CN112645873A - Synthetic method of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide - Google Patents
Synthetic method of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide Download PDFInfo
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- QVZFLVYSPCZQCM-UHFFFAOYSA-N [N]=O.CC1=NC=C(C(=C1C)OC)C Chemical compound [N]=O.CC1=NC=C(C(=C1C)OC)C QVZFLVYSPCZQCM-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000010189 synthetic method Methods 0.000 title claims abstract description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006467 substitution reaction Methods 0.000 claims abstract description 18
- 238000005893 bromination reaction Methods 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- -1 4-bromo-2, 3, 5-trimethyl-pyridine nitrogen oxide Chemical compound 0.000 claims abstract description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 10
- YSBDSWBSEXCSSE-UHFFFAOYSA-N 2,3,5-trimethyl-1-oxidopyridin-1-ium Chemical compound CC1=CC(C)=C(C)[N+]([O-])=C1 YSBDSWBSEXCSSE-UHFFFAOYSA-N 0.000 claims abstract description 8
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960000381 omeprazole Drugs 0.000 claims abstract description 4
- UTCFYSGOQHYTAT-UHFFFAOYSA-N 4-bromo-2,3,5-trimethylpyridine Chemical compound CC1=CN=C(C)C(C)=C1Br UTCFYSGOQHYTAT-UHFFFAOYSA-N 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- XJTFVTIYKKOOCN-UHFFFAOYSA-N 4-bromo-2,3,5-trimethyl-1-oxidopyridin-1-ium Chemical compound CC1=C[N+]([O-])=C(C)C(C)=C1Br XJTFVTIYKKOOCN-UHFFFAOYSA-N 0.000 claims description 5
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 5
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical group [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000003444 phase transfer catalyst Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 230000031709 bromination Effects 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 abstract description 4
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 abstract description 2
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 abstract description 2
- 150000003842 bromide salts Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- GFYHSKONPJXCDE-UHFFFAOYSA-N 2,3,5-trimethylpyridine Chemical compound CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000006396 nitration reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000001311 chemical methods and process Methods 0.000 description 3
- 239000002351 wastewater Substances 0.000 description 3
- JOXZAMWCPXYFKC-UHFFFAOYSA-N 4-methoxy-2,3,5-trimethyl-1-oxidopyridin-1-ium Chemical compound COC1=C(C)C=[N+]([O-])C(C)=C1C JOXZAMWCPXYFKC-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- PSEPRWKZZJWRCB-UHFFFAOYSA-N (4-methoxy-3,5-dimethylpyridin-2-yl)methanol Chemical compound COC1=C(C)C=NC(CO)=C1C PSEPRWKZZJWRCB-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- LELDJUYQEMKHJH-UHFFFAOYSA-N 4-methoxy-2,3,5-trimethylpyridine Chemical compound COC1=C(C)C=NC(C)=C1C LELDJUYQEMKHJH-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000006198 methoxylation reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000000126 substance 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
- C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a synthetic method of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide, which comprises the following steps: s1, carrying out bromination reaction and methoxy substitution on the 2,3, 5-trimethylpyridine-N-oxide to obtain 4-bromo-2, 3, 5-trimethylpyridine oxynitride; s2, 4-bromo-2, 3, 5-trimethyl-pyridine nitrogen oxide is subjected to sodium methoxide substitution reaction to generate an important intermediate 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide of omeprazole. The process route of the invention adopts the mild bromination reaction condition of bromate and bromide salt, and then utilizes the bromide intermediate to carry out methoxy substitution reaction, the whole process design is simple, the reaction condition is mild, and the operation is simple and easy to implement.
Description
Technical Field
The invention belongs to the field of pharmacy, and relates to synthesis of a compound 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide.
Background
The omeprazole with the chemical name of 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] sulfinyl ] -1H-benzimidazole is applied to clinically treating acid-related diseases such as gastric ulcer, duodenal ulcer and gastroesophageal reflux disease. 4-methoxy-3, 5-dimethyl-2-pyridinemethanol generated by rearrangement reaction of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide is an important intermediate for synthesizing omeprazole.
Junggren et al in U.S. Pat. No. 4,55431, Brandstrom et al in U.S. Pat. No. 4,4620008 describe that 2,3, 5-trimethylpyridine is subjected to nitroxidation, nitration, methoxy substitution under sodium methoxide conditions to give 4-methoxy-2, 3, 5-trimethyl-pyridine nitroxide.
