of 89.6 percent.
Example 5: preparation of 2-hydroxy-5-nitropyridine (V) (route 2 of step (1))
200 g of tetrahydrofuran, 26.6 g (0.2 mol) of 2-nitroaldehyde ethylene acetal (II 2), 0.5 g of DBU, 21.0 g (0.21 mol) of ethyl acrylate are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and reflux condenser, the mixture is stirred and reacted for 3 hours at the temperature of 45-50 ℃, the reaction solution is cooled to 25 ℃, 10.0 g of ammonium chloride and 100 g of 17% ammonia methanol solution are added, and the mixture is stirred and reacted for 3 hours at the temperature of 50-55 ℃. Then 28.5 g (0.22 mol) of 70 wt% t-butyl hydroperoxide was added and the reaction was stirred at 30-35 ℃ for 4 hours. Adding 150 g of water, slightly decompressing and recovering tetrahydrofuran, cooling to 20-25 ℃, filtering, washing for 1 time by 20 g of water, and drying to obtain 25.7 g of 2-hydroxy-5-nitropyridine with the liquid phase purity of 99.6 percent and the yield of 91.8 percent.
Example 6: preparation of 2-chloro-5-nitropyridine (I)
To a 500 ml four-necked flask equipped with a thermometer, a stirring and reflux condenser were charged 50 g of phosphorus oxychloride, 14.0 g (0.1 mol) of 2-hydroxy-5-nitropyridine prepared in example 1, 25.0 g (0.12 mol) of phosphorus pentachloride, 100 ℃ and 105 ℃ with stirring to react for 5 hours, then the phosphorus oxychloride was recovered by distillation under reduced pressure, the residue was slowly poured into 120 g of ice water, sufficiently stirred, then neutralized with a 40 wt% aqueous solution of sodium hydroxide at a pH of 8 to 9, layered, the aqueous layer was extracted three times with 60 g of methylene chloride each time, the organic phases were combined, washed with 20 g of saturated brine, then dried with 2.0 g of anhydrous sodium sulfate, and the methylene chloride was recovered by distillation and dried to obtain 15.1 g of 2-chloro-5-nitropyridine (I), yield 95.3%, and gas phase purity 99.8%.
The nuclear magnetic data of the product obtained are as follows:
1H NMR(CDCl3,δ,ppm)：
9.68(s，1H)，8.64(d，1H)，7.45(d，1H)。
example 7: preparation of 2-chloro-5-nitropyridine (I)
100 g of 1, 2-dichloroethane, 25.0 g (0.12 mol) of phosphorus pentachloride, 14.0 g (0.1 mol) of 2-hydroxy-5-nitropyridine prepared in example 2 were charged into a 500 ml four-neck flask equipped with a thermometer, a stirring and reflux condenser, stirred and reacted at 80 to 85 ℃ for 6 hours, then 1, 2-dichloroethane was recovered by distillation under reduced pressure, the reaction solution was cooled to 25 ℃ and slowly poured into 150 g of ice water, sufficiently stirred, then neutralized to a pH of 8 to 9 with a 40 wt% aqueous solution of sodium hydroxide, the layers were separated, the aqueous layer was extracted three times with 1, 2-dichloroethane, 20 g each time, the organic phases were combined, washed with 20 g of saturated brine, then dried with 2.0 g of anhydrous sodium sulfate, 1, 2-dichloroethane was recovered by distillation, dried to give 14.9 g of 2-chloro-5-nitropyridine (I), the yield is 94.0 percent, and the gas phase purity is 99.9 percent.
Example 8: preparation of 2-chloro-5-nitropyridine (I)
Into a 500 ml four-necked flask equipped with a thermometer, a stirring and reflux condenser tube were charged 50 g of N, N-dimethylformamide, 40 g of thionyl chloride, 14.0 g (0.1 mol) of 2-hydroxy-5-nitropyridine prepared in example 3, and the reaction was carried out under stirring at 75 to 80 ℃ for 8 hours, followed by recovery of thionyl chloride by distillation under reduced pressure, the residue was cooled to 25 ℃ and 100 g of methylene chloride was added, dissolved under stirring, and the resultant liquid was poured into 100 g of ice water, sufficiently stirred, then neutralized with 40 wt% aqueous sodium hydroxide solution at pH 8 to 9, layer separation was carried out, the aqueous layer was extracted three times with methylene chloride, 20 g each time, the organic phases were combined, washed with 20 g of saturated brine, then dried with 2.0 g of anhydrous sodium sulfate, methylene chloride was recovered by distillation, and dried to obtain 14.7 g of 2-chloro-5-nitropyridine (I), the yield was 92.7%, and the gas phase purity was 99.5%.
