CN109721529B - Simple preparation method of 2, 5-dichloropyridine - Google Patents
Simple preparation method of 2, 5-dichloropyridine Download PDFInfo
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- CN109721529B CN109721529B CN201711020260.5A CN201711020260A CN109721529B CN 109721529 B CN109721529 B CN 109721529B CN 201711020260 A CN201711020260 A CN 201711020260A CN 109721529 B CN109721529 B CN 109721529B
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- GCTFDMFLLBCLPF-UHFFFAOYSA-N 2,5-dichloropyridine Chemical compound ClC1=CC=C(Cl)N=C1 GCTFDMFLLBCLPF-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000005690 diesters Chemical class 0.000 claims abstract description 13
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 7
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 239000011976 maleic acid Substances 0.000 claims description 12
- -1 maleic acid diester Chemical class 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 9
- 150000007530 organic bases Chemical class 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 239000007868 Raney catalyst Substances 0.000 claims description 7
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 7
- 238000006482 condensation reaction Methods 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- LDCRTTXIJACKKU-ARJAWSKDSA-N dimethyl maleate Chemical compound COC(=O)\C=C/C(=O)OC LDCRTTXIJACKKU-ARJAWSKDSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000012320 chlorinating reagent Substances 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 4
- IEPRKVQEAMIZSS-UHFFFAOYSA-N Di-Et ester-Fumaric acid Natural products CCOC(=O)C=CC(=O)OCC IEPRKVQEAMIZSS-UHFFFAOYSA-N 0.000 claims description 3
- IEPRKVQEAMIZSS-WAYWQWQTSA-N Diethyl maleate Chemical compound CCOC(=O)\C=C/C(=O)OCC IEPRKVQEAMIZSS-WAYWQWQTSA-N 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- FNMTVMWFISHPEV-WAYWQWQTSA-N dipropan-2-yl (z)-but-2-enedioate Chemical compound CC(C)OC(=O)\C=C/C(=O)OC(C)C FNMTVMWFISHPEV-WAYWQWQTSA-N 0.000 claims description 3
- MSVGHYYKWDQHFV-FPLPWBNLSA-N ditert-butyl (z)-but-2-enedioate Chemical compound CC(C)(C)OC(=O)\C=C/C(=O)OC(C)(C)C MSVGHYYKWDQHFV-FPLPWBNLSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 9
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 239000002351 wastewater Substances 0.000 abstract description 3
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- CHGPEDOMXOLANF-UHFFFAOYSA-N pyridine-2,5-diol Chemical compound OC1=CC=C(O)N=C1 CHGPEDOMXOLANF-UHFFFAOYSA-N 0.000 description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000010992 reflux Methods 0.000 description 11
- 239000007791 liquid phase Substances 0.000 description 10
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 5
- GPAKJVMKNDXBHH-UHFFFAOYSA-N 2,3,6-trichloropyridine Chemical compound ClC1=CC=C(Cl)C(Cl)=N1 GPAKJVMKNDXBHH-UHFFFAOYSA-N 0.000 description 4
- MAKFMOSBBNKPMS-UHFFFAOYSA-N 2,3-dichloropyridine Chemical compound ClC1=CC=CN=C1Cl MAKFMOSBBNKPMS-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000006193 diazotization reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound 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
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WKHWRUVMZFLCPX-UHFFFAOYSA-N 2-butoxy-3-chloropyridine Chemical compound CCCCOC1=NC=CC=C1Cl WKHWRUVMZFLCPX-UHFFFAOYSA-N 0.000 description 1
- UAFDMOYAUDSRDB-UHFFFAOYSA-N 2-butoxy-5-chloropyridine Chemical compound CCCCOC1=CC=C(Cl)C=N1 UAFDMOYAUDSRDB-UHFFFAOYSA-N 0.000 description 1
- OFLSKXBALZCMCX-UHFFFAOYSA-N 2-butoxypyridine Chemical compound CCCCOC1=CC=CC=N1 OFLSKXBALZCMCX-UHFFFAOYSA-N 0.000 description 1
- MAXBVGJEFDMHNV-UHFFFAOYSA-N 5-chloropyridin-2-amine Chemical compound NC1=CC=C(Cl)C=N1 MAXBVGJEFDMHNV-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000002467 anti-pepsin effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a green, safe, simple and convenient preparation method of 2, 5-dichloropyridine. The invention takes maleic diester as an initial raw material, and prepares 2, 5-dichloropyridine by condensation with nitromethane, hydrogenation cyclization and chlorination. The preparation method is simple, easy to operate, high in reaction selectivity, high in product yield and purity; the method has the advantages of less waste water generation amount, environmental protection and high reaction safety; and the used raw materials are cheap and easy to obtain, and the cost is low.
