CN113072441A - Preparation method of 2-methoxy-6-methylbenzoic acid - Google Patents
Preparation method of 2-methoxy-6-methylbenzoic acid Download PDFInfo
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- CN113072441A CN113072441A CN202110420389.5A CN202110420389A CN113072441A CN 113072441 A CN113072441 A CN 113072441A CN 202110420389 A CN202110420389 A CN 202110420389A CN 113072441 A CN113072441 A CN 113072441A
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- methylbenzoic acid
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- MICCJGFEXKNBLU-UHFFFAOYSA-N 2-methoxy-6-methylbenzoic acid Chemical compound COC1=CC=CC(C)=C1C(O)=O MICCJGFEXKNBLU-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 75
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 43
- 238000007069 methylation reaction Methods 0.000 claims abstract description 35
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 32
- 230000007062 hydrolysis Effects 0.000 claims abstract description 31
- 238000010438 heat treatment Methods 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229940095102 methyl benzoate Drugs 0.000 claims abstract description 21
- 239000002994 raw material Substances 0.000 claims abstract description 20
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 19
- 239000003513 alkali Substances 0.000 claims abstract description 15
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000005580 one pot reaction Methods 0.000 claims abstract description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 11
- 238000005886 esterification reaction Methods 0.000 claims abstract description 9
- CCXSGQZMYLXTOI-UHFFFAOYSA-N 13506-76-8 Chemical compound CC1=CC=CC([N+]([O-])=O)=C1C(O)=O CCXSGQZMYLXTOI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 8
- SWZOXFSVZHAWQN-UHFFFAOYSA-N methyl 2-methoxy-6-methylbenzoate Chemical compound COC(=O)C1=C(C)C=CC=C1OC SWZOXFSVZHAWQN-UHFFFAOYSA-N 0.000 claims abstract description 8
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 5
- XPVBLOOMFDNJTH-UHFFFAOYSA-N methyl 2-methyl-6-nitrobenzoate Chemical compound COC(=O)C1=C(C)C=CC=C1[N+]([O-])=O XPVBLOOMFDNJTH-UHFFFAOYSA-N 0.000 claims abstract description 5
- XHYVBIXKORFHFM-UHFFFAOYSA-N 2-amino-6-methylbenzoic acid Chemical compound CC1=CC=CC(N)=C1C(O)=O XHYVBIXKORFHFM-UHFFFAOYSA-N 0.000 claims abstract description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000032050 esterification Effects 0.000 claims abstract description 3
- HCLLOQLXKCCWLJ-UHFFFAOYSA-N methyl 2-amino-6-methylbenzoate Chemical compound COC(=O)C1=C(C)C=CC=C1N HCLLOQLXKCCWLJ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- GPNCYIZKJTXKRO-UHFFFAOYSA-N methyl 2-hydroxy-6-methylbenzoate Chemical compound COC(=O)C1=C(C)C=CC=C1O GPNCYIZKJTXKRO-UHFFFAOYSA-N 0.000 claims description 63
- JHBYQJRHJVEKPK-UHFFFAOYSA-N 4-chloro-7-fluoroquinazoline Chemical compound ClC1=NC=NC2=CC(F)=CC=C21 JHBYQJRHJVEKPK-UHFFFAOYSA-N 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 230000002829 reductive effect Effects 0.000 claims description 30
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 21
- 238000004821 distillation Methods 0.000 claims description 19
- 230000011987 methylation Effects 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- VQTGUFBGYOIUFS-UHFFFAOYSA-N nitrosylsulfuric acid Chemical compound OS(=O)(=O)ON=O VQTGUFBGYOIUFS-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- -1 nitrous acid ester Chemical class 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 13
- 239000003638 chemical reducing agent Substances 0.000 claims 2
- 230000017858 demethylation Effects 0.000 claims 1
- 238000010520 demethylation reaction Methods 0.000 claims 1
- 238000001816 cooling Methods 0.000 abstract description 8
- 239000012022 methylating agents Substances 0.000 abstract 1
- 239000010410 layer Substances 0.000 description 29
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- HCJMNOSIAGSZBM-UHFFFAOYSA-N 6-methylsalicylic acid Chemical compound CC1=CC=CC(O)=C1C(O)=O HCJMNOSIAGSZBM-UHFFFAOYSA-N 0.000 description 14
- 238000006722 reduction reaction Methods 0.000 description 10
- 239000012452 mother liquor Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000005810 Metrafenone Substances 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- AMSPWOYQQAWRRM-UHFFFAOYSA-N metrafenone Chemical compound COC1=CC=C(Br)C(C)=C1C(=O)C1=C(C)C=C(OC)C(OC)=C1OC AMSPWOYQQAWRRM-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000003899 bactericide agent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 241000221785 Erysiphales Species 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000006136 alcoholysis reaction Methods 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 description 1
- 244000241257 Cucumis melo Species 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- QQZWEECEMNQSTG-UHFFFAOYSA-N Ethyl nitrite Chemical compound CCON=O QQZWEECEMNQSTG-UHFFFAOYSA-N 0.000 description 1
- 239000005917 Methoxyfenozide Substances 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 241000219094 Vitaceae Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229960003116 amyl nitrite Drugs 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 235000021021 grapes Nutrition 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000006140 methanolysis reaction Methods 0.000 description 1