Comparative example: preparation of 2-hydroxy-5-nitropyridine (V) (route 1 of step (1))
200 g of dichloromethane, 27.0 g (0.2 mol) of 2-nitroacetaldehyde dimethyl acetal (II 1), 0.5 g of piperidine and 25.3 g (0.21 mol) of 2-methyl chloroacrylate (III 1) are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and reflux condenser, the mixture is stirred and reacted for 3 hours at the temperature of 40-45 ℃, the reaction liquid is cooled to 25 ℃, 100 g of 17 percent ammonia water is added, and the mixture is stirred and reacted for 5 hours at the temperature of 35-40 ℃. 100 g of water is added, dichloromethane is recovered under slight reduced pressure, the mixture is cooled to 20-25 ℃, filtered, washed for 1 time by 20 g of water and dried to obtain 17.2 g of 2-hydroxy-5-nitropyridine with the liquid phase purity of 97.3 percent and the yield of 61.2 percent.
The comparative example shows that the addition of ammonium chloride is beneficial to improving the reaction yield and purity, and the analytical reason is that an acid substance is needed to convert acetal into aldehyde group when the ammonium chloride reacts with ammonia, so that the reaction of the ammonia and the aldehyde group to generate imine is facilitated, and the cyclization is further carried out.
Claims (14)
1. A preparation method of 2-chloro-5-nitropyridine comprises the following steps:
(1) preparing a compound shown in a formula V by using a compound shown in a formula II as an initial raw material;
wherein in the structural formula of the compound of the formula II, R1、R2Independently selected from alkyl with carbon number of 1 to 4 or R1And R2Combined to ethylene radical-CH2CH2-, trimethylene-CH2CH2CH2-, substituted ethylene radical-CHRCH2-, substituted trimethylene-CHRCH2CH2-or substituted propylene-CH2CHRCH2-, wherein R is selected from alkyl groups having 1 to 4 carbon atoms;
the process for the preparation of the compound of formula v starting from a compound of formula ii is route 1 or route 2, respectively, wherein,
route 1 comprises the steps of:
in a solvent A and under the action of a catalyst B, a compound shown in a formula II and a compound shown in a formula III are subjected to addition reaction to prepare a compound shown in a formula IV; directly carrying out cyclization reaction on the compound of the formula IV and ammonia without separation to prepare a compound of a formula V;
the solvent A is one or the combination of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, acetonitrile, 1, 2-dichloroethane, dichloromethane or chloroform; the catalyst B is an organic base catalyst; the temperature of the addition reaction is 20-80 ℃; the cyclization reaction temperature is 0-100 ℃; the ammonia is one or the combination of more than two of ammonia gas, ammonium chloride, ammonia water or ammonia alcohol solution;
wherein, in the structural formula of the compound shown in the formula III, X is Cl or Br, R3Selected from alkyl groups having a carbon number of 1 to 4; in the structural formula of the compound of the formula IV, X, R3According to formula III of X, R3Are as defined above, R1、R2Independently selected from alkyl with carbon number of 1 to 4 or R1And R2Combined to ethylene radical-CH2CH2-, trimethylene-CH2CH2CH2-, substituted ethylene radical-CHRCH2-, substituted trimethylene-CHRCH2CH2-or substituted propylene-CH2CHRCH2-, wherein R is selected from alkyl groups having 1 to 4 carbon atoms;
route 2 comprises the steps of:
in a solvent C and under the action of a catalyst D, a compound shown in a formula II and acrylic ester are subjected to addition reaction to prepare a compound shown in a formula VI; the compound shown in the formula VI reacts with ammonia and an oxidant in sequence without separation to prepare a compound shown in the formula V;
the solvent C is one or the combination of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, acetonitrile, 1, 2-dichloroethane, dichloromethane or chloroform; the catalyst D is an organic base catalyst; the temperature of the addition reaction is 20-80 ℃; the reaction temperature of the compound shown in the formula VI and ammonia is 0-100 ℃; the oxidant is tert-butyl hydroperoxide, hydrogen peroxide, 3-chloroperoxybenzoic acid, sodium hypochlorite or nitric acid; the temperature of the oxidation reaction with the oxidant is 10-80 ℃; the ammonia is one or the combination of more than two of ammonia gas, ammonium chloride, ammonia water or ammonia alcohol solution;
wherein in the structural formula of the compound shown in the formula VI, R1、R2Independently selected from carbonAlkyl radicals having a number of 1 to 4 or R1And R2Combined to ethylene radical-CH2CH2-, trimethylene-CH2CH2CH2-, substituted ethylene radical-CHRCH2-, substituted trimethylene-CHRCH2CH2-or substituted propylene-CH2CHRCH2-, wherein R is selected from alkyl groups having 1 to 4 carbon atoms; r3Selected from alkyl groups having a carbon number of 1 to 4;
(2) 2-chloro-5-nitropyridine (I) is prepared by chlorination of a compound of formula V and a chlorinating agent.