Description
Technical Field
The invention relates to a simple preparation method of 2, 5-dichloropyridine, belonging to the technical field of medical chemistry.
Background
2, 5-dichloropyridine is an important pesticide and a medicine intermediate, can be used for synthesizing medicine intermediates of anti-AIDS, anti-peptic ulcer and the like, can also be used as an intermediate of pyridine insecticides, and has wide application in the fields of dyes, medicines, pesticides and the like.
The 2, 5-dichloropyridine mainly comprises the following three synthesis methods, and is prepared by respectively taking 2-chloropyridine, 2-aminopyridine and 2,3, 6-trichloropyridine as starting materials.
1.2, 5-dichloropyridine and 2, 3-dichloropyridine were prepared by reacting 2-chloropyridine as a starting material with n-butanol to give 2-butoxypyridine, introducing chlorine gas to give a mixture of 85 wt% of 2-butoxy-5-chloropyridine and 15 wt% of 2-butoxy-3-chloropyridine, and then chlorinating with phosphorus oxychloride, and the mixture was separated with an aqueous isopropanol solution to give 2, 5-dichloropyridine in a total yield of 36.29%, as illustrated in scheme 1 below (see patent document US 5380862):
the method in the synthetic route 1 has the advantages of multiple steps, long period, complex treatment, large toxicity of the used raw material chlorine, no contribution to safety and environmental protection, poor reaction selectivity, large separation difficulty, low total yield and difficult realization of industrialization, and the mixture of the 2, 5-dichloropyridine and the 2, 3-dichloropyridine needs to be separated.
2. 2-aminopyridine is taken as a raw material, 2-aminopyridine is dissolved in concentrated hydrochloric acid and hydrogen peroxide for chlorination to generate an intermediate product 2-amino-5-chloropyridine, and then diazotization and sandmeyer reaction are carried out to obtain a target product 2, 5-dichloropyridine with the total yield of 58 percent, which is described as the following synthetic route 2 (see the document: the master paper of Harbin university of science and technology, 2012, the synthesis of dichloropyridine, Wang Hui Juan):
the diazonium salt generated by the diazotization reaction in the synthetic route 2 is easy to decompose at a slightly high temperature or under the action of light, the diazonium salt is unstable, high in activity, and can be decomposed and exploded by heating or friction and impact, so that the method is not beneficial to safety and environmental protection, and the yield of the target product 2, 5-dichloropyridine is low, so that the method is not suitable for industrial development.
3. Using 2,3, 6-trichloropyridine as a raw material, dissolving 2,3, 6-trichloropyridine in benzene or toluene, adding a sodium hydroxide solution, heating to reflux, adding zinc powder in three batches for reduction reaction, cooling and filtering to obtain a crude product of 2, 5-dichloropyridine, and then recrystallizing with ethanol to obtain 2, 5-dichloropyridine with a total yield of 78.3%, which is described as the following synthetic route 3 (see patent document CN 101709050A):
the raw material 2,3, 6-trichloropyridine used in the method of the synthesis route 3 is expensive, a solvent with high toxicity of benzene and toluene is used, zinc powder is added in batches, the operation is inconvenient, a crude product needs to be recrystallized and refined, a large amount of ethanol solvent is needed, and a large amount of solid waste is generated, so that the method is not safe and environment-friendly.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a green, safe, simple and convenient preparation method of 2, 5-dichloropyridine. The preparation method is simple, easy to operate, high in reaction selectivity, high in product yield and purity; the method has the advantages of less waste water generation amount, environmental protection and high reaction safety; and the used raw materials are cheap and easy to obtain, and the cost is low.