- QCAWEPFNJXQPAN-UHFFFAOYSA-N methoxyfenozide Chemical compound COC1=CC=CC(C(=O)NN(C(=O)C=2C=C(C)C=C(C)C=2)C(C)(C)C)=C1C QCAWEPFNJXQPAN-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- BLLFVUPNHCTMSV-UHFFFAOYSA-N methyl nitrite Chemical compound CON=O BLLFVUPNHCTMSV-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- CSDTZUBPSYWZDX-UHFFFAOYSA-N n-pentyl nitrite Chemical compound CCCCCON=O CSDTZUBPSYWZDX-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- KAOQVXHBVNKNHA-UHFFFAOYSA-N propyl nitrite Chemical compound CCCON=O KAOQVXHBVNKNHA-UHFFFAOYSA-N 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000035806 respiratory chain Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis process of 2-methoxy-6-methylbenzoic acid, which comprises the following steps: (1) reduction hydrogenation reaction: using 2-methyl-6-nitrobenzoic acid or 2-methyl-6-nitrobenzoic acid methyl ester as a raw material, methanol as a solvent, hydrogen as a hydrogen source, palladium carbon or platinum carbon as a catalyst, and preparing 2-amino-6-methylbenzoic acid or 2-amino-6-methylbenzoic acid methyl ester by hydrogenation reduction; (2) diazotization, hydrolysis and esterification one-pot reaction: carrying out diazotization, hydrolysis and esterification reaction under the action of a diazotization reagent by taking a reduction product as a raw material and methanol as a solvent to prepare 2-hydroxy-6-methyl benzoate; (3) methylation reaction: taking 2-hydroxy-6-methyl benzoate as a raw material, taking dimethyl sulfate as a methylating agent, and carrying out methylation reaction in the presence of alkali to prepare 2-methoxy-6-methyl benzoate; (4) and (3) hydrolysis reaction: mixing 2-methoxy-6-methyl benzoic acid methyl ester with alkali and water, heating for hydrolysis, cooling to adjust the PH value to 1-3 by acid after the reaction is finished, separating out a product, filtering, and drying to obtain 2-methoxy-6-methyl benzoic acid.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, relates to synthesis of an organic intermediate, and particularly relates to a preparation method of 2-methoxy-6-methylbenzoic acid.
Background
2-methoxy-6-methyl benzoic acid is a key synthetic intermediate of pesticide bactericide metrafenone. The metrafenone is a benzophenone type bactericide of American cyanamide company (now belonging to Pasteur Germany), has a unique action mechanism, is different from the common bactericide that the action sites are respiratory chain, cell wall and the like, and the metrafenone directly acts on the cytoskeleton-actin of pathogenic bacteria, so that the actin is damaged and disintegrated to cause abnormal branching of mycelium, and simultaneously, the growth is slowed down, thereby achieving the aim of preventing and treating powdery mildew. The bactericidal composition has excellent activity on powdery mildew and eyespot diseases of crops such as grains, melons and fruits, beans, grapes and the like, the bactericidal composition is marketed in the United kingdom in 2004, and 98% of original drug of metrafenone and 42% of metrafenone suspending agent are temporarily registered in China in the next year by Basff.
In the prior art, the 2-methoxy-6-methylbenzoic acid is difficult to obtain and few reports exist, so that the development of a new synthesis process has important significance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of 2-methoxy-6-methylbenzoic acid, and the invention provides a new synthetic raw material and a new method for preparing 2-methoxy-6-methylbenzoic acid by taking 2-methyl-6-nitrobenzoic acid as a raw material.
The invention is realized by the following technical scheme:
a synthesis process of 2-methoxy-6-methylbenzoic acid comprises the following steps:
(1) reduction hydrogenation reaction: using 2-methyl-6-nitrobenzoic acid or 2-methyl-6-nitrobenzoic acid methyl ester as a raw material, methanol as a solvent, hydrogen as a hydrogen source, palladium carbon or platinum carbon as a catalyst, and preparing 2-amino-6-methylbenzoic acid or 2-amino-6-methylbenzoic acid methyl ester by hydrogenation reduction;
(2) diazotization, hydrolysis and esterification one-pot reaction: carrying out diazotization, hydrolysis and esterification reaction under the action of a diazotization reagent by taking a reduced substance as a raw material and methanol as a solvent to prepare 2-hydroxy-6-methyl benzoate;
(3) methylation reaction: using the obtained 2-hydroxy-6-methyl benzoate as a raw material, using dimethyl sulfate as a methylation reagent, and carrying out methylation reaction in the presence of alkali to prepare 2-methoxy-6-methyl benzoate;
(4) and (3) hydrolysis reaction: mixing and stirring 2-methoxy-6-methyl benzoic acid methyl ester, alkali and water, heating to react until hydrolysis reaction is completed, cooling, adjusting pH to 1-3 with acid to precipitate a product, filtering, and drying to obtain 2-methoxy-6-methyl benzoic acid;
the reaction equation is as follows:
the further scheme of the invention is as follows:
the reduction hydrogenation reaction in the step (1) is carried out at the temperature of 60-90 ℃ and the hydrogen pressure of 0.5-1.5 MPa; in the one-pot reaction in the step (2), a diazotization reagent is dropwise added at 0-5 ℃, after the dropwise addition is finished, the temperature is raised to 50-66 ℃, the reaction is kept at the temperature until the reaction is finished, and the required reaction time is 4-16 h; the reaction temperature of the methylation reaction in the step (3) is 30-45 ℃, and the reaction time is 1-2 hours; the temperature of the hydrolysis reaction in the step (4) is 80-100 ℃. And (3) after the reduction hydrogenation reaction in the step (1) is finished, filtering and recovering the catalyst, and directly carrying out diazotization reaction on the filtrate in the step (2).
