CN114702390A - Preparation method of 4-chloro-3-nitrobenzyl ether - Google Patents
Preparation method of 4-chloro-3-nitrobenzyl ether Download PDFInfo
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- CN114702390A CN114702390A CN202210226200.3A CN202210226200A CN114702390A CN 114702390 A CN114702390 A CN 114702390A CN 202210226200 A CN202210226200 A CN 202210226200A CN 114702390 A CN114702390 A CN 114702390A
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- ILFDRUFFPZTDRV-UHFFFAOYSA-N C1=CC(=C(C=C1COCC2=CC(=C(C=C2)Cl)[N+](=O)[O-])[N+](=O)[O-])Cl Chemical compound C1=CC(=C(C=C1COCC2=CC(=C(C=C2)Cl)[N+](=O)[O-])[N+](=O)[O-])Cl ILFDRUFFPZTDRV-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- REZRIKRVMBDGSU-UHFFFAOYSA-N 2-(4-chloro-3-nitrophenoxy)pyridine Chemical compound [O-][N+](C(C=C(C=C1)OC2=NC=CC=C2)=C1Cl)=O REZRIKRVMBDGSU-UHFFFAOYSA-N 0.000 claims abstract description 20
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000006396 nitration reaction Methods 0.000 claims abstract description 4
- JUIKCULGDIZNDI-UHFFFAOYSA-N 4-chloro-3-nitrophenol Chemical compound OC1=CC=C(Cl)C([N+]([O-])=O)=C1 JUIKCULGDIZNDI-UHFFFAOYSA-N 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 20
- SMINLYVPAJMVQW-UHFFFAOYSA-N 2-(4-chlorophenoxy)pyridine Chemical compound C1=CC(Cl)=CC=C1OC1=CC=CC=N1 SMINLYVPAJMVQW-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 13
- 229910017604 nitric acid Inorganic materials 0.000 claims description 13
- 239000011230 binding agent Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 10
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 9
- 229960000583 acetic acid Drugs 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 claims description 7
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical group COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 5
- 235000011009 potassium phosphates Nutrition 0.000 claims description 5
- 239000012022 methylating agents Substances 0.000 claims description 4
- 238000007069 methylation reaction Methods 0.000 claims description 4
- 238000010504 bond cleavage reaction Methods 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 230000011987 methylation Effects 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 4
- 239000003440 toxic substance Substances 0.000 abstract description 4
- 238000010923 batch production Methods 0.000 abstract description 3
- 231100000614 poison Toxicity 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- MEAAWTRWNWSLPF-UHFFFAOYSA-N 2-phenoxypyridine Chemical compound C=1C=CC=NC=1OC1=CC=CC=C1 MEAAWTRWNWSLPF-UHFFFAOYSA-N 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 37
- 239000007787 solid Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000012295 chemical reaction liquid Substances 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- 238000001914 filtration Methods 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 238000001816 cooling Methods 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 238000010438 heat treatment Methods 0.000 description 13
- 239000012043 crude product Substances 0.000 description 12
- 238000002156 mixing Methods 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000007710 freezing Methods 0.000 description 8
- 230000008014 freezing Effects 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- YRGAYAGBVIXNAQ-UHFFFAOYSA-N 1-chloro-4-methoxybenzene Chemical compound COC1=CC=C(Cl)C=C1 YRGAYAGBVIXNAQ-UHFFFAOYSA-N 0.000 description 4
- NBKMLXONPWESHJ-UHFFFAOYSA-N ClC1=CC(=C(COCC2=C(C=C(C=C2)Cl)[N+](=O)[O-])C=C1)[N+](=O)[O-] Chemical compound ClC1=CC(=C(COCC2=C(C=C(C=C2)Cl)[N+](=O)[O-])C=C1)[N+](=O)[O-] NBKMLXONPWESHJ-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- -1 4-amino-3-nitrobenzyl ether Chemical compound 0.000 description 3