2. The process of claim 1, wherein route 1 of the process for preparing the compound of formula v starting from the compound of formula ii comprises one or more of the following conditions:
a. the mass ratio of the solvent A to the compound shown in the formula II is (5-15) to 1;
b. the catalyst B is piperidine, 4-dimethylaminopyridine, tri-n-butylamine or 1, 8-diazabicycloundecen-7-ene (DBU); the mass of the catalyst B is 0.5-5.0% of that of the compound of the formula II;
c. the molar ratio of the compound shown in the formula II to the compound shown in the formula III is 1 (1.0-1.2);
d. the temperature of the addition reaction is 40-60 ℃.
3. The process of claim 1, wherein route 1 of the process for preparing the compound of formula v starting from the compound of formula ii comprises one or more of the following conditions:
a. the ammonia is ammonium chloride, a combination of ammonium chloride and ammonia gas, a combination of ammonium chloride and ammonia water or a combination of ammonium chloride and ammonia alcohol solution; the molar ratio of ammonia to the compound of formula II is (2.0-10.0) 1;
b. the temperature of the cyclization reaction is 30-60 ℃.
4. The process for the preparation of 2-chloro-5-nitropyridine of claim 3, wherein the molar ratio of ammonia to the compound of formula II is (4.0-7.0): 1.
5. The process of claim 1, wherein route 2 of the process for preparing the compound of formula v starting from the compound of formula ii comprises one or more of the following conditions:
a. the mass ratio of the solvent C to the compound shown in the formula II is (5-15) to 1;
b. the catalyst D is piperidine, 4-dimethylaminopyridine, tri-n-butylamine or 1, 8-diazabicycloundec-7-ene (DBU); the mass of the catalyst D is 0.5-5.0% of that of the compound shown in the formula II;
c. the molar ratio of the compound shown in the formula II to the acrylate is 1 (1.0-1.2);
d. the temperature of the addition reaction is 40-60 ℃.
6. The process of claim 1, wherein route 2 of the process for preparing the compound of formula v starting from the compound of formula ii comprises one or more of the following conditions:
a. the ammonia is ammonium chloride, a combination of ammonium chloride and ammonia gas, a combination of ammonium chloride and ammonia water or a combination of ammonium chloride and ammonia alcohol solution; the molar ratio of ammonia to the compound of formula II is (2.0-10.0) 1;
b. the reaction temperature of the compound of the formula VI and ammonia is 30-60 ℃.
7. The process according to claim 6, wherein the molar ratio of ammonia to the compound of formula II is (4.0-7.0): 1.
8. The process of claim 1, wherein route 2 of the process for preparing the compound of formula v starting from the compound of formula ii comprises one or more of the following conditions:
a. the molar ratio of the oxidant to the compound of formula II is (1.0-2.0): 1;
b. the temperature of the oxidation reaction with the oxidant is 30-50 ℃.
9. The process according to claim 8, wherein the molar ratio of the oxidizing agent to the compound of formula II is (1.1-1.5): 1.
10. The process for preparing 2-chloro-5-nitropyridine according to claim 1, wherein in step (2), the chlorination of the compound of formula v and the chlorinating agent is carried out in solvent E.
11. The process of claim 10, wherein one or more of the following conditions are included:
a. the solvent E is one or the combination of more than two of dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, N-dimethylformamide, chlorobenzene or phosphorus oxychloride; the mass ratio of the solvent E to the compound of the formula V is (5-10) to 1;
b. the chlorinated reagent is one or the combination of more than two of thionyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, diphosgene or triphosgene; the molar ratio of the chlorinated reagent to the compound of the formula V is (0.5-20): 1.
12. The method for preparing 2-chloro-5-nitropyridine according to claim 11, wherein the molar ratio of the chlorinating agent to the compound of formula v is (1-10): 1.
13. The method for preparing 2-chloro-5-nitropyridine according to claim 10, wherein the chlorination reaction temperature is 40 to 160 ℃.
14. The method for preparing 2-chloro-5-nitropyridine according to claim 13, wherein the chlorination reaction temperature is 60 to 120 ℃.
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| US4288599A (en) * | 1979-03-09 | 1981-09-08 | Ishihara Sangyo Kaisha Ltd. | Process for producing pyridine derivatives having a trifluoromethyl group at β-position thereof |
| CN103435556A (en) * | 2013-08-26 | 2013-12-11 | 新发药业有限公司 | Simple and quick method for synthesizing improved vitamin B1 intermediate 2-methyl-4-amino-5-aminomethylpyrimidine |
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| US4288599A (en) * | 1979-03-09 | 1981-09-08 | Ishihara Sangyo Kaisha Ltd. | Process for producing pyridine derivatives having a trifluoromethyl group at β-position thereof |
| CN103435556A (en) * | 2013-08-26 | 2013-12-11 | 新发药业有限公司 | Simple and quick method for synthesizing improved vitamin B1 intermediate 2-methyl-4-amino-5-aminomethylpyrimidine |
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Denomination of invention: A preparation method of 2-chloro-5-nitropyridine Effective date of registration: 20231130 Granted publication date: 20210720 Pledgee: Dongying Branch of China CITIC Bank Co.,Ltd. Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2023980068537 |