CN114591225A - Method for large-scale production of 2, 6-dibromo-4-methylpyridine - Google Patents
Method for large-scale production of 2, 6-dibromo-4-methylpyridine Download PDFInfo
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- CN114591225A CN114591225A CN202210197836.XA CN202210197836A CN114591225A CN 114591225 A CN114591225 A CN 114591225A CN 202210197836 A CN202210197836 A CN 202210197836A CN 114591225 A CN114591225 A CN 114591225A
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- methylpyridine
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- dibromo
- dihydroxy
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- OHBIPNNTWKNAGC-UHFFFAOYSA-N 2,6-dibromo-4-methylpyridine Chemical compound CC1=CC(Br)=NC(Br)=C1 OHBIPNNTWKNAGC-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000011031 large-scale manufacturing process Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- JJHVYGVVMBYCMQ-UHFFFAOYSA-N 6-hydroxy-4-methyl-1h-pyridin-2-one Chemical compound CC=1C=C(O)NC(=O)C=1 JJHVYGVVMBYCMQ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 229910001507 metal halide Inorganic materials 0.000 claims abstract description 11
- 150000005309 metal halides Chemical class 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 238000005893 bromination reaction Methods 0.000 claims abstract description 8
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 7
- 238000001953 recrystallisation Methods 0.000 claims abstract description 5
- 230000031709 bromination Effects 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000003208 petroleum Substances 0.000 claims description 15
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 14
- 239000005457 ice water Substances 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 230000007935 neutral effect Effects 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 6
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 2
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims 1
- 229910052723 transition metal Inorganic materials 0.000 claims 1
- 150000003624 transition metals Chemical class 0.000 claims 1
- 238000002474 experimental method Methods 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000007787 solid Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 4
- HQYNSFAFYFMRLG-UHFFFAOYSA-N tribromo phosphite Chemical compound BrOP(OBr)OBr HQYNSFAFYFMRLG-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- HUQGLWLBOCSVMD-UHFFFAOYSA-N 4-methylpyridine-2,6-diamine Chemical compound CC1=CC(N)=NC(N)=C1 HUQGLWLBOCSVMD-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000000297 Sandmeyer reaction Methods 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- -1 2-bromo-6-oxazinyl-4-methylpyridine Chemical compound 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000077 insect repellent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 239000005871 repellent Substances 0.000 description 1
- 230000002940 repellent Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- 239000004753 textile Substances 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P70/00—Climate change mitigation technologies in the production process for final industrial or consumer products
- Y02P70/50—Manufacturing or production processes characterised by the final manufactured product
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a method for producing 2, 6-dibromo-4-methylpyridine in a large scale, which is used for preparing the 2, 6-dibromo-4-methylpyridine by carrying out bromination reaction on 2, 6-dihydroxy-4-methylpyridine and a bromination reagent under the catalysis of metal halides. Experiments prove that: the method has the advantages of mild reaction conditions, simple operation, low requirement on equipment, easy purification treatment and high product yield, and the target product with the HPLC purity of 99.5 percent can be obtained through simple recrystallization treatment; particularly, the method of the invention is easy to realize the production scale of kilogram level to hundred kilogram level, and has extremely high practical value for realizing the large-scale production of 2, 6-dibromo-4-methylpyridine.
Description
Technical Field
The invention relates to a method for producing 2, 6-dibromo-4-methylpyridine in a large scale, belonging to the technical field of organic synthesis.
Background
Pyridine and its derivatives are widely present in the natural world, and many plant components have pyridine ring compounds in their structures, which are the basis of many important chemical raw materials and organic intermediates, and have been widely used in fine chemical industries such as pesticides, medicines, etc., for example, as pesticides (herbicides, acaricides, bird repellents, insect repellents), solvents, reagent intermediates, surfactants, binders, etc. for pharmaceutical, polymer and textile industries, and various pyridine derivatives have been studied for such uses, and these compounds generally have an additional substituent of the central pyridine ring.
2, 6-dibromo-4-methylpyridine
The intermediate is widely applied to the fields of pharmaceutical engineering, photoelectric materials and the like, and the 2, 6-dibromo-4-methylpyridine can be used as a medicine synthesis intermediate in the medicine industry, such as: can be used for preparing 2-bromo-6-oxazinyl-4-methylpyridine; in addition, the 2, 6-dibromo-4-methylpyridine is a heterocyclic organic matter and can also be used as a photoelectric material.