- ANMATWQYLIFGOK-UHFFFAOYSA-N Iguratimod Chemical compound CS(=O)(=O)NC1=CC=2OC=C(NC=O)C(=O)C=2C=C1OC1=CC=CC=C1 ANMATWQYLIFGOK-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 238000006193 diazotization reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229950003909 iguratimod Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001247821 Ziziphus Species 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000001546 nitrifying effect Effects 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- GUSAZEAOPZVXBH-UHFFFAOYSA-N (4-chloro-3-nitrophenyl) acetate Chemical compound CC(=O)OC1=CC=C(Cl)C([N+]([O-])=O)=C1 GUSAZEAOPZVXBH-UHFFFAOYSA-N 0.000 description 1
- KEUPLGRNURQXAR-UHFFFAOYSA-N (4-chlorophenyl) acetate Chemical compound CC(=O)OC1=CC=C(Cl)C=C1 KEUPLGRNURQXAR-UHFFFAOYSA-N 0.000 description 1
- FLZUSUKBKOZJLG-UHFFFAOYSA-N 2-(4-chloro-2-nitrophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C=C1[N+]([O-])=O FLZUSUKBKOZJLG-UHFFFAOYSA-N 0.000 description 1
- JAHIPDTWWVYVRV-UHFFFAOYSA-M 4-chloro-2-nitrobenzoate Chemical compound [O-]C(=O)C1=CC=C(Cl)C=C1[N+]([O-])=O JAHIPDTWWVYVRV-UHFFFAOYSA-M 0.000 description 1
- DFXQXFGFOLXAPO-UHFFFAOYSA-M 4-chloro-3-nitrobenzoate Chemical compound [O-]C(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 DFXQXFGFOLXAPO-UHFFFAOYSA-M 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KJAFZRCNIJFECP-UHFFFAOYSA-N benzoic acid chlorobenzene Chemical compound ClC1=CC=CC=C1.C(C1=CC=CC=C1)(=O)O KJAFZRCNIJFECP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910001510 metal chloride Inorganic materials 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 4-chloro-3-nitrobenzyl ether, wherein raw material substances related to each step do not belong to highly toxic substances, the reaction safety related to each step is higher, the whole operation is simple and easy to implement, scientific research foundation is laid for batch production of the 4-chloro-3-nitrobenzyl ether, and the economic practicability is high; the preparation method of 2- (4-chloro-3-nitrophenoxy) pyridine involved in the step S2 is characterized in that p-chlorophenol is taken as an initial raw material, and due to the positioning effect of phenolic hydroxyl, the p-chlorophenol is easy to perform on the 2 th position in the nitration reaction process, and the 3 rd position is difficult to introduce, so that the structure of the p-hydroxyl needs to be changed, and the phenoxypyridine is introduced as a positioning group to increase the steric hindrance of the p-hydroxyl, so that most of nitro can react on the 3 rd position, the nitro product on the 2 nd position is reduced, and the yield of the target product is greatly improved.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of 4-chloro-3-nitrobenzyl ether.
Background
Iguratimod (trade name: Idexine) is an innovative medicine independently developed in China and mainly used for treating active rheumatoid arthritis, and compared with methotrexate, leflunomide and other medicines, the Iguratimod is a novel medicine for improving the state of illness and resisting rheumatism, is not only a latest one of all antirheumatic medicines, and simultaneously has a new action mechanism and clinical characteristics. Not only is applicable to rheumatoid arthritis, but also can be used for treating other autoimmune diseases such as primary sicca syndrome, systemic lupus erythematosus, ankylosing spondylitis and the like due to the unique immunoregulation function of the rheumatoid arthritis, and has wide market and development requirements. Iguratimod is marketed in China and Japan in 2011 and 2012 successively, is written into a Japanese rheumatology society rheumatoid arthritis diagnosis and treatment guide, a Asia-Tai rheumatism-resisting alliance rheumatoid arthritis treatment guide and a Chinese rheumatoid arthritis diagnosis and treatment guide successively, is incorporated into Chinese medical insurance in 2017, and has great advantages in selling price and market share.