Description of terms:
maleic acid diester: also known as maleic diesters;
a compound of formula II: cis-5-nitro-4-oxo-2-pentenoate;
a compound of formula III: 2, 5-dihydroxypyridine, also known as 5-hydroxypyridin-2 (1H) -one.
The technical scheme of the invention is as follows:
a preparation method of 2, 5-dichloropyridine comprises the following steps:
(1) carrying out condensation reaction on maleic diester and nitromethane under the catalysis of organic base to prepare reaction liquid containing a compound shown in a formula II; adding a solvent and a catalyst into the reaction solution without separating, and carrying out hydrogenation cyclization on the compound of the formula II in the reaction solution to prepare a compound of a formula III;
wherein R in the compound of the formula II is one of C1-4 alkyl; preferably, R is one of methyl, ethyl, isopropyl or tert-butyl;
(2) and (3) chlorinating the compound shown in the formula III and a chlorinating reagent to prepare the 2, 5-dichloropyridine.
According to the invention, the mole ratio of the maleic acid diester and the nitromethane in the step (1) is preferably 1 (0.90-1.1).
Preferably, in step (1), the maleic acid diester is one of dimethyl maleate, diethyl maleate, diisopropyl maleate or di-tert-butyl maleate.
Preferably according to the invention, the organic base in step (1) is one or a combination of two of 1, 8-diazabicyclo [5.4.0] -7-undecene (DBU) or 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN).
According to the invention, the mass of the organic base in the step (1) is preferably 1.2-5% of that of the maleic acid diester; preferably, the mass of the organic base in step (1) is 1.5-4% of the mass of the maleic acid diester.
According to the invention, the condensation reaction temperature in the step (1) is preferably 30-90 ℃; preferably, the condensation reaction temperature in step (1) is 60-70 ℃. The reaction time is 2-8 hours.
According to the invention, the mass of the catalyst in the step (1) is preferably 0.5-15% of that of the maleic acid diester.
Preferably according to the invention, the catalyst in step (1) is palladium on carbon or Raney nickel.
Preferably, the mass of the palladium carbon is 0.5-5% of that of the maleic diester; more preferably, the mass of the palladium-carbon is 1 to 3 percent of that of the maleic acid diester.
Preferably, the mass of the raney nickel is 1 to 15% of the mass of the maleic acid diester, and more preferably, the mass of the raney nickel is 5 to 10% of the mass of the maleic acid diester. The type and amount of the catalyst are important for improving the yield of the 2, 5-dihydroxypyridine.
According to the present invention, the solvent in step (1) is one or a mixture of two or more of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, or toluene.
According to the invention, the mass ratio of the maleic acid diester to the solvent in the step (1) is preferably 1 (3-15).
Preferably, according to the invention, in the step (1) of the hydrocyclization reaction, the hydrogen pressure is 0.1-0.3 MPa; the temperature of the hydrogenation cyclization reaction in the step (1) is 20-80 ℃; preferably, the temperature of the hydrogenation cyclization reaction in the step (1) is 50-70 ℃. The reaction time is 3-8 hours.
According to the invention, the chlorinating reagent in the step (2) is one or the combination of more than two of thionyl chloride, phosphorus oxychloride or phosphorus pentachloride.
According to the invention, the molar ratio of the compound shown in the formula III and the chlorinated reagent in the step (2) is 1 (5-15).