With respect to the synthesis of 2, 6-dibromo-4-methylpyridine, currently, 2, 6-dihydroxy-4-methylpyridine is mainly used as a raw material, and a bromination reaction is performed with a brominating agent to obtain 2, 6-dibromo-4-methylpyridine, for example: reacting 2, 6-dihydroxy-4-methylpyridine with liquid bromine under the catalysis of triphenylphosphine to prepare 2, 6-dibromo-4-methylpyridine; reacting 2, 6-dihydroxy-4-methylpyridine with tetrabutylammonium bromide in the presence of phosphorus pentoxide to prepare 2, 6-dibromo-4-methylpyridine; 2, 6-dihydroxy-4-methylpyridine reacts with hydrobromic acid acetic acid solution in the presence of concentrated sulfuric acid to prepare 2, 6-dibromo-4-methylpyridine; 2, 6-dihydroxy-4-methylpyridine is reacted with tribromooxyphosphorus to prepare 2, 6-dibromo-4-methylpyridine (see patent WO 2009/68652); 2, 6-dihydroxy-4-methylpyridine with phosphorus tribromide to prepare 2, 6-dibromo-4-methylpyridine (see "Synthesis, (12), 1665-1667; 2000" and "Journal of the American Chemical Society,1947,69, p.1147-1148"), among others.
However, the method of reacting 2, 6-dihydroxy-4-methylpyridine with liquid bromine, tetrabutylammonium bromide or hydrobromic acid acetic acid solution not only has long reaction time (usually two days), low yield (less than 35%), but also has troublesome post-treatment, and the target product with purity higher than 95% can be obtained only by column chromatography, thus the method cannot meet the requirement of large-scale production.
Although the reaction time of the method for reacting 2, 6-dihydroxy-4-methylpyridine with tribromooxyphosphorus or phosphorus tribromide is short (about 6 hours), the post-treatment is troublesome, the product also needs to be purified by column chromatography, and the yield of the tribromooxyphosphorus method is only 16%; in addition, the phosphorus tribromide process needs to be carried out at a high temperature of 170 ℃; therefore, the two methods cannot meet the requirement of scale production.
The sandmeyer reaction is a reaction that a diazo functional group is replaced by halogen or cyano under the catalysis of cuprous salt, so that theoretically, 4-methyl-2, 6-diaminopyridine can be prepared first, and then the 4-methyl-2, 6-diaminopyridine is subjected to diazo reaction and sandmeyer reaction sequentially to obtain the 2, 6-dibromo-4-methylpyridine. However, the sandmeyer reaction is not only relatively large in reaction system and relatively troublesome in post-treatment, but at present, 4-methylpyridine is usually used as a starting material, sodium amide and tetrahydronaphthalene are firstly used for reflux reaction to generate 4-methyl-2, 6-diaminopyridine (see literature "Tetrahedron Letters,2016,57(3), 333-. Therefore, the method can not meet the requirement of scale production.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a method for producing 2, 6-dibromo-4-methylpyridine in a large scale.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for producing 2, 6-dibromo-4-methylpyridine in a large scale is characterized in that 2, 6-dihydroxy-4-methylpyridine and a brominating reagent are subjected to bromination reaction under the catalysis of metal halides to obtain the 2, 6-dibromo-4-methylpyridine.
In one embodiment, the metal halide is selected from one or more of aluminum chloride, cupric bromide, and cuprous bromide, preferably cupric bromide.
In one embodiment, the brominating reagent is one or more of N-bromosuccinimide (NBS), liquid bromine, 33% hydrobromic acid in acetic acid, 48% hydrobromic acid in water, phosphorus tribromide, phosphorus oxybromide, and trimethylbromosilane, preferably phosphorus tribromide or phosphorus oxybromide, more preferably phosphorus tribromide.
One embodiment, the 2, 6-dihydroxy-4-methylpyridine: brominating reagent: the molar ratio of the metal halides is 1: (0.5-4.5): (0.1 to 1), preferably 1: 1.5: 0.2.
an embodiment of the method for producing 2, 6-dibromo-4-methylpyridine in a large scale comprises the following operations:
adding a reaction solvent, 2, 6-dihydroxy-4-methylpyridine, a brominating agent and a metal halide into a reaction vessel at room temperature, and then carrying out stirring reaction at 50-140 ℃ (preferably 100-140 ℃, and preferably 120 ℃); and after the reaction is finished, carrying out post-treatment to obtain the 2, 6-dibromo-4-methylpyridine.
According to a preferable scheme, the reaction solvent is one or more of acetonitrile, tetrahydrofuran, carbon tetrachloride, 1, 2-dichloroethane, dimethyl sulfoxide and cyclobutylmaple, and acetonitrile is preferable.