In the face of increasing market demand, the synthetic preparation of 4-chloro-3-nitrobenzyl ether, a key intermediate, is becoming increasingly important. Chinese patent No. 201410467955.8 discloses a preparation method of 4-chloro-3-nitrobenzyl ether, which takes 4-amino-3-nitrobenzyl ether, sodium nitrite and hydrochloric acid as raw materials and metal chloride as a catalyst to prepare the 4-chloro-3-nitrobenzyl ether through a two-step one-pot reaction of diazotization and chlorination. The preparation method takes 4-amino-3-nitrobenzyl ether (also known as jujube red group GP) as a starting material to prepare the 4-chloro-3-nitrobenzyl ether through diazotization hydrolysis reaction, the jujube red group GP is a highly toxic substance, and the diazotization reaction belongs to high-risk reaction, so that the reaction process has great potential safety hazard, and irrecoverable production safety accidents can be caused once the operation is improper; meanwhile, cuprous chloride wastewater generated by post-treatment also has the problems of high treatment difficulty, high environmental pollution and the like. Therefore, there is a need to provide a new preparation method of 4-chloro-3-nitrobenzyl ether, which is intended to solve the above technical problems.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a preparation method of 4-chloro-3-nitrobenzyl ether, raw material substances involved in each step do not belong to highly toxic substances, the reaction safety involved in each step is higher, the whole operation is simple and easy to implement, a scientific research foundation is laid for batch production of the 4-chloro-3-nitrobenzyl ether, and the economic practicability is high.
In order to realize the purpose, the technical scheme of the invention is to design a preparation method of 4-chloro-3-nitrobenzyl ether, which comprises the following steps:
step S1: p-chlorophenol and 2-bromopyridine are taken as raw materials, and the 2- (4-chlorophenoxy) pyridine is prepared by nucleophilic substitution reaction in a solvent in the presence of an acid-binding agent;
step S2: taking the 2- (4-chlorophenoxy) pyridine prepared in the step S1 as a raw material, and carrying out nitration reaction in a mixed acid solution of nitric acid and concentrated sulfuric acid to prepare 2- (4-chloro-3-nitrophenoxy) pyridine;
step S3: taking the 2- (4-chloro-3-nitrophenoxy) pyridine prepared in the step S2 as a raw material, and performing ether bond cleavage reaction in a mixed acid solution of hydrobromic acid and glacial acetic acid to prepare 4-chloro-3-nitrophenol;
step S4: and (4) taking the 4-chloro-3-nitrophenol prepared in the step (S3) as a raw material, and carrying out methylation reaction in a solvent in the presence of an acid binding agent and a methylation reagent to prepare the 4-chloro-3-nitrobenzyl ether.
The preferable technical scheme is that in the step S1, the molar feeding ratio of the p-chlorophenol to the 2-bromopyridine is 1: 1-2, the acid-binding agent is potassium phosphate, the molar feeding ratio of the p-chlorophenol to the acid-binding agent is 1: 1-3, the solvent is dimethyl sulfoxide, the weight feeding ratio of the p-chlorophenol to the solvent is 1: 5-10, the reaction temperature is 80-120 ℃, and the reaction time is 16-24 hours.
In the preferable technical scheme, in the step S2, the concentration of the nitric acid is 65 wt%, the molar feeding ratio of the 2- (4-chlorophenoxy) pyridine to the nitric acid is 1: 4-6, the molar feeding ratio of the 2- (4-chlorophenoxy) pyridine to the concentrated sulfuric acid is 1: 2-4, the reaction temperature is 0-10 ℃, and the reaction time is 8-16 h.
In the preferable technical scheme, in the step S3, the concentration of hydrobromic acid is 50 wt%, the weight feed ratio of 2- (4-chloro-3-nitrophenoxy) pyridine to hydrobromic acid is 1: 5-10, the weight feed ratio of 2- (4-chloro-3-nitrophenoxy) pyridine to glacial acetic acid is 1: 5-10, the reaction temperature is 90-110 ℃, and the reaction time is 16-24 h.
In the step S4, the molar charge ratio of the 4-chloro-3-nitrophenol to the methylating agent is 1: 1-3, the molar charge ratio of the 4-chloro-3-nitrophenol to the acid-binding agent is 1: 1-3, the acid-binding agent is potassium carbonate, the methylating agent is dimethyl sulfate, the solvent is acetone, the weight charge ratio of the 4-chloro-3-nitrophenol to the solvent is 1: 8-15, the reaction temperature is 30-50 ℃, and the reaction time is 4-8 hours.
The invention has the advantages and beneficial effects that:
1. according to the preparation method of the 4-chloro-3-nitrobenzyl ether, the raw material substances involved in each step do not belong to highly toxic substances, the reaction safety involved in each step is high, the overall operation is simple and easy to implement, a scientific research foundation is laid for batch production of the 4-chloro-3-nitrobenzyl ether, and the economic practicability is high.