In 2004, xu baocai et al described that 2,3, 5-trimethylpyridine first produced pyridine-N-oxide by oxynitridation with hydrogen peroxide/glacial acetic acid, and through nitration, methoxy substitution under sodium hydrogen conditions produced 4-methoxy-2, 3, 5-trimethyl-pyridine nitroxide. (Fine chemical engineering, 2004, 21 (1): 67-69)
The method adopts 2,3, 5-trimethylpyridine as a starting material to prepare the 4-methoxy-2, 3, 5-trimethyl-pyridine oxynitride through nitrogen oxidation, bromination and methoxy substitution, avoids the use of dangerous processes such as nitration reaction and the like, ensures safer production operation, simultaneously can recycle and reuse sodium bromide serving as a byproduct generated after the methoxylation of bromide, reduces the cost of production raw materials, has simple two-step synthesis operation and mild reaction conditions, does not need to adopt a dangerous chemical process which is seriously regulated in China, reduces the difficulty in treating a large amount of wastewater generated by nitration of mixed acid, and is very suitable for industrial production.
Disclosure of Invention
The invention aims to provide a synthetic method of a compound 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide, which has the advantages of simple synthetic process, mild reaction conditions, no need of dangerous chemical process, small waste water production amount, high overall yield and suitability for industrial scale-up production.
The purpose of the invention is realized by the following technical scheme: 2,3, 5-trimethyl pyridine is taken as a starting material, and is subjected to nitrogen oxidation reaction, bromination reaction and methoxy substitution to obtain 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide, wherein the reaction formula of each step is as follows,
in the bromination reaction, the bromination reagent is sodium bromate or sodium bromide under the synthesis condition of 4-bromo-2, 3, 5-trimethyl-pyridine nitrogen oxide.
In the bromination reaction, the synthesis condition of 4-bromo-2, 3, 5-trimethyl-pyridine nitrogen oxide adopts sulfuric acid catalytic reaction.
In the methoxy substitution reaction, in the synthesis of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide, sodium methoxide is adopted as a substitution reagent, and methanol or N, N-dimethylformamide or dimethyl sulfoxide is adopted as a solvent.
In the methoxy substitution reaction, tetrabutylammonium bromide or triethylbenzylammonium chloride is added as a phase transfer catalyst in the synthesis of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide.
The bromination reaction in S1 includes: adding sodium bromide, sodium bromate and 2,3, 5-trimethylpyridine-N-oxide into water, stirring and dissolving at room temperature, slowly dropwise adding concentrated sulfuric acid at 0-5 ℃, and stirring and reacting for 15 hours at room temperature after dropwise adding.
The substitution reaction in S2 includes: adding 4-bromo-2, 3, 5-trimethylpyridine-N-oxide into anhydrous DMF or anhydrous methanol, adding sodium methoxide at room temperature, adding tetrabutylammonium bromide or triethylbenzylammonium chloride as a phase transfer catalyst, heating to 80-100 ℃, and stirring for reacting for 6 hours.
In the process route, mild bromination reaction conditions of bromate and bromide are adopted, and then a bromide intermediate is used for carrying out methoxy substitution reaction, so that the whole process is simple in design, mild in reaction conditions and simple and easy to operate, meanwhile, the critical chemical process of national key supervision of nitration reaction is avoided, the generation of mixed acid wastewater which is difficult to treat is reduced, and sodium bromide serving as a byproduct can be recycled and reused. Therefore, the process has the advantages of safety, environmental protection, lower production cost and the like when being used for industrial production.
Detailed Description
The present invention will be further illustrated with reference to the following examples.
Example 1: synthesis of 2,3, 5-trimethylpyridine-N-oxide
2,3, 5-trimethylpyridine oxide (30.00g,0.248mol) is added to DCM (150g) and dissolved with stirring at room temperature, and m-chloroperoxybenzoic acid (51.43g,0.298mol) is added in portions at 0 ℃. After the addition, the reaction was stirred at room temperature for 1.5 hours, and after monitoring the completion of the reaction, a saturated sodium bisulfite solution was dropped into the above reaction solution to quench. Extracting with dichloromethane for 5 times, mixing organic phases, drying with anhydrous sodium sulfate, filtering, and spin-drying solvent to obtain light yellow solid 2,3, 5-trimethylpyridine-N-oxide.
1HNMR(CDCl3) δ 8.03(s,1H), 6.91(s,1H), 2.46(s,3H), 2.30(s, 3H),2.23 (s, 3H).
Example 2: 4-bromo-2, 3, 5-trimethylpyridine-N-oxide
Sodium bromide (13.63g,0.1325mol), sodium bromate (4.00g,0.0265mol) and 2,3, 5-trimethylpyridine-N-oxide (3.64g,0.0265mol) were added to water (80ml) and dissolved with stirring at room temperature. Slowly dropwise adding concentrated sulfuric acid (7.80g,0.0795mol) at 0-5 ℃, stirring and reacting for 15h at room temperature after dropwise adding. After completion of the reaction, the reaction mixture was quenched by addition of a saturated sodium hydrogen sulfite solution under ice-water conditions, and then stirred for 1 hour by addition of methylene chloride (40 ml). Separating, separating organic layer, extracting water layer with DCM for 6 times, mixing organic phases, adding anhydrous sodium sulfate, drying, filtering, concentrating filtrate under reduced pressure to obtain light yellow solid crude product, pulping crude product with dichloromethane/petroleum ether (2: 1), and purifying to obtain white solid 4-bromo-2, 3, 5-trimethylpyridine-N-oxide.