In a preferred embodiment, the post-treatment is performed as follows:
cooling the reaction system to room temperature, pouring the reaction liquid into ice water, adjusting the pH value to be neutral by using alkali or alkaline solution, filtering, drying a filter cake, and recrystallizing by using an organic solvent to obtain the 2, 6-dibromo-4-methylpyridine.
In a preferable scheme, the organic solvent for recrystallization is one or more of methanol, isopropanol, ethanol, ethyl acetate, dichloromethane, petroleum ether, n-heptane, n-hexane and methyl tert-butyl ether, and preferably petroleum ether.
Compared with the prior art, the invention has the following remarkable beneficial effects:
experiments prove that: the 2, 6-dihydroxy-4-methylpyridine is subjected to bromination reaction with a bromination reagent under the catalysis of metal halide to prepare the 2, 6-dibromo-4-methylpyridine, so that the method has the advantages of mild reaction conditions, simplicity in operation, low equipment requirement, easiness in purification treatment, high product yield (the molar yield can reach 68.5%), and capability of obtaining a target product with the HPLC purity of 99.5% through simple recrystallization treatment, and in addition, the raw materials used in the method are low in price, simple and easy to obtain, low in production cost and very suitable for industrial production; particularly, the method can break through the bottleneck of the existing method, is easy to realize the production scale of kilogram level to hundred kilogram level, has extremely strong practical value for realizing the large-scale production of the 2, 6-dibromo-4-methylpyridine, and has significant progress compared with the prior art.
Detailed Description
The technical scheme of the invention is further detailed and completely explained by combining the embodiment and the comparative example.
Comparative example 1
At room temperature, sequentially adding triphenylphosphine (2.20kg,1.0eq) and acetonitrile (10L) into a high-low temperature jacketed reaction kettle, after adding, cooling to about 0 ℃ of internal temperature, then dropping liquid bromine (1.28kg, 2.0eq) into the reaction kettle, after dropping, reacting for 30 minutes to separate out yellow solid, then adding 2, 6-dihydroxy-4-methylpyridine (0.5kg, 1.0eq) into the mixture, heating to 140 ℃ to react for two days, after the reaction is finished, slowly pouring the reaction liquid into ice water, extracting with dichloromethane, drying the organic phase obtained by extraction with anhydrous sodium sulfate, filtering, concentrating, purifying the obtained crude product by column chromatography (eluent: petroleum ether/ethyl acetate is 20:1) to obtain 0.33kg of 2, 6-dibromo-4-methylpyridine (white solid), the molar yield is 32.50%, the GC purity was 96.2%.
After testing:1H NMR(CDCl3,300Hz)δ7.47(s,2H),4.29(s,2H)；13C NMR(CDCl3,75Hz)δ150.6,140.8,126.7,28.0。
comparative example 2
At room temperature, 2, 6-dihydroxy-4-methylpyridine (0.5kg, 1.0eq), phosphorus pentoxide (1.16kg, 2.05eq), tetrabutylammonium bromide (2.84kg, 2.20eq) and toluene (5L) were sequentially added to a high-low temperature jacketed reaction kettle, the temperature was raised to reflux reaction, after the reaction was completed, the reaction solution was slowly poured into ice water, filtered, separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate 20:1) to obtain 0.26kg of 2, 6-dibromo-4-methylpyridine (white solid) with a molar yield of 25.30% and a GC purity of 97.0%.
Comparative example 3
At room temperature, sequentially adding 2, 6-dihydroxy-4-methylpyridine (0.5kg, 1.0eq), 48% hydrobromic acid acetic acid solution (10L) and concentrated sulfuric acid (3L) into a high-low temperature jacketed reaction kettle, heating to reflux for two days, after the reaction is finished, slowly pouring the reaction liquid into ice water, extracting with dichloromethane, drying the organic phase obtained by extraction with anhydrous sodium sulfate, filtering, concentrating, and purifying the obtained crude product by column chromatography (eluent: petroleum ether/ethyl acetate 20:1) to obtain 0.28kg of 2, 6-dibromo-4-methylpyridine (white solid), wherein the molar yield is 27.35% and the GC purity is 97.5%.
Comparative example 4
At room temperature, adding 2, 6-dihydroxy-4-methylpyridine (0.50kg, 1.0eq) and tribromooxyphosphorus (1.72kg, 1.50eq) into a 50L high-low temperature jacket reaction kettle, heating to 120 ℃ for reaction for 24 hours after the addition is finished, cooling to room temperature after the reaction is finished, pouring the reaction into 20L of ice water, adjusting the pH to be neutral by using 40% sodium hydroxide solution, separating out white solid, filtering, recrystallizing a filter cake by using petroleum ether to obtain 0.36kg of 2, 6-dibromo-4-methylpyridine (white solid), wherein the molar yield is 35.80%, and the GC purity is 96.4%.