2. The preparation method of 4-chloro-3-nitrobenzyl ether provided by the invention is a preparation method of 2- (4-chloro-3-nitrophenoxy) pyridine related in step S2, p-chlorophenol is taken as a starting material, and due to the positioning effect of phenolic hydroxyl, the p-chlorophenol is very easy to be carried out on the 2-position in the nitration reaction process, and the 3-position is difficult to be introduced, so that the structure of the p-hydroxyl needs to be changed, and phenoxypyridine is introduced as a positioning group to increase the steric hindrance of the p-chlorophenol, so that most of nitro can be reacted on the 3-position, and the 2-position nitro product is reduced, thereby greatly improving the yield of the target product.
Drawings
FIG. 1 is a reaction scheme of a process for the preparation of 4-chloro-3-nitrobenzyl ether according to the present invention;
FIG. 2 is a High Performance Liquid Chromatogram (HPLC) of the target product.
Detailed Description
The following description of the embodiments of the present invention will be made with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
Example 1
The method for preparing the 4-chloro-3-nitrobenzyl ether has the reaction flow shown in the attached figure 1, and comprises the following specific operation steps:
step S1: putting (10g, 0.0781mol) p-chlorophenol, (12.3g, 0.0781mol) 2-bromopyridine, (24.8g, 0.1171mol) potassium phosphate) and 50ml dimethyl sulfoxide into a three-neck flask, stirring, mixing, heating to 100 ℃, keeping the temperature for reaction for 16 hours, cooling to normal temperature after the reaction is finished, filtering to remove insoluble solids by filtration and separating, and clarifying the filtrate in black; dropwise adding the filtrate into 200ml of water, wherein no solid is separated out after dropwise adding; then, the reaction mixture was extracted with dichloromethane, and the organic phase was concentrated to dryness under reduced pressure to obtain 14.71g of a product. The HPLC results showed that: the product had a percent 2- (4-chlorophenoxy) pyridine content of 98.76% and a molar yield of 91.9% (based on p-chlorophenol). MS (ESI) m/z: 206(M + H) +, in agreement with theoretical mass spectrometric data for 2- (4-chlorophenoxy) pyridine;
step S2: adding (22.68g, 0.234mol)65 wt% nitric acid into a three-neck flask, freezing and cooling to 0 ℃, slowly adding (11.47g, 0.117mol) concentrated sulfuric acid into the reaction liquid, wherein the obvious heat release phenomenon exists, adding (12g, 0.0585mol)2- (4-chlorophenoxy) pyridine prepared in the step S1 into the reaction liquid in batches under the stirring state after the adding is finished, controlling the temperature of the reaction system to be not more than 5 ℃, keeping the reaction system white and turbid after the adding is finished, keeping the temperature at 5 ℃ for reaction for 8 hours, gradually changing the reaction system into yellow and turbid, cooling to 0 ℃ after the reaction is finished, slowly adding 60ml water into the reaction system, precipitating a large amount of yellow granular solid, freezing and crystallizing at 0-5 ℃ for 30 minutes, and filtering and separating to obtain 15g of crude product; and putting 15g of the crude product into another three-neck flask, adding 60ml of methanol, stirring and mixing, heating to reflux, cooling to 10 ℃ for recrystallization, filtering and separating to obtain a light yellow solid, and drying to obtain 11g of the product. The HPLC results showed that: the percentage of 2- (4-chloro-3-nitrophenoxy) pyridine in the product was 98.25% with a molar yield of 75.2% (based on 2- (4-chlorophenoxy) pyridine). MS (ESI) m/z: 251(M + H) +, consistent with theoretical mass spectrum data for 2- (4-chloro-3-nitrophenoxy) pyridine;
