CN115784846A - Preparation method of 2,6-dihydroxytoluene - Google Patents
Preparation method of 2,6-dihydroxytoluene Download PDFInfo
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- CN115784846A CN115784846A CN202211505345.3A CN202211505345A CN115784846A CN 115784846 A CN115784846 A CN 115784846A CN 202211505345 A CN202211505345 A CN 202211505345A CN 115784846 A CN115784846 A CN 115784846A
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- Prior art keywords
- dihydroxytoluene
- methyl
- producing
- nitrophenol
- aminophenol
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- ZTMADXFOCUXMJE-UHFFFAOYSA-N 2-methylbenzene-1,3-diol Chemical compound CC1=C(O)C=CC=C1O ZTMADXFOCUXMJE-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 13
- GAKLFAZBKQGUBO-UHFFFAOYSA-N 2-methyl-3-nitrophenol Chemical compound CC1=C(O)C=CC=C1[N+]([O-])=O GAKLFAZBKQGUBO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 12
- FLROJJGKUKLCAE-UHFFFAOYSA-N 3-amino-2-methylphenol Chemical compound CC1=C(N)C=CC=C1O FLROJJGKUKLCAE-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000007062 hydrolysis Effects 0.000 claims abstract description 10
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 8
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 14
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 7
- 235000010288 sodium nitrite Nutrition 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 3
- 238000006722 reduction reaction Methods 0.000 claims description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000003963 antioxidant agent Substances 0.000 abstract description 3
- 230000003078 antioxidant effect Effects 0.000 abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 235000013824 polyphenols Nutrition 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- ZUVPLKVDZNDZCM-UHFFFAOYSA-N 3-chloro-2-methylaniline Chemical compound CC1=C(N)C=CC=C1Cl ZUVPLKVDZNDZCM-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241001122767 Theaceae Species 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- -1 dyeing Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 150000008442 polyphenolic compounds Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- GXPIVRKDWZKIKZ-UHFFFAOYSA-N 1-fluoro-2-methyl-3-nitrobenzene Chemical compound CC1=C(F)C=CC=C1[N+]([O-])=O GXPIVRKDWZKIKZ-UHFFFAOYSA-N 0.000 description 1
- XCSNRORTQRKCHB-UHFFFAOYSA-N 2-chloro-6-nitrotoluene Chemical compound CC1=C(Cl)C=CC=C1[N+]([O-])=O XCSNRORTQRKCHB-UHFFFAOYSA-N 0.000 description 1
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 1
- NHMJKYVPXYBHSL-UHFFFAOYSA-N 3-hydroxy-2-methylcyclohex-2-en-1-one Chemical compound CC1=C(O)CCCC1=O NHMJKYVPXYBHSL-UHFFFAOYSA-N 0.000 description 1
- WBZRSFDJNJXREC-UHFFFAOYSA-N Cl[Cl]Cl Chemical compound Cl[Cl]Cl WBZRSFDJNJXREC-UHFFFAOYSA-N 0.000 description 1
- 241000594402 Damnacanthus Species 0.000 description 1
- QCWPXJXDPFRUGF-UHFFFAOYSA-N N1C=2C=C(N=3)C=CC=3C=C(N3)C=CC3=CC(=N3)C=CC3=CC1=CC=2C1=CC=CC=C1 Chemical class N1C=2C=C(N=3)C=CC=3C=C(N3)C=CC3=CC(=N3)C=CC3=CC1=CC=2C1=CC=CC=C1 QCWPXJXDPFRUGF-UHFFFAOYSA-N 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- UDEGSYXELBQAAG-UHFFFAOYSA-N azanium;methanol;chloride Chemical compound [NH4+].[Cl-].OC UDEGSYXELBQAAG-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000118 hair dye Substances 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000011755 sodium-L-ascorbate Substances 0.000 description 1
- 235000019187 sodium-L-ascorbate Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 2,6-dihydroxytoluene, belonging to the technical field of organic synthesis. The method takes 2-fluoro/chloro-6-nitrotoluene as a raw material, hydrolyzes under the action of potassium hydroxide and an antioxidant to obtain 2-methyl-3-nitrophenol, then adds a reducing agent to reduce nitro to obtain 2-methyl-3-aminophenol, and finally carries out diazotization hydrolysis to obtain 2, 6-dihydroxytoluene.
Description
Technical Field
The invention relates to a preparation method of 2,6-dihydroxytoluene, belonging to the technical field of organic synthesis.
Background
2,6-dihydroxytoluene, CAS:608-25-3, english name: 2,6-Dihydroxytoluene contains two meta-phenolic hydroxyl groups and one ortho-methyl group, can be subjected to different modifications, has special physical and chemical properties, is an important chemical raw material, and has very important application in the chemical field, such as synthetic resin, dyeing, medicines, pesticides, pigments, dyes, hair dyes, agricultural chemicals, catalytic application, photosensitive materials, explosives and the like. Such as 2,6-dihydroxytoluene and phthalic anhydride, to obtain anthraquinone compounds, and then modifying the hydroxyl and methyl thereof to synthesize the antitumor drug damnacanthus brevis essence; for example, 2,6-dihydroxytoluene is used as a raw material to synthesize a series of phenyl porphyrin compounds applied to high molecular materials, molecular targeted drugs, chemical catalysis and the like; derivatives such as 2,6-dihydroxytoluene are also used in large quantities in shampoos, skin-care products and the like.
The literature [ Chemical Science,2015, vol.6, #8, p.4674-4680] uses 2-methyl-1, 3-cyclohexanedione as a raw material, obtained in 92% yield by catalytic hydrogenation and dehydrogenation in Pd/C, which is more expensive than the product, and uses a Pd/C expensive catalyst, which is too costly. The reaction equation is as follows:
at present, the relatively economic synthesis method comprises the introduction of phenolic hydroxyl (such as halogen high-temperature hydrolysis CN113698276,2021, A and the like or amino diazotization hydrolysis CN114085132,2022, A) or the introduction of methyl (such as methanol ammonium chloride high-temperature high-pressure methylation CN106554255,2017, A), but the reaction has the defects of limitation, poor selectivity, low yield, difficult purification and high requirement on equipment.
Patent CN104341275,2016, B reports that 3-chloro-2-methylaniline is used as a raw material, one of the phenolic hydroxyl groups is introduced by diazotization hydrolysis of amino group, and the other phenolic hydroxyl group is introduced by halogen high-temperature hydrolysis, so that the method has relatively high yield and high purity of the obtained product, but the temperature needs 190-200 ℃ in the halogen high-temperature hydrolysis process, and the requirement on equipment is high. The reaction equation is as follows:
in view of the above problems, there is a need to provide a novel process, which has relatively low reaction temperature, relatively safe operation, stable process and high product purity, and avoids the problems of poor reaction selectivity, high equipment requirement, and the like, so as to meet the increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the invention provides an improved preparation method of 2, 6-dihydroxytoluene. The method comprises the steps of taking 2-fluoro/chloro-6-nitrotoluene as a raw material, hydrolyzing under the action of potassium hydroxide and an antioxidant to obtain 2-methyl-3-nitrophenol, then adding a reducing agent to reduce nitro to obtain 2-methyl-3-aminophenol, and finally diazotizing and hydrolyzing to obtain 2, 6-dihydroxytoluene.
The preparation method of 2,6-dihydroxytoluene comprises the following steps:
a first step of hydrolysis reaction: mixing the 2-fluoro/chloro-6-nitrotoluene with an organic solvent, dropwise adding a potassium hydroxide aqueous solution, and reacting at a raised temperature to obtain 2-methyl-3-nitrophenol;
and a second step of reduction reaction: mixing the 2-methyl-3-nitrophenol with an organic solvent, heating, and adding a reducing agent in batches for reaction to obtain 2-methyl-3-aminophenol;
the third step is diazotization hydrolysis: mixing 2-methyl-3-aminophenol with dilute sulfuric acid, adding sodium nitrite in batches, adding a quenching reagent to quench redundant sodium nitrite, and adding concentrated sulfuric acid to raise the temperature and hydrolyze to obtain 2, 6-dihydroxytoluene.