According to the invention, the chlorination reaction temperature in the step (2) is preferably 40-160 ℃; preferably, the chlorination reaction temperature in the step (2) is 60-150 ℃. The reaction time is 2-18 hours.
The process of the present invention is depicted as scheme 4 below:
the invention has the technical characteristics and beneficial effects that:
1. the invention uses maleic diester and nitromethane to carry out condensation reaction under the catalysis of organic base to prepare cis-5-nitryl-4-oxo-2-n-pentenoic acid ester (II), then prepares 2, 5-dihydroxypyridine (III) through hydrogenation cyclization, and then prepares 2, 5-dichloropyridine (I) through chlorination with a chlorination reagent.
2. The designed unit reaction has high safety, does not relate to low-temperature chlorination reaction or diazotization reaction with large potential safety hazard, does not use toxic gases such as chlorine gas with large toxicity, has high reaction selectivity, is easy to operate, has high product yield and high purity, has the total yield of 88.6 percent, and is suitable for industrial production.
3. The method has the advantages of cheap and easily obtained raw materials, simple and convenient route, simple post-treatment and low cost, and does not need to use a solvent to recrystallize a final product, thereby having less waste water generation amount and being green and environment-friendly.
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, 5-dihydroxypyridine
30.5 g (0.5 mol) of nitromethane, 72.0 g (0.5 mol) of dimethyl maleate and 1.8 g of DBU are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and reflux condenser, stirred and reacted at the temperature of 60-65 ℃ for 5 hours, and cooled to 20-25 ℃. Transferring the obtained reaction liquid into a 1-liter autoclave, adding 400 g of methanol and 1.0 g of palladium-carbon (containing 50wt percent of water) catalyst with the palladium mass content of 5 percent, replacing the mixture by nitrogen for three times, introducing hydrogen, keeping the hydrogen pressure at 0.1-0.2MPa, and reacting for 4 hours at 50-55 ℃. After nitrogen replacement for three times, the catalyst is removed by filtration, the filtrate is concentrated and evaporated to dryness, 100 g of methyl tertiary butyl ether is added for recrystallization, 51.7 g of light yellow solid 2, 5-dihydroxypyridine (III) is obtained, the liquid phase purity is 99.7 percent, and the product yield is 93.1 percent.
Example 2: preparation of 2, 5-dihydroxypyridine
30.5 g (0.5 mol) of nitromethane, 86.1 g (0.5 mol) of diethyl maleate and 1.8 g of DBN are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and reflux condenser, stirred and reacted at 65-70 ℃ for 5 hours, and cooled to 20-25 ℃. Transferring the obtained reaction liquid into a 1-liter autoclave, adding 400 g of ethanol and 1.2 g of palladium-carbon (containing 50wt percent of water) catalyst with the palladium mass content of 5 percent, replacing the mixture by nitrogen for three times, introducing hydrogen, keeping the hydrogen pressure at 0.1-0.2MPa, and reacting for 4 hours at 50-55 ℃. After nitrogen replacement for three times, the catalyst is removed by filtration, the filtrate is concentrated and evaporated to dryness, 100 g of methyl tertiary butyl ether is added for recrystallization, 52.2 g of light yellow solid 2, 5-dihydroxypyridine (III) is obtained, the liquid phase purity is 99.8 percent, and the product yield is 94.0 percent.
Example 3: preparation of 2, 5-dihydroxypyridine
30.5 g (0.5 mol) of nitromethane, 100.1 g (0.5 mol) of diisopropyl maleate and 1.8 g of DBU are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and reflux condenser, stirred and reacted at 65-70 ℃ for 5 hours, and cooled to 20-25 ℃. Transferring the obtained reaction liquid into a 1-liter autoclave, adding 400 g of isopropanol and 8.0 g of Raney nickel (containing 50wt percent of water) catalyst with the nickel content of 50 percent by mass, replacing the catalyst with nitrogen for three times, introducing hydrogen, keeping the pressure of the hydrogen at 0.1-0.2MPa, and reacting for 4 hours at the temperature of 60-65 ℃. After nitrogen replacement for three times, the catalyst is removed by filtration, the filtrate is concentrated and evaporated to dryness, 100 g of methyl tertiary butyl ether is added for recrystallization, 52.0 g of light yellow solid 2, 5-dihydroxypyridine (III) is obtained, the liquid phase purity is 99.6 percent, and the product yield is 93.6 percent.