step S3: the (10g, 0.04mol)2- (4-chloro-3-nitrophenoxy) pyridine prepared in the step S2, (50g, 0.3086mol)50 wt% hydrobromic acid and (50g, 0.8333mol) glacial acetic acid are put into a three-neck flask, the reaction solution is light orange, clear and transparent after the feeding is finished, the temperature is raised to 100 ℃, the reaction solution is kept for 16 hours under heat, the reaction solution is transferred into 200ml of water after the reaction is finished, the dichloromethane is used for extraction, the organic phase is washed to be neutral by saturated sodium bicarbonate solution and then is concentrated to be dry under reduced pressure, and 5.78g of a product is obtained. The HPLC results showed that: the 4-chloro-3-nitrophenol content in the product was 98.46% with a molar yield of 83.6% (based on 2- (4-chloro-3-nitrophenoxy) pyridine). MS (ESI) m/z: 174(M + H) +, in agreement with the theoretical mass spectrometric data for 4-chloro-3-nitrophenol;
step S4: adding 5g (0.0267 mol) of 4-chloro-3-nitrophenol prepared in the step S3 and 50ml of acetone into a three-neck flask, stirring and mixing until the mixture is clear, adding 5.52g (0.04 mol) of potassium carbonate into the reaction liquid, slowly adding 5.04g (0.04 mol) of dimethyl sulfate dropwise, heating the reaction liquid to 40 ℃ after the dropwise addition is finished, keeping the temperature for reaction for 6 hours, adding the reaction liquid into 150ml of water dropwise after the reaction is finished, extracting the reaction liquid with ethyl acetate, washing an organic phase with saturated salt water until the organic phase is neutral, and concentrating the organic phase under reduced pressure until the organic phase is dry to obtain 5.64g of a crude product; and putting 5.64g of the crude product into another three-neck flask, adding 11ml of ethanol, stirring and mixing, heating to reflux, cooling to 0-5 ℃, recrystallizing, filtering and separating to obtain a light brown solid, and drying to obtain 4.34g of the target product. The HPLC profile results on figure 2 show: the percentage content of 4-chloro-3-nitrobenzyl ether in the target product is 99.25%, and the molar yield is 80.3% (calculated by 4-chloro-3-nitrophenol). MS (ESI) m/z: 188(M + H) +, in agreement with the theoretical mass spectrum data of 4-chloro-3-nitrobenzyl ether.
Example 2
Step S1: adding (10g, 0.0781mol) p-chlorophenol, (12.3g, 0.0781mol) 2-bromopyridine, (16.5g, 0.0781mol) potassium phosphate) and 50ml dimethyl sulfoxide into a three-neck flask, stirring, mixing, heating to 80 ℃, carrying out heat preservation reaction for 24 hours, cooling to normal temperature after the reaction is finished, filtering to remove insoluble solids by filtration, and clarifying the filtrate in black; dropwise adding the filtrate into 200ml of water, wherein no solid is separated out after dropwise adding; the reaction mixture was then extracted with dichloromethane and the organic phase was concentrated to dryness under reduced pressure to give 12.34g of product. The HPLC results showed that: the product had a percent 2- (4-chlorophenoxy) pyridine content of 98.21% and a molar yield of 77% (based on p-chlorophenol).
Step S2: adding (22.68g, 0.234mol)65 wt% nitric acid into a three-neck flask, freezing and cooling to 0 ℃, slowly adding (11.47g, 0.117mol) concentrated sulfuric acid into the reaction liquid, wherein the obvious heat release phenomenon exists, adding (12g, 0.0585mol)2- (4-chlorophenoxy) pyridine prepared in the step S1 into the reaction liquid in batches under the stirring state after the adding is finished, controlling the temperature of the reaction system to be not more than 5 ℃, keeping the temperature at 0 ℃ for reaction for 16 hours, gradually changing the reaction system into yellow and turbid, slowly adding 60ml water into the reaction system after the reaction is finished, precipitating a large amount of yellow granular solid, freezing and crystallizing at 0-5 ℃ for 30 minutes, and filtering and separating to obtain 14.3g crude product; and putting 14.3g of the crude product into another three-neck flask, adding 57ml of methanol, stirring and mixing, heating to reflux, cooling to 10 ℃ for recrystallization, filtering and separating to obtain a light yellow solid, and drying to obtain 10.2g of the product. The HPLC results showed that: the product contained 98.14% of 2- (4-chloro-3-nitrophenoxy) pyridine in a molar yield of 69.73% (based on 2- (4-chlorophenoxy) pyridine).