Further, in the reduction hydrogenation reaction of the step (1), the weight ratio of the 2-methyl-6-nitrobenzoic acid to the catalyst is 1: 0.02 to 0.2; the methanol is used as a reaction solvent, the solvent amount can meet the reaction requirement, and the weight ratio of the 2-methyl-6-nitrobenzoic acid or the methyl ester thereof to the methanol is 1: 3-15; in the methylation reaction in the step (3), the mass ratio of methyl 2-hydroxy-6-methylbenzoate to dimethyl sulfate is 1: 1.3-2.20, the alkali is used for adjusting the pH value of a reaction system and neutralizing phenolic hydroxyl to increase the methylation reaction activity, and the required amount of the alkali is related to the usage amount of dimethyl sulfate and is usually 1.5-1.8 times of the mass amount of dimethyl sulfate; during the hydrolysis reaction in the step (4), the mass ratio of the methyl 2-methoxy-6-methylbenzoate to the alkali is 1: 1.01-1.05.
Further, in the one-pot reaction of the step (2), diazotization, hydrolysis and esterification reactions are carried out to prepare 2-hydroxy-6-methyl benzoate by using a sulfuric acid solution of nitroso sulfuric acid or nitrite ester as a diazotization reagent. The nitroso sulfuric acid is a sulfuric acid solution of nitroso sulfuric acid with a mass concentration of 40%, and the nitrite is nitrite formed by alcohol with 1-5 carbon atoms, such as methyl nitrite, ethyl nitrite, propyl nitrite, butyl nitrite, amyl nitrite and the like.
In the one-pot reaction in the step (2), the molar ratio of the 2-amino-6-methylbenzoic acid to the diazotization reagent is 1: 1.02-1.5; the diazotization reaction solution may contain a portion of water derived from the water produced by the hydrogenation reduction reaction.
Further, the alkali in the step (3) or (4) is one or more of inorganic alkali which is conventionally used, such as sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide; the acid in the step (4) is a conventionally used inorganic acid such as sulfuric acid, hydrochloric acid, etc., and the preferred acid is sulfuric acid with a mass concentration of 10-30% or hydrochloric acid with a mass concentration of 10-30%.
The further scheme of the invention is as follows:
when the reaction in the step (2) is finished in one pot, recovering the solvent methanol by atmospheric or reduced pressure distillation, diluting and layering the concentrated solution by adding water, separating out a water layer, directly carrying out methylation on an oil layer in the step (3), extracting the water layer by using an organic solvent, then removing the water layer, concentrating and desolventizing the organic layer obtained by extraction, and carrying out methylation in the step (3);
in the step, methanol is used as a solvent to carry out diazotization and diazonium salt decomposition reaction, so that hydrolysis and alcoholysis reaction can simultaneously occur to obtain a mixture of 2-methoxy-6-methylbenzoic acid/2-hydroxy-6-methylbenzoic acid; in addition, because the reaction is carried out under sulfuric acid, the esterification reaction of a sulfuric acid catalyst is carried out while the hydrolysis reaction is carried out, so that a mixture of 2-methoxy-6-methyl benzoate/2-hydroxy-6-methyl benzoate can be obtained after hydrolysis/alcoholysis, separation and purification. Therefore, after the one-pot reaction in the step (2) is completed, the methyl 2-hydroxy-6-methylbenzoate and the separated oil layer and organic layer from the post-treatment are a mixture of methyl 2-methoxy-6-methylbenzoate/methyl 2-hydroxy-6-methylbenzoate.
During the methylation reaction in the step (3), after the reaction is finished, washing and layering reaction liquid containing the crude methyl 2-methoxy-6-methylbenzoate to obtain a crude methyl 2-methoxy-6-methylbenzoate, purifying by reduced pressure distillation to obtain a refined methyl 2-methoxy-6-methylbenzoate, and hydrolyzing the refined product serving as a raw material in the step (4); the distillation temperature of the reduced pressure distillation process in the step (3) is related to the vacuum degree of the reduced pressure distillation process, and when the absolute pressure is 100Pa, the distillation temperature is 104-108 ℃; the content of the methyl 2-methoxy-6-methylbenzoate obtained by reduced pressure distillation is more than 99.5%.
After the 2-methoxy-6-methyl benzoic acid methyl ester is purified by reduced pressure distillation, the purity of the obtained 2-methoxy-6-methyl benzoic acid product is higher, generally more than 99.8 percent, after hydrolysis and neutralization in the step (4), recrystallization is not needed for further controlling the product quality, the operation steps are simple and clean, the product quality is stable and controllable, and the method is more suitable for industrialization.
The invention further improves the scheme as follows:
and (3) after the one-pot reaction in the step (2) is finished, carrying out reduced pressure distillation on the crude product of the methyl 2-hydroxy-6-methylbenzoate to separate methyl 2-methoxy-6-methylbenzoate and a mixture of methyl 2-hydroxy-6-methylbenzoate and methyl 2-hydroxy-6-methylbenzoate/methyl 2-methoxy-6-methylbenzoate. The 2-methoxy-6-methyl benzoic acid methyl ester can directly enter the step (4) to carry out hydrolysis reaction to prepare 2-methoxy-6-methyl benzoic acid; the reduced pressure distillation separation of 2-hydroxy-6-methyl benzoate or 2-hydroxy-6-methyl benzoate/2-methoxy-6-methyl benzoate mixture can be used for preparing 2-methoxy-6-methyl benzoic acid after methylation in the step (3). When the improved scheme is adopted, the method can separate the 2-hydroxy-6-methyl benzoate intermediate after the post-treatment in the step (2) is completed, reduce the amount of impurities entering the methylation step and finally control the product quality.
The invention has the beneficial effects that:
the post-treatment process of the invention has less purification steps: from hydrogenation reduction to methylation, each step can be reacted in a crude product form, so that unnecessary purification operation is reduced, and the production cost is reduced;
hydrolysis and methanolysis products exist simultaneously in the diazotization process, and partial methylation of materials is realized in the hydrolysis process, so that the use amount of a methylation reagent can be reduced, and the waste salt amount caused by the methylation process is reduced. The method has favorable influence on the ecological environment while reducing the material loss and the production cost.
During the diazotization hydrolysis process, the esterification reaction of acid and methanol under the catalysis of excessive sulfuric acid can be carried out simultaneously, so that the reaction steps are simplified, and the effect of reducing the production cost can be achieved.
Methanol is adopted as a solvent in the steps of hydrogenation and diazotization hydrolysis, and a methanol byproduct is generated in the steps of methylation and hydrolysis, so that the solvent can be conveniently recycled, and the ecological environment is protected.
The invention can purify the 2-methoxy-6-methyl benzoate crude product by reduced pressure distillation, and has more convenient operation while the product quality is stable and controllable.
In conclusion, compared with the prior art, the technical scheme adopted by the invention has the characteristics of compact reaction steps, less separation and purification, simple and convenient operation and easy separation and purification. Meanwhile, the obtained product has high purity and controllable quality, and can meet the quality requirement of methoxyfenozide production.
Detailed Description
Example 1
(1) Reductive hydrogenation
Adding 500 g of 2-methyl-6-nitrobenzoic acid, 50 g of platinum carbon (platinum content: 2 percent) and 2000 g of methanol into a pressure kettle, replacing with nitrogen, introducing hydrogen to 1.0-1.3 MPa, heating to 70-80 ℃, controlling the reaction pressure until the reaction is complete (raw materials are less than 0.5 percent), continuing stirring for 60 min, filtering while hot, collecting and recycling the catalyst, and directly carrying out diazotization hydrolysis on the mother liquor.
(2) Diazotization hydrolysis
And (2) cooling the reduction mother liquor obtained in the step (1) to 0-5 ℃, dropwise adding 900 g (weight percentage: 40%,1.02 eq.) of nitroso sulfuric acid at a controlled temperature, heating to 50-60 ℃ after adding, heating for not less than 30min, stirring for 1 hour, heating to 64-66 ℃, and carrying out reflux reaction for 8-12 hours until the reaction is finished (HPLC: 2-hydroxy-6-methylbenzoic acid + 2-methoxy-6-methylbenzoic acid is less than 1%).
Heating the reaction liquid to 85-100 ℃, distilling at normal pressure to recover methanol, adding 1200 g of water after recovering 1500-1600 g of methanol, standing for layering, separating an oil layer and collecting.
The aqueous layer was extracted with 800ml of MIBK, the separated organic layer was concentrated and combined with the oil layer to give 430 g of crude methyl 2-hydroxy-6-methylbenzoate (HPLC: 42.4% methyl 2-hydroxy-6-methylbenzoate, 51.0% methyl 2-methoxy-6-methylbenzoate) which was directly subjected to methylation reaction.
(3) Methylation of
100 g of the crude product of the methyl 2-hydroxy-6-methylbenzoate obtained in the step (2), dimethyl sulfate (58.5 g, 1.8 eq.) is added, the temperature is increased to 30-35 ℃, 30% sodium hydroxide solution (103.0 g, 3.0 eq.) is added dropwise, the temperature is controlled not to exceed 40 ℃, and after the addition is finished, the stirring is continued for 1 hour until the reaction is finished.
Standing for layering, separating an oil layer, and washing with water to obtain 102g of a crude product of methyl 2-methoxy-6-methylbenzoate. Vacuum distillation is carried out, the vacuum degree is controlled to be less than 100Pa, the gas phase temperature is controlled to be 104-
(4) Neutralization by hydrolysis
50 g of the crude 2-methoxy-6-methylbenzoic acid methyl ester obtained in the step (3), 37.8 g of sodium hydroxide solution (1.02 eq., concentration: 30%) and 100 g of water are added, the mixture is heated to 80-90 ℃ to react until the reaction is finished, the temperature of the reaction liquid is reduced to 50-60 ℃, 69.7 g of sulfuric acid (concentration: 20%) is added to adjust the pH to 1-2, after the addition is finished, the mixture is stirred for 1 hour under the condition of heat preservation, and the mixture is filtered and dried to obtain 44.6 g of the crude 2-methoxy-6-methylbenzoic acid (HPLC: 99.5%, yield: 96.6%).