Example 4: preparation of 2, 5-dihydroxypyridine
30.5 g (0.5 mol) of nitromethane, 114.1 g (0.5 mol) of di-tert-butyl maleate and 1.8 g of DBU are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and reflux condenser, stirred and reacted at 65-70 ℃ for 5 hours, and cooled to 20-25 ℃. Transferring the obtained reaction liquid into a 1-liter autoclave, adding 400 g of tetrahydrofuran and 9.0 g of Raney nickel (containing 50wt percent of water) catalyst with the nickel content of 50 percent by mass, replacing the catalyst with nitrogen for three times, introducing hydrogen, keeping the pressure of the hydrogen at 0.1-0.2MPa, and reacting for 5 hours at the temperature of 60-65 ℃. After nitrogen replacement for three times, the catalyst is removed by filtration, the filtrate is concentrated and evaporated to dryness, 100 g of methyl tertiary butyl ether is added for recrystallization, 50.8 g of light yellow solid 2, 5-dihydroxypyridine (III) is obtained, the liquid phase purity is 99.7 percent, and the product yield is 91.5 percent.
Example 5: preparation of 2, 5-dichloropyridine
Into a 500 ml four-necked flask equipped with a thermometer, mechanical stirring, and reflux condenser were charged 150 g of phosphorus oxychloride, 22.0 g (0.2 mol) of 2, 5-dihydroxypyridine prepared in example 2, 105.0 g (0.5 mol) of phosphorus pentachloride, and the mixture was stirred at 70-75 ℃ for reaction for 12 hours, then the excess phosphorus oxychloride was recovered by distillation under reduced pressure, the residue was slowly poured into 300 g of ice water, sufficiently stirred, then neutralized with 40% aqueous sodium hydroxide solution at pH 7-9, extracted three times with dichloromethane, 50 g each, the organic phases were combined, washed with 30 g of saturated common salt, then dried with 5 g of anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give 27.5 g of 2, 5-dichloropyridine (I) as a pale yellow powder in 92.9% yield with 99.7% liquid phase purity. The nuclear magnetic data of the product are as follows:
1H NMR(CDCl3,,ppm)：
7.38(d，1H)，7.64(d，1H)，8.35(s，1H)。
example 6: preparation of 2, 5-dichloropyridine
To a 500 ml four-necked flask equipped with a thermometer, mechanical stirring, reflux condenser, 200 g of thionyl chloride, 22.0 g (0.2 mol) of 2, 5-dihydroxypyridine prepared in example 2, 105.0 g (0.5 mol) of phosphorus pentachloride, stirred at 60-65 ℃ for reaction for 15 hours, then distilled under reduced pressure to recover the excess thionyl chloride, the residue was slowly poured into 300 g of ice water, sufficiently stirred, then neutralized to pH 7-9 with 40% aqueous sodium hydroxide solution, extracted three times with dichloromethane, 50 g each time, the organic phases were combined, washed with 30 g of saturated brine, then dried with 5 g of anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 26.8 g of 2, 5-dichloropyridine (I) as a pale yellow powder in 90.5% yield and 99.8% purity of the liquid phase.