Step S3: the (10g, 0.04mol)2- (4-chloro-3-nitrophenoxy) pyridine prepared in the step S2, (50g, 0.3086mol)50 wt% hydrobromic acid and (50g, 0.8333mol) glacial acetic acid are put into a three-neck flask, the reaction solution is light orange, clear and transparent after the feeding is finished, the temperature is raised to 90 ℃, the reaction solution is kept for 24 hours under the condition of heating, the reaction solution is transferred into 200ml of water after the reaction is finished, the dichloromethane is used for extraction, the organic phase is washed to be neutral by saturated sodium bicarbonate solution and then is concentrated to be dry under reduced pressure, and 5.63g of a product is obtained. The HPLC results showed that: the product had a percent 4-chloro-3-nitrophenol content of 98.26% and a molar yield of 81.43% (based on 2- (4-chloro-3-nitrophenoxy) pyridine).
Step S4: adding 5g (0.0267 mol) of 4-chloro-3-nitrophenol prepared in the step S3 and 40ml of acetone into a three-neck flask, stirring and mixing until the mixture is clear, adding 3.68g (0.0267 mol) of potassium carbonate into the reaction solution, slowly dropwise adding 3.36g (0.0267 mol) of dimethyl sulfate, heating the reaction solution to 30 ℃ after the dropwise adding is finished, keeping the temperature for reaction for 8 hours, dropwise adding the reaction solution into 120ml of water after the reaction is finished, extracting the reaction solution by using ethyl acetate, washing an organic phase by using saturated salt water until the organic phase is neutral, and concentrating the organic phase under reduced pressure until the organic phase is dry to obtain 4.86g of a crude product; putting 4.86g of the crude product into another three-neck flask, adding 10ml of ethanol, stirring and mixing, heating to reflux, cooling to 0-5 ℃ for recrystallization, filtering and separating to obtain light brown solid, and drying to obtain 3.7g of the target product. HPLC spectrum results show that: the target product has a 4-chloro-3-nitrobenzyl ether percentage of 99.46% and a molar yield of 68.45% (based on 4-chloro-3-nitrophenol).
Example 3
Step S1: putting (10g, 0.0781mol) p-chlorophenol, (24.6g, 0.1562mol) 2-bromopyridine, (49.5g, 0.2343mol) potassium phosphate) and 100ml dimethyl sulfoxide into a three-neck flask, stirring, mixing, heating to 120 ℃, keeping the temperature for reaction for 16h, cooling to normal temperature after the reaction is finished, filtering to remove insoluble solids by filtration, and clarifying the filtrate in black; dropwise adding the filtrate into 400ml of water, wherein no solid is separated out after dropwise adding; the reaction mixture was then extracted with dichloromethane and the organic phase was concentrated to dryness under reduced pressure to give 15.23g of product. The HPLC results showed that: the product had a percent 2- (4-chlorophenoxy) pyridine content of 98.21% and a molar yield of 95% (based on p-chlorophenol).
Step S2: adding (34.02g, 0.351mol)65 wt% nitric acid into a three-neck flask, freezing and cooling to 0 ℃, slowly adding (22.94g, 0.234mol) concentrated sulfuric acid into the reaction liquid, so as to have obvious heat release phenomenon, adding (12g, 0.0585mol)2- (4-chlorophenoxy) pyridine prepared in the step S1 into the reaction liquid in batches under the stirring state after the adding is finished, controlling the temperature of the reaction system to be not more than 5 ℃, keeping the reaction system white and turbid after the adding is finished, keeping the temperature at 10 ℃ for reaction for 8 hours, gradually changing the reaction system into yellow and turbid, after the reaction is finished, slowly adding 120ml water into the reaction system, precipitating a large amount of yellow granular solid, freezing and crystallizing at 0-5 ℃ for 30 minutes, and filtering and separating to obtain 16.8g of crude product; putting 16.8g of the crude product into another three-neck flask, adding 68ml of methanol, stirring and mixing, heating to reflux, cooling to 10 ℃ for recrystallization, filtering and separating to obtain a light yellow solid, and drying to obtain 12.3g of the product. The HPLC results showed that: the percentage of 2- (4-chloro-3-nitrophenoxy) pyridine in the product was 98.31% with a molar yield of 84% (based on 2- (4-chlorophenoxy) pyridine).