Example 2
(1) Reductive hydrogenation
Adding 2-methyl-6-nitrobenzoic acid (450 g), platinum carbon (platinum content: 2%, 9.0 g) and methanol (1350 g) into a pressure kettle, replacing with nitrogen, introducing hydrogen pressure to 0.9-1.1 MPa, heating to 60-70 ℃, controlling the reaction pressure until the reaction is complete (raw material < 0.5%), continuing stirring for 30min, filtering while hot, dividing the mother liquor into three parts while hot, and directly performing diazotization hydrolysis.
(2) Diazotization hydrolysis
Cooling the reduction mother liquor (1/3 amount) obtained in the step (1) to 5-10 ℃, dropwise adding 317.3 g (mass concentration 40%, 1.2 eq.) of nitroso sulfuric acid at a controlled temperature, slowly heating to 50-60 ℃ after adding, controlling the heating time to be not less than 30min, stirring for 1 h, heating to 64-66 ℃ for reflux reaction for 12-16 h until the reaction is finished (HPLC: 2-hydroxy-6-methylbenzoic acid + 2-methoxy-6-methylbenzoic acid is less than 1%).
Heating to 85-100 ℃, distilling to recover about 360 g of methanol, adding 400 g of water, standing for layering, and separating out 110g of an oil layer.
The aqueous layer was extracted with 100ml of MTBE, the organic layer was separated and concentrated, and the resulting mixture was combined with the oil layer to obtain 135 g of crude methyl 2-hydroxy-6-methylbenzoate (HPLC: methyl 2-hydroxy-6-methylbenzoate: 56.25%, methyl 2-methoxy-6-methylbenzoate = 33.68%) which was directly subjected to methylation reaction.
(3) Methylation of
135 g of the crude product of methyl 2-hydroxy-6-methylbenzoate obtained in the step (2), dimethyl sulfate (74.9 g, 1.3 eq.), heating to 35-40 ℃, dropwise adding 30% sodium hydroxide solution (121.8 g, 2.0 eq.), controlling the temperature not to exceed 40 ℃, and continuing stirring for 1 hour after the addition is finished until the reaction is finished. Standing for layering, separating an oil layer, and washing with water to obtain 138g (HPLC: 91.5%) of crude methyl 2-methoxy-6-methylbenzoate.
Example 3
Diazotization hydrolysis
The temperature of the reducing mother liquor (1/3 wt.) obtained in the step (1) of the example 2 is reduced to 10-15 ℃, 277.6 g (40% by mass, 1.05 eq.) of sodium nitrite solution is dropwise added at a controlled temperature, after the addition is finished, the temperature is slowly increased to 50-60 ℃, and after stirring for 1 hour, the temperature is increased to 64-66 ℃ to carry out reflux reaction for 8-16 hours until the reaction is finished (HPLC: 2-hydroxy-6-methylbenzoic acid + 2-methoxy-6-methylbenzoic acid < 1%).
Heating to 85-100 ℃, distilling at normal pressure to recover about 360 g of methanol, adding 400 g of water, standing for layering, and separating out 105 g of oil layer.
The aqueous layer was extracted with 100ml of MIBK, the separated organic layer was concentrated and combined with the oil layer to give 141 g of crude methyl 2-hydroxy-6-methylbenzoate (HPLC: methyl 2-hydroxy-6-methylbenzoate: 45.6%; methyl 2-methoxy-6-methylbenzoate = 48.3%) which was directly subjected to methylation reaction.
Methylation of
Adding 41 g of the crude product of the 2-hydroxy-6-methyl benzoic acid methyl ester in the step into dimethyl sulfate (21.3 g,1.5 eq.), heating to 40-45 ℃, dropwise adding 30% sodium hydroxide solution (34.6 g, 2.3 eq.), controlling the temperature not to exceed 40 ℃, and continuing stirring for 1 hour after the addition is finished until the reaction is finished. The reaction solution is directly subjected to hydrolysis reaction.
Standing for layering, separating an oil layer, and washing with water to obtain 39g (HPLC: 95.7%) of crude methyl 2-methoxy-6-methylbenzoate.
Example 4
Diazotization hydrolysis
The temperature of the reducing mother liquor (1/3 wt.) obtained in the step (1) of the example 2 is reduced to 50-55 ℃, 290.87 g of sodium nitrite solution (40% by mass, 1.1 eq.) is dropwise added at a controlled temperature, after the addition is finished, the temperature is slowly increased to 50-60 ℃, and after stirring for 1 hour, the temperature is increased to 64-66 ℃ to carry out reflux reaction for 20-24 hours until the reaction is finished (HPLC: 2-hydroxy-6-methylbenzoic acid + 2-methoxy-6-methylbenzoic acid is less than 1%).
After the temperature was raised and about 360 g of methanol was recovered by atmospheric distillation, 330 g of water was added, and the mixture was allowed to stand for layering, thereby separating 102g of an oil layer.
The aqueous layer was extracted with 100ml of ethyl acetate, the organic layer was separated and concentrated, and the resulting mixture was combined with the oil layer to obtain 136 g of crude methyl 2-hydroxy-6-methylbenzoate (HPLC: methyl 2-hydroxy-6-methylbenzoate: 42.05%; methyl 2-methoxy-6-methylbenzoate = 45.59%) which was directly subjected to methylation reaction.
Methylation of
43.4 g of the crude 2-hydroxy-6-methyl benzoate obtained in the step is added with dimethyl sulfate (28.9 g, 2.2 eq.), heated to 30-40 ℃, added with 30% sodium hydroxide solution (55.5 g, 4.0 eq.) dropwise, controlled at the temperature not exceeding 40 ℃, and stirred for 1 hour continuously after the addition is finished until the reaction is finished.
Standing for layering, separating an oil layer, and washing with water to obtain 42 g (HPLC:95.8%) of crude methyl 2-methoxy-6-methylbenzoate.
Example 5
Distillation under reduced pressure
The crude methyl 2-methoxy-6-methylbenzoate obtained in example 2, example 3 and example 4 were combined (about 219 g), distilled under reduced pressure with the vacuum degree <100Pa and the steam temperature 105-
Neutralization by hydrolysis
Adding 74.7 g (1.01 eq., concentration: 30%) of sodium hydroxide solution and 200 g of water into 100 g of the crude 2-methoxy-6-methylbenzoic acid methyl ester obtained in the above steps, heating to 90-100 ℃ for reaction until the reaction is finished, cooling to 50-60 ℃, adding 136.3 g (concentration: 20%) of sulfuric acid at the controlled temperature to adjust the pH to 2-3, cooling to 20-30 ℃ after the addition is finished, keeping the temperature and stirring for 1 hour, filtering and drying to obtain 89.1 g (HPLC: 99.6%, yield: 96.6%) of the crude 2-methoxy-6-methylbenzoic acid.
Example 6
(1) Reductive hydrogenation
Adding 2-methyl-6-nitrobenzoic acid methyl ester (300 g), palladium carbon (palladium content: 2%, 15 g) and methanol (1500 g) into a pressure kettle, replacing by nitrogen, introducing hydrogen pressure to 0.5-0.7 MPa, heating to 90 ℃, controlling the temperature, controlling the reaction pressure until the reaction is complete (raw material < 0.5%), continuing stirring for 60 min, filtering while hot to recover the catalyst, and carrying out diazotization hydrolysis on the mother liquor.
(2) Diazotization hydrolysis
And (2) cooling the reducing solution obtained in the step (1) to 20-30 ℃, dropwise adding 498 g (1.02 eq. weight percentage: 40%) of nitroso sulfuric acid at a controlled temperature, slowly heating to 50-60 ℃ after adding, stirring for 1 hour, heating to 64-66 ℃, and carrying out reflux reaction for 20-24 hours until the reaction is finished (HPLC: 2-hydroxy-6-methylbenzoic acid + 2-methoxy-6-methylbenzoic acid is less than 1%). .
Heating to 85-100 deg.C, distilling under normal pressure to recover 545 g methanol, adding 900 g water, standing for layering, and separating oil layer.
The aqueous layer was extracted with 500ml of n-butyl acetate, the organic layer separated was concentrated and then combined with the oil layer to obtain 240 g of crude methyl 2-hydroxy-6-methylbenzoate (HPLC: 33.3% for methyl 2-hydroxy-6-methylbenzoate and 62.9% for methyl 2-methoxy-6-methylbenzoate) which was directly subjected to methylation reaction.
(3) Methylation of
125 g of the crude product of the methyl 2-hydroxy-6-methylbenzoate obtained in the step (2), adding dimethyl sulfate (50.5 g, 1.6 eq.), heating to 35-40 ℃, dropwise adding 30% sodium hydroxide solution (93.5 g, 2.8 eq.), controlling the temperature not to exceed 40 ℃, and continuing stirring for 1 hour after the addition is finished until the reaction is finished.
Standing for layering, separating an oil layer, and washing with water to obtain 126 g of a crude product of methyl 2-methoxy-6-methylbenzoate.
The obtained crude product is subjected to reduced pressure distillation under the conditions that the vacuum degree is controlled to be less than 100Pa, the steam temperature is controlled to be 105-109 ℃, and 100 g of product is collected (GC:99.6%)
(4) Neutralization by hydrolysis
50 g of the crude 2-methoxy-6-methylbenzoic acid methyl ester obtained in the step (3), 38.9 g of sodium hydroxide solution (1.05 eq., concentration: 30%) and 100 g of water are added, the mixture is heated to 80-90 ℃ to react until the reaction is finished, the temperature is reduced to 50-60 ℃, 139.3 g of sulfuric acid (concentration: 10%) is added to regulate the pH to 1-2 under the condition of controlling the temperature, after the addition is finished, the temperature is reduced to 20-30 ℃, the mixture is kept and stirred for 1 hour, and the mixture is filtered and dried to obtain 44.0 g of the crude 2-methoxy-6-methylbenzoic acid (HPLC: 99.8%, yield: 96.0%).
Example 7
(1) Reductive hydrogenation
Adding 2-methyl-6-nitrobenzoic acid methyl ester (50 g), platinum carbon (platinum content: 2%, 10 g) and methanol (250 g) into a pressure kettle, replacing by nitrogen, introducing hydrogen pressure to 1.3-1.5 MPa, heating to 80-90 ℃, controlling the reaction pressure until the reaction is complete (raw material < 0.5%), continuing stirring for 30min, filtering while hot to recover the catalyst, and directly carrying out diazotization hydrolysis on the mother liquor.
(2) Diazotization hydrolysis
And (2) cooling the reduction mother liquor obtained in the step (1) to 10-15 ℃, dropwise adding nitroso-tert-butyl ester (39.6 g,1.5 eq.) under controlled temperature, continuously stirring for 30min after the addition is finished, slowly heating to 50-60 ℃, stirring for 1 hour, adding 20 g of sulfuric acid, heating to 64-66 ℃, and carrying out reflux reaction for 8-16 hours until the reaction is finished (HPLC: 2-hydroxy-6-methylbenzoic acid + 2-methoxy-6-methylbenzoic acid is less than 1%).
Heating to 85-100 ℃, distilling at normal pressure to recover about 200 g of methanol, adding 120 g of water, standing for layering, and separating out an oil layer of 30 g.
The aqueous layer was extracted with 100ml of ethyl acetate, the organic layer was separated and concentrated, and then the mixture was combined with the oil layer to obtain 40 g of crude methyl 2-hydroxy-6-methylbenzoate (HPLC: 40.1% for methyl 2-hydroxy-6-methylbenzoate and 53.7% for methyl 2-methoxy-6-methylbenzoate), and the crude product was collected and directly subjected to methylation reaction.
Example 8
310 g of crude methyl 2-hydroxy-6-methylbenzoate (HPLC: 42.4% methyl 2-hydroxy-6-methylbenzoate, 51.0% methyl 2-methoxy-6-methylbenzoate) obtained in example 1 was subjected to distillation under reduced pressure, and 142 g of methyl 2-methoxy-6-methylbenzoate (GC:99.5%) was collected under the conditions of an absolute pressure of 80-100 Pa, a vapor temperature of 104-. Continuing to heat until the steam temperature reaches 120 ℃ and 130 ℃, and starting to collect 85 g (GC: 98.5%) of methyl 2-hydroxy-6-methylbenzoate; about 76 g of a mixed material of methyl 2-hydroxy-6-methylbenzoate and methyl 2-methoxy-6-methylbenzoate collected during the temperature rise (108 ℃ C.) and 120 ℃ C. (GC: 72.8% for methyl 2-hydroxy-6-methylbenzoate; 26.3% for methyl 2-methoxy-6-methylbenzoate).
Example 9
100 g of the crude methyl 2-methoxy-6-methylbenzoate obtained in example 8 was added with 75.0 g of a sodium hydroxide solution (1.01 eq., concentration: 30%) and 200 g of water, heated to 80-90 ℃ to complete the reaction, the reaction solution was cooled to 20-30 ℃, 103 g of hydrochloric acid (concentration: 20%) was added to adjust the pH to 1-2, and after the addition was completed, stirring was carried out under constant temperature for 1 hour, followed by filtration and drying at 90-110 ℃ to obtain 87.8 g of 2-methoxy-6-methylbenzoic acid (HPLC: 99.8%, yield: 95.3%).
Example 10
50 g of a mixture of methyl 2-hydroxy-6-methylbenzoate and methyl 2-methoxy-6-methylbenzoate (GC: 72.8% of methyl 2-hydroxy-6-methylbenzoate; 26.3% of methyl 2-methoxy-6-methylbenzoate), dimethyl sulfate (44.2 g, 1.6 eq.), 30% liquid alkali (2.5 eq, 73.1 g) dropwise at a temperature of 30-40 ℃ with stirring for about 0.5-1.5 h, and stirring is continued until the amount of methyl 2-hydroxy-6-methylbenzoate is less than 1%.
Standing for layering, separating an oil layer, washing with water to obtain 48 g (HPLC:95.6%) of crude methyl 2-methoxy-6-methylbenzoate, and distilling under reduced pressure to obtain 35 g (GC:99.6%) of methyl 2-methoxy-6-methylbenzoate.
Claims (14)
1. A synthesis process of 2-methoxy-6-methylbenzoic acid is characterized by comprising the following steps:
reduction hydrogenation reaction: using 2-methyl-6-nitrobenzoic acid or 2-methyl-6-nitrobenzoic acid methyl ester as a raw material, methanol as a solvent, hydrogen as a hydrogen source, palladium carbon or platinum carbon as a catalyst, and preparing a 2-amino-6-methylbenzoic acid or 2-amino-6-methylbenzoic acid methyl ester reducing substance by hydrogenation reduction;
diazotization, hydrolysis and esterification one-pot reaction: carrying out diazotization, hydrolysis and esterification reaction under the action of a diazotization reagent by taking a reduced substance as a raw material and methanol as a solvent to prepare 2-hydroxy-6-methyl benzoate;
methylation reaction: using the obtained 2-hydroxy-6-methyl benzoate as a raw material, using dimethyl sulfate as a methylation reagent, and carrying out methylation reaction in the presence of alkali to prepare 2-methoxy-6-methyl benzoate;
(4) and (3) hydrolysis reaction: mixing and stirring 2-methoxy-6-methyl benzoic acid methyl ester, alkali and water, heating to react until hydrolysis reaction is completed, adjusting pH to 1-3 with acid to separate out a product, filtering, and drying to obtain 2-methoxy-6-methyl benzoic acid;
the reaction equation is as follows:
the diazotization reagent in the step (2) is nitroso sulfuric acid or nitrous acid ester.
2. The process for synthesizing 2-methoxy-6-methylbenzoic acid according to claim 1, which is characterized in that: in the one-pot reaction in the step (2), the nitrite ester is nitrite ester formed by alcohol with 1-5 carbon atoms.
3. The process for synthesizing 2-methoxy-6-methylbenzoic acid according to claim 1, which is characterized in that: the reduction hydrogenation reaction in the step (1) is carried out at the temperature of 60-90 ℃ and under the hydrogen pressure of 0.5-1.5 MPa, and the reaction is stopped until the content of the raw material is less than 0.5%.
4. The process for synthesizing 2-methoxy-6-methylbenzoic acid according to claim 1, which is characterized in that: and (3) carrying out one-pot reaction in the step (2), wherein the temperature of the diazotization reagent dropwise added is 0-15 ℃, and after the dropwise addition is finished, the reaction is carried out for 4-16 h at the temperature of 50-66 ℃.
5. The process for synthesizing 2-methoxy-6-methylbenzoic acid according to claim 1, which is characterized in that: the reaction temperature of the methylation reaction in the step (3) is 30-45 ℃, and the reaction time is 1-2 hours; the temperature of the hydrolysis reaction in the step (4) is 80-100 ℃.
6. The process for synthesizing 2-methoxy-6-methylbenzoic acid according to claim 1, which is characterized in that: in the reduction hydrogenation reaction in the step (1), the weight ratio of the raw material to the catalyst is 1: 0.02 to 0.2; the weight ratio of the raw materials to the methanol is 1: 3 to 15.
7. The process for synthesizing 2-methoxy-6-methylbenzoic acid according to claim 1, which is characterized in that: in the step (2), in one-pot reaction, the molar ratio of the reducing substance to the diazotization reagent is 1: 1.02-1.5.
8. The process for synthesizing 2-methoxy-6-methylbenzoic acid according to claim 1, which is characterized in that: in the methylation reaction in the step (3), the molar ratio of the raw material to the dimethyl sulfate is 1: 1.3-2.20, and the molar weight of the alkali is 1.5-1.8 times of that of the dimethyl sulfate.
9. The process for synthesizing 2-methoxy-6-methylbenzoic acid according to claim 1, which is characterized in that: in the hydrolysis reaction in the step (4), the molar ratio of the methyl 2-methoxy-6-methylbenzoate to the alkali is 1: 1.01-1.05.
10. The process for synthesizing 2-methoxy-6-methylbenzoic acid according to claim 1, which is characterized in that: in the step (3) or (4), the alkali is one or a mixture of more than two of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; in the step (4), the acid is sulfuric acid or hydrochloric acid, and the mass concentration of the acid is 10-30%.
11. The process for synthesizing 2-methoxy-6-methylbenzoic acid according to claim 1, which is characterized in that: after the one-pot reaction in the step (2) is finished, after the solvent is recovered from the reaction solution by distillation, washing and layering to obtain a crude product of 2-hydroxy-6-methyl benzoate, which is a mixture of 2-hydroxy-6-methyl benzoate and 2-methoxy-6-methyl benzoate.
12. The process for synthesizing 2-methoxy-6-methylbenzoic acid according to claim 11, which comprises the following steps: the mixture of the 2-hydroxy-6-methyl benzoate and the 2-methoxy-6-methyl benzoate can directly enter the next step for methylation reaction, or the mixture of the 2-methoxy-6-methyl benzoate and the 2-hydroxy-6-methyl benzoate can be separated by reduced pressure distillation;
the methyl 2-hydroxy-6-methylbenzoate obtained by distillation and separation is subjected to demethylation, and then is subjected to hydrolysis to prepare 2-methoxy-6-methylbenzoic acid; the methyl 2-methoxy-6-methylbenzoate obtained by distillation and separation is directly subjected to hydrolysis step to prepare 2-methoxy-6-methylbenzoic acid.
13. The process for synthesizing 2-methoxy-6-methylbenzoic acid according to claim 6, which is characterized in that: and (3) filtering the catalyst from the reduction hydrogenation reaction liquid in the step (1), and directly using the filtrate in the step (2).
14. The process for synthesizing 2-methoxy-6-methylbenzoic acid according to claim 1, which is characterized in that: the steps (3) to (4) further comprise a post-treatment step.
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| CN102351707A (en) * | 2011-11-18 | 2012-02-15 | 苏州诚和医药化学有限公司 | Method for preparing methyl o-anisate |
| CN105272925A (en) * | 2015-11-25 | 2016-01-27 | 常州大学 | Preparation method of paddy field herbicide pyriminobac-methyl |
| CN109384667A (en) * | 2017-08-02 | 2019-02-26 | 江苏永安化工有限公司 | A kind of synthesis technology of 2- methyl -3- methoxy benzoyl chloride |
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| CN102351707A (en) * | 2011-11-18 | 2012-02-15 | 苏州诚和医药化学有限公司 | Method for preparing methyl o-anisate |
| CN105272925A (en) * | 2015-11-25 | 2016-01-27 | 常州大学 | Preparation method of paddy field herbicide pyriminobac-methyl |
| CN109384667A (en) * | 2017-08-02 | 2019-02-26 | 江苏永安化工有限公司 | A kind of synthesis technology of 2- methyl -3- methoxy benzoyl chloride |
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| CN114989025A (en) * | 2022-05-30 | 2022-09-02 | 沈阳万菱生物技术有限公司 | Preparation method of 2-amino-6-methyl benzoate |
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