Example 7: preparation of 2, 5-dichloropyridine
200 g of phosphorus oxychloride, 22.0 g (0.2 mol) of 2, 5-dihydroxypyridine prepared in example 2, stirring and reacting at 145 ℃ for 4 hours in a 500 ml four-neck flask equipped with a thermometer, a mechanical stirrer and a reflux condenser were added, then the excess phosphorus oxychloride was recovered by distillation under reduced pressure, the residue was slowly poured into 300 g of ice water and stirred well, then neutralized with 40% aqueous sodium hydroxide solution to a pH of 7-9, extracted three times with dichloromethane, 50 g each time, the organic phases were combined, washed with 30 g of saturated brine, then dried with 5 g of anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give 27.9 g of 2, 5-dichloropyridine (I) as a pale yellow powder with a yield of 94.3% and a liquid phase purity of 99.5%.
Comparative example 1: preparation of 2, 5-dihydroxypyridine
30.5 g (0.5 mol) of nitromethane, 72.0 g (0.5 mol) of dimethyl maleate and 0.8 g of DBU are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and reflux condenser, stirred and reacted for 5 hours at the temperature of 60-65 ℃ and cooled to 20-25 ℃. Transferring the obtained reaction liquid into a 1-liter autoclave, adding 400 g of methanol and 1.0 g of palladium-carbon (containing 50wt percent of water) catalyst with the palladium mass content of 5 percent, replacing the mixture by nitrogen for three times, introducing hydrogen, keeping the hydrogen pressure at 0.1-0.2MPa, and reacting for 4 hours at 50-55 ℃. After nitrogen replacement for three times, the catalyst is removed by filtration, the filtrate is concentrated and evaporated to dryness, 100 g of methyl tertiary butyl ether is added for recrystallization, 31.2 g of light yellow solid 2, 5-dihydroxypyridine (III) is obtained, the liquid phase purity is 99.1 percent, and the product yield is 56.2 percent.
From this comparative example, it can be seen that the use of organic base catalyst was too low and the reaction was not complete, resulting in a lower yield of 2, 5-dihydroxypyridine.
Comparative example 2: preparation of 2, 5-dihydroxypyridine
30.5 g (0.5 mol) of nitromethane, 72.0 g (0.5 mol) of dimethyl maleate and 1.8 g of DBU are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and reflux condenser, stirred and reacted at the temperature of 98-100 ℃ for 3 hours, and cooled to 20-25 ℃. Transferring the obtained reaction liquid into a 1-liter autoclave, adding 400 g of methanol and 1.0 g of palladium-carbon (containing 50wt percent of water) catalyst with the palladium mass content of 5 percent, replacing the mixture by nitrogen for three times, introducing hydrogen, keeping the hydrogen pressure at 0.1-0.2MPa, and reacting for 4 hours at 50-55 ℃. After nitrogen replacement for three times, the catalyst is removed by filtration, the filtrate is concentrated and evaporated to dryness, 100 g of methyl tertiary butyl ether is added for recrystallization, 28.5 g of light yellow solid 2, 5-dihydroxypyridine (III) is obtained, the liquid phase purity is 98.6 percent, and the product yield is 51.4 percent.
From this comparative example, it is clear that the condensation reaction temperature is too high, other by-products are large, and the yield is lowered.
Comparative example 3: preparation of 2, 5-dihydroxypyridine
42.0 g (0.7 mol) of nitromethane, 72.0 g (0.5 mol) of dimethyl maleate and 1.8 g of DBU are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and reflux condenser, stirred and reacted at the temperature of 60-65 ℃ for 5 hours, and cooled to 20-25 ℃. Transferring the obtained oily liquid into a 1-liter autoclave, adding 400 g of methanol and 1.0 g of palladium-carbon (containing 50 wt% of water) catalyst with the palladium mass content of 5%, replacing with nitrogen for three times, introducing hydrogen, keeping the hydrogen pressure at 0.1-0.2MPa, and reacting at 50-55 ℃ for 4 hours. After nitrogen replacement for three times, the catalyst is removed by filtration, the filtrate is concentrated and evaporated to dryness, 100 g of methyl tertiary butyl ether is added for recrystallization, 34.1 g of light yellow solid 2, 5-dihydroxypyridine (III) is obtained, the liquid phase purity is 99.3 percent, and the product yield is 61.5 percent.