1HNMR(CDCl3)δ 8.55(s,1H), 2.73(s,3H), 2.56(s, 3H),2.46 (s, 3H).Ms=216,218.
Example 3: 4-methoxy-2, 3, 5-trimethylpyridine-N-oxide
4-bromo-2, 3, 5-trimethylpyridine-N-oxide (40 g,0.2 mol) was taken, anhydrous DMF (400 ml) was added, sodium methoxide (54g, 1mol) and tetrabutylammonium bromide (4 g) were added at room temperature, and the mixture was heated to 80 ℃ and stirred for reaction for 6 hours. After the reaction is finished, the solvent DMF is evaporated by reduced pressure, dichloromethane is added, stirring is carried out for 1 hour, filtering and spin-drying are carried out, dichloromethane/petroleum ether (1:1) is added, stirring and filtering are carried out, and petroleum ether is washed to obtain light yellow solid 4-methoxy-2, 3, 5-trimethylpyridine-N-oxide.
1HNMR(CDCl3)δ 8.03(s,1H), 3.68(s,3H), 2.42(s, 3H),2.14-2.18 (d, 6H).Ms=168.
Example 4: 4-methoxy-2, 3, 5-trimethyl-pyridine nitroxide
4-bromo-2, 3, 5-trimethyl-pyridine oxynitride (32 g,0.16 mol) was taken and added to anhydrous methanol (320 ml), sodium methoxide (43.2g, 0.8mol) and triethylbenzylammonium chloride (3.2 g) were added at room temperature, the autoclave was sealed and reacted, and the temperature was raised to 100 ℃ and stirred for 6 hours. After the detection reaction is finished, the solvent is evaporated to dryness under reduced pressure, dichloromethane is added, stirring is carried out, filtering is carried out, filtrate is dried in a spinning mode, dichloromethane/petroleum ether (1:1) is added, stirring is carried out for 1 hour, filtering is carried out, and air blowing and drying are carried out at the temperature of 50 ℃ to obtain light yellow solid 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention.
Claims (7)
1. A synthetic method of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide is characterized by comprising the following steps:
s1, carrying out bromination reaction and methoxy substitution on the 2,3, 5-trimethylpyridine-N-oxide to obtain 4-bromo-2, 3, 5-trimethylpyridine oxynitride;
s2, 4-bromo-2, 3, 5-trimethyl-pyridine nitrogen oxide is subjected to sodium methoxide substitution reaction to generate an important intermediate 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide of omeprazole; the chemical reaction formula is as follows:
2. the method for synthesizing 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide according to claim 1, wherein in S1 bromination reaction, the bromination reagent is sodium bromate or sodium bromide under the synthesis conditions of 4-bromo-2, 3, 5-trimethyl-pyridine nitrogen oxide.
3. The method for synthesizing 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide according to claim 1, wherein in S1 bromination reaction, sulfuric acid is adopted as the synthesis condition of 4-bromo-2, 3, 5-trimethyl-pyridine nitrogen oxide.
4. The method according to claim 1, wherein in the substitution reaction of S2, the substitution reagent is sodium methoxide, and the solvent is methanol, N-dimethylformamide or dimethylsulfoxide.
5. The method for synthesizing 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide according to claim 1, wherein tetrabutylammonium bromide or triethylbenzylammonium chloride is added as a phase transfer catalyst in the S2 substitution reaction for synthesizing 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide.
6. The method for synthesizing 4-methoxy-2, 3, 5-trimethyl-pyridine nitroxide as claimed in claim 1, wherein the bromination reaction in S1 comprises: adding sodium bromide, sodium bromate and 2,3, 5-trimethylpyridine-N-oxide into water, stirring and dissolving at room temperature, slowly dropwise adding concentrated sulfuric acid at 0-5 ℃, and stirring and reacting for 15 hours at room temperature after dropwise adding.
7. The method for synthesizing 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide according to claim 1, wherein the substitution reaction in S2 comprises: adding 4-bromo-2, 3, 5-trimethylpyridine-N-oxide into anhydrous DMF or anhydrous methanol, adding sodium methoxide at room temperature, adding tetrabutylammonium bromide or triethylbenzylammonium chloride as a phase transfer catalyst, heating to 80-100 ℃, and stirring for reacting for 6 hours.
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