Comparative example 5
At room temperature, adding 2, 6-dihydroxy-4-methylpyridine (0.50kg, 1.0eq) and phosphorus tribromide (3.26kg, 3.00eq) into a high-low temperature jacket reaction kettle, after the addition is finished, heating to 120 ℃ for reaction for 24 hours, after the reaction is finished, cooling to room temperature, pouring the reaction into 10L of ice water, adjusting the pH to be neutral by using 40% sodium hydroxide solution, separating out a white solid, filtering, recrystallizing a filter cake by using petroleum ether, and obtaining 0.38kg of 2, 6-dibromo-4-methylpyridine (the white solid), wherein the molar yield is 38.20%, and the GC purity is 97.8%.
Example 1
At room temperature, adding 2, 6-dihydroxy-4-methylpyridine (0.50kg, 1.0eq), phosphorus tribromide (3.26kg, 3.00eq) and copper chloride (80g, 0.20eq) into a high-low temperature jacket reaction kettle containing 5L of acetonitrile, heating to 140 ℃ for reaction for 24 hours after the addition is finished, cooling to room temperature after the reaction is finished, pouring the reaction into 10L of ice water, adjusting the pH to be neutral by using 40% sodium hydroxide solution, separating out white solid, filtering, recrystallizing a filter cake by using petroleum ether to obtain 0.48kg of 2, 6-dibromo-4-methylpyridine (white solid), wherein the molar yield is 48.35%, and the GC purity is 99.1%.
Example 2
At room temperature, 0.5kg of 2, 6-dihydroxy-4-methylpyridine (0.50kg, 1.0eq), phosphorus tribromide (3.26kg, 3.00eq) and aluminum chloride (106.56g, 0.20eq) are added into a high-temperature and low-temperature jacket reaction kettle containing 5L of acetonitrile, after the addition is finished, the temperature is raised to 140 ℃ for reaction for 24 hours, after the reaction is finished, the reaction is cooled to room temperature, the reaction is poured into 10L of ice water, the pH value is adjusted to be neutral by using 40% of sodium hydroxide solution, white solid is separated out, the mixture is filtered and dried, and a filter cake is recrystallized by using petroleum ether to obtain 0.50kg of 2, 6-dibromo-4-methylpyridine (white solid), wherein the molar yield is 50.20% and the GC purity is 99.1%.
Example 3
At room temperature, adding 2, 6-dihydroxy-4-methylpyridine (0.50kg, 1.0eq), phosphorus tribromide (3.26kg, 3.00eq) and copper bromide (178.50g, 0.20eq) into a high-low temperature jacket reaction kettle containing 5L of acetonitrile, heating to 140 ℃ for reaction for 24 hours after the addition is finished, cooling to room temperature after the reaction is finished, pouring the reaction into 10L of ice water, adjusting the pH to be neutral by using 40% sodium hydroxide solution, separating out white solid, filtering, drying, and recrystallizing a filter cake by using petroleum ether to obtain 0.66kg of 2, 6-dibromo-4-methylpyridine (white solid), wherein the molar yield is 65.80%, and the GC purity is 99.2%.
Example 4
At room temperature, adding 2, 6-dihydroxy-4-methylpyridine (0.50kg, 1.0eq), phosphorus tribromide (1.63kg, 1.50eq) and copper bromide (178.50g, 0.20eq) into a high-low temperature jacket reaction kettle containing 5L of acetonitrile, heating to 140 ℃ for reaction for 24 hours after the addition is finished, cooling to room temperature after the reaction is finished, pouring the reaction into 10L of ice water, adjusting the pH to be neutral by using 40% sodium hydroxide solution, separating out white solid, filtering, drying, and recrystallizing a filter cake by using petroleum ether to obtain 0.68kg of 2, 6-dibromo-4-methylpyridine (white solid), wherein the molar yield is 67.25%, and the GC purity is 99.2%.
Example 5
At room temperature, 0.5kg of 2, 6-dihydroxy-4-methylpyridine (0.50kg, 1.0eq), phosphorus tribromide (1.63kg, 1.50eq) and copper bromide (178.50g, 0.20eq) are added into a high-low temperature jacket reaction kettle containing 5L of acetonitrile, after the addition is finished, the temperature is raised to 120 ℃ for reaction for 24 hours, after the reaction is finished, the reaction is cooled to room temperature, the reaction is poured into 10L of ice water, the pH value is adjusted to be neutral by using 40% sodium hydroxide solution, white solid is separated out, the mixture is filtered and dried, and a filter cake is recrystallized by using petroleum ether to obtain 0.65kg of 2, 6-dibromo-4-methylpyridine (white solid), wherein the molar yield is 64.87% and the GC purity is 99.4%.