From this comparative example, it is seen that an inappropriate ratio of nitromethane to maleic diester results in the condensation of two molecules of nitromethane and 1 molecule of maleic diester with more viscous by-products and a lower yield.
Claims (10)
1. A preparation method of 2, 5-dichloropyridine comprises the following steps:
(1) carrying out condensation reaction on maleic diester and nitromethane under the catalysis of organic base to prepare reaction liquid containing a compound shown in a formula II; adding a solvent and a catalyst into the reaction solution without separating, and carrying out hydrogenation cyclization on the compound of the formula II in the reaction solution to prepare a compound of a formula III; the organic base is one or the combination of two of 1, 8-diazabicyclo [5.4.0] -7-undecene (DBU) or 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN); the catalyst is palladium carbon or Raney nickel;
wherein R in the compound of formula II is C1-4One of the alkyl groups of (a);
(2) and (3) chlorinating the compound shown in the formula III and a chlorinating reagent to prepare the 2, 5-dichloropyridine.
2. The method for preparing 2, 5-dichloropyridine according to claim 1, wherein the molar ratio of the maleic diester to the nitromethane in step (1) is 1 (0.90-1.1); in the step (1), the maleic acid diester is one of dimethyl maleate, diethyl maleate, diisopropyl maleate or di-tert-butyl maleate.
3. The method for preparing 2, 5-dichloropyridine according to claim 1, wherein the mass of the organic base in step (1) is 1.2-5% of the mass of the maleic diester.
4. The process for producing 2, 5-dichloropyridine according to claim 1, wherein the condensation reaction temperature in step (1) is from 30 to 90 ℃.
5. The method for preparing 2, 5-dichloropyridine according to claim 1, wherein the mass of the catalyst in step (1) is 0.5-15% of that of the maleic diester.
6. The method for preparing 2, 5-dichloropyridine according to claim 1, wherein the mass of the palladium-carbon in step (1) is 0.5-5% of the mass of the maleic diester; the mass of the Raney nickel is 1-15% of that of the maleic diester.
7. The process for producing 2, 5-dichloropyridine according to claim 1, wherein the solvent in step (1) is one or a mixture of two or more of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane and toluene; in the step (1), the mass ratio of the maleic acid diester to the solvent is 1 (3-15).
8. The process according to claim 1, wherein the hydrogen pressure in the hydrocyclization reaction in the step (1) is 0.1 to 0.3 MPa; the temperature of the hydrogenation cyclization reaction in the step (1) is 20-80 ℃.
9. The process for preparing 2, 5-dichloropyridine according to claim 1, wherein the chlorinating reagent in step (2) is one or a combination of more than two of thionyl chloride, phosphorus oxychloride and phosphorus pentachloride; the molar ratio of the compound shown in the formula III to the chlorinated reagent in the step (2) is 1 (5-15).
10. The process for preparing 2, 5-dichloropyridine according to claim 1, wherein the chlorination reaction temperature in step (2) is 40-160 ℃.
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| US5380862A (en) * | 1992-10-07 | 1995-01-10 | Rutgerswerke Aktiengesellschaft | Preparation of isomer-free 2,5-dichloro-pyridine |
| CN101709050A (en) * | 2009-11-24 | 2010-05-19 | 南京第一农药集团有限公司 | New method for synthesizing 2, 5-dichloropyridine |
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|---|---|---|---|---|
| US5380862A (en) * | 1992-10-07 | 1995-01-10 | Rutgerswerke Aktiengesellschaft | Preparation of isomer-free 2,5-dichloro-pyridine |
| CN101709050A (en) * | 2009-11-24 | 2010-05-19 | 南京第一农药集团有限公司 | New method for synthesizing 2, 5-dichloropyridine |
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Denomination of invention: A simple preparation method of 2,5-dichloropyridine Effective date of registration: 20211130 Granted publication date: 20200901 Pledgee: Zhejiang Commercial Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2021980013546 |