Step S3: the (10g, 0.04mol)2- (4-chloro-3-nitrophenoxy) pyridine prepared in the step S2, (100g, 0.6172mol)50 wt% hydrobromic acid and (100g, 1.6666mol) glacial acetic acid are put into a three-neck flask, the reaction solution is light orange, clear and transparent after the feeding is finished, the temperature is raised to 100 ℃, the reaction solution is kept for 16 hours under heat, after the reaction is finished, the reaction solution is transferred into 400ml of water and extracted by dichloromethane, an organic phase is washed to be neutral by a saturated sodium bicarbonate solution and then concentrated to be dry under reduced pressure, and 5.92g of a product is obtained. The HPLC results showed that: the 4-chloro-3-nitrophenol content in the product was 98.41% with a molar yield of 85.5% (based on 2- (4-chloro-3-nitrophenoxy) pyridine).
Step S4: adding 5g (0.0267 mol) of 4-chloro-3-nitrophenol prepared in the step S3 and 75ml of acetone into a three-neck flask, stirring and mixing until the mixture is clear, adding 11.04g (0.0801 mol) of potassium carbonate into the reaction liquid, slowly adding 10.08g (0.0801 mol) of dimethyl sulfate dropwise, heating the reaction liquid to 50 ℃ after the dropwise addition is finished to obtain orange turbid reaction liquid, keeping the temperature for reaction for 4 hours, adding the reaction liquid into 225ml of water dropwise after the reaction is finished, extracting with ethyl acetate, washing an organic phase with saturated salt water until the organic phase is neutral, and concentrating the organic phase under reduced pressure until the organic phase is dry to obtain 6.2g of a crude product; and putting 6.2g of the crude product into another three-neck flask, adding 12.2ml of ethanol, stirring and mixing, heating to reflux, cooling to 0-5 ℃, recrystallizing, filtering and separating to obtain a light brown solid, and drying to obtain 4.77g of a target product. HPLC spectrum results show that: the percentage content of 4-chloro-3-nitrobenzyl ether in the target product is 99.65%, and the molar yield is 88.25% (calculated by 4-chloro-3-nitrophenol).
Comparative example 1
Taking p-chloro anisole with the purity of more than 98 percent as a raw material, nitrifying the p-chloro anisole by using mixed acid of 65 percent nitric acid and glacial acetic acid, reacting for 72 hours at the temperature of 25 ℃, cooling the reaction liquid to 0 ℃ after the reaction is finished, dropwise adding water into the reaction liquid, separating out a large amount of yellow granular solids, freezing and crystallizing for 30min, and filtering and separating to obtain yellow solids. The HPLC results showed that: the content of 4-chloro-2-nitrobenzyl ether in the product is 96.7 wt%, and the content of 4-chloro-3-nitrobenzyl ether is only 0.2%, namely the main component of the product prepared by the method is 4-chloro-2-nitrobenzyl ether, and the target product 4-chloro-3-nitrobenzyl ether is not successfully prepared, and the reaction of the preparation method is as follows:
comparative example 2
Taking p-chloroanisole with the purity of more than 98% as a raw material, nitrifying the p-chloroanisole with mixed acid of 65% nitric acid and concentrated sulfuric acid, reacting for 1 hour at 10 ℃, cooling reaction liquid to 0 ℃ after the reaction is finished, dropwise adding water into the reaction liquid, separating out a large amount of yellow granular solids, freezing and crystallizing for 30min, and filtering and separating to obtain yellow solids. The HPLC results showed that: the content of 4-chloro-2-nitrobenzyl ether in the product is 97.9 wt%, the molar yield is 85.4%, and 4-chloro-3-nitrobenzyl ether is not detected, namely the main component of the product prepared by the method is 4-chloro-2-nitrobenzyl ether, and the target product, namely 4-chloro-3-nitrobenzyl ether, is not successfully prepared, and the reaction of the preparation method is as follows:
comparative example 3
4-chlorophenylacetate with the purity of more than 98 percent is taken as a raw material, is nitrified by mixed acid of 65 percent nitric acid and concentrated sulfuric acid, and reacts for 24 hours at 25 ℃, and the HPLC result shows that: the content of 4-chloro-2-nitrophenylacetate in the product was 99.7 wt%, the molar yield was 79%, the Melting Point (MP) was 76-78.5 ℃, and no 4-chloro-3-nitrophenylacetate was detected, indicating that this method uses ethyl ester as a directing group to increase the ortho steric hindrance and that the 3-nitro substituted product was not successfully prepared, the reaction of this preparation method being as follows:
comparative example 4
The 4-chlorobenzene benzoate with the purity of more than 98 percent is taken as a raw material, is nitrified by mixed acid of 65 percent nitric acid and concentrated sulfuric acid, and reacts for 24 hours at 25 ℃, and the HPLC result shows that: the content of 4-chloro-2-nitrobenzoate in the product is 95.6 wt%, the molar yield is 68%, and 4-chloro-3-nitrobenzoate is not detected, which indicates that the method uses phenyl ester as a positioning group to increase the ortho steric hindrance, and the 3-nitro-substituted product is not successfully prepared, and the reaction of the preparation method is as follows:
in conclusion, the preparation methods in comparative examples 1 to 4 can not successfully prepare the 4-chloro-3-nitrobenzyl ether, the 4-chloro-3-nitrobenzyl ether is successfully prepared in examples 1 to 3 by adopting the method, the molar yield and the purity of the 4-chloro-3-nitrobenzyl ether are high, the whole reaction process is simple and easy to operate, the safety is high, and the purpose of the invention is achieved.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the technical principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (5)
1. The preparation method of the 4-chloro-3-nitrobenzyl ether is characterized by comprising the following steps:
step S1: p-chlorophenol and 2-bromopyridine are taken as raw materials, and the 2- (4-chlorophenoxy) pyridine is prepared by nucleophilic substitution reaction in a solvent in the presence of an acid-binding agent;
step S2: taking the 2- (4-chlorophenoxy) pyridine prepared in the step S1 as a raw material, and carrying out nitration reaction in a mixed acid solution of nitric acid and concentrated sulfuric acid to prepare 2- (4-chloro-3-nitrophenoxy) pyridine;
step S3: taking the 2- (4-chloro-3-nitrophenoxy) pyridine prepared in the step S2 as a raw material, and performing ether bond cleavage reaction in a mixed acid solution of hydrobromic acid and glacial acetic acid to prepare 4-chloro-3-nitrophenol;
step S4: and (4) taking the 4-chloro-3-nitrophenol prepared in the step (S3) as a raw material, and carrying out methylation reaction in a solvent in the presence of an acid binding agent and a methylation reagent to prepare the 4-chloro-3-nitrobenzyl ether.
2. The method for preparing 4-chloro-3-nitrobenzyl ether according to claim 1, wherein in step S1, the molar charge ratio of the p-chlorophenol to the 2-bromopyridine is 1: 1-2, the acid-binding agent is potassium phosphate, the molar charge ratio of the p-chlorophenol to the acid-binding agent is 1: 1-3, the solvent is dimethyl sulfoxide, the weight charge ratio of the p-chlorophenol to the solvent is 1: 5-10, the reaction temperature is 80-120 ℃, and the reaction time is 16-24 h.
3. The method of claim 1, wherein in step S2, the concentration of nitric acid is 65 wt%, the molar feed ratio of 2- (4-chlorophenoxy) pyridine to nitric acid is 1: 4-6, the molar feed ratio of 2- (4-chlorophenoxy) pyridine to concentrated sulfuric acid is 1: 2-4, the reaction temperature is 0-10 ℃, and the reaction time is 8-16 h.
4. The method of claim 1, wherein in step S3, the hydrobromic acid concentration is 50 wt%, the weight ratio of 2- (4-chloro-3-nitrophenoxy) pyridine to hydrobromic acid is 1: 5-10, the weight ratio of 2- (4-chloro-3-nitrophenoxy) pyridine to glacial acetic acid is 1: 5-10, the reaction temperature is 90-110 ℃, and the reaction time is 16-24 h.
5. The method for preparing 4-chloro-3-nitrobenzyl ether according to claim 1, wherein in step S4, the molar charge ratio of 4-chloro-3-nitrophenol to methylating agent is 1: 1 to 3, the molar charge ratio of 4-chloro-3-nitrophenol to acid-binding agent is 1: 1 to 3, the acid-binding agent is potassium carbonate, the methylating agent is dimethyl sulfate, the solvent is acetone, the weight charge ratio of 4-chloro-3-nitrophenol to solvent is 1: 8 to 15, the reaction temperature is 30 to 50 ℃, and the reaction time is 4 to 8 hours.
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