Example 6
At room temperature, adding 2, 6-dihydroxy-4-methylpyridine (5kg, 1.0eq) and copper bromide (1.79kg, 0.20eq) into a high-temperature and low-temperature jacket reaction kettle containing 50L of acetonitrile, starting refrigeration, cooling the inner temperature to 0 ℃, slowly dropping 16.3kg of phosphorus tribromide (1.50eq) into the reaction kettle, after the addition is finished, heating to 120 ℃ for reaction for 24 hours, cooling to room temperature after the reaction is finished, pouring the reaction into 50L of ice water, adjusting the pH to be neutral by using 40% sodium hydroxide solution, separating out a white solid, filtering and drying, and recrystallizing a filter cake by using petroleum ether to obtain 6.87kg of 2, 6-dibromo-4-methylpyridine (the white solid), wherein the molar yield is 68.50%, and the GC purity is 99.5%.
In summary, the invention can prepare 2, 6-dibromo-4-methylpyridine by brominating 2, 6-dihydroxy-4-methylpyridine with a brominating reagent under the catalysis of metal halide, compared with the traditional liquid bromine, tetrabutylammonium bromide and hydrobromic acid acetic acid solution method (see comparative examples 1-3), the reaction time is shorter (reduced from 2 days of comparative examples 1-3 to 24 hours of example), the yield is high (increased from the highest 32.5% of comparative examples 1-3 to 68.50% of example), the post-treatment operation is simple (from column chromatography of comparative examples 1-3 to petroleum ether recrystallization of example), and the purity of the obtained product is high (increased from the highest 97.5% of comparative examples 1-3 to 99.5% of example); furthermore, as can be seen by comparing comparative examples 4 to 5 with the examples, the presence of the metal halide is effective in improving the molar yield of the reaction and the product purity; particularly, the method can break through the bottleneck of the existing method, is easy to realize the production scale of kilogram level to hundred kilogram level (see example 6), has extremely high practical value for realizing the large-scale production of the 2, 6-dibromo-4-methylpyridine, and has remarkable progress compared with the prior art.
Finally, it should be pointed out here that: the above is only a part of the preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention, and the insubstantial modifications and adaptations of the present invention by those skilled in the art based on the above description are intended to be covered by the present invention.
Claims (8)
1. A method for producing 2, 6-dibromo-4-methylpyridine in a large scale is characterized by comprising the following steps: the method comprises the step of carrying out bromination reaction on 2, 6-dihydroxy-4-methylpyridine and a bromination reagent under the catalysis of metal halide to prepare the 2, 6-dibromo-4-methylpyridine.
2. The method of claim 1, wherein: the transition metal halide is selected from one or more of aluminum chloride, cupric bromide and cuprous bromide.
3. The method of claim 1, wherein: the brominating reagent is one or more of N-bromosuccinimide (NBS), liquid bromine, 33% hydrobromic acid acetic acid solution, 48% hydrobromic acid water solution, phosphorus tribromide, phosphorus oxybromide and trimethyl bromosilane.
4. The method of claim 1, wherein: the 2, 6-dihydroxy-4-methylpyridine: brominating reagent: the molar ratio of the metal halides is 1: (0.5-4.5): (0.1-1).
5. The method of claim 1, wherein the method comprises the operations of:
adding a reaction solvent, 2, 6-dihydroxy-4-methylpyridine, a brominating agent and a metal halide into a reaction vessel at room temperature, and then carrying out stirring reaction at 50-140 ℃; and after the reaction is finished, carrying out post-treatment to obtain the 2, 6-dibromo-4-methylpyridine.
6. The method of claim 5, wherein: the reaction solvent is one or more of acetonitrile, tetrahydrofuran, carbon tetrachloride, 1, 2-dichloroethane, dimethyl sulfoxide and cyclobutylmaple.
7. The method of claim 5, wherein the post-processing operates as follows:
and cooling the reaction system to room temperature, pouring the reaction solution into ice water, adjusting the pH value to be neutral by using alkali or an alkali solution, filtering, drying a filter cake, and recrystallizing by using an organic solvent to obtain the 2, 6-dibromo-4-methylpyridine.
8. The method of claim 7, wherein: the organic solvent for recrystallization is one or more of methanol, isopropanol, ethanol, ethyl acetate, dichloromethane, petroleum ether, n-heptane, n-hexane and methyl tert-butyl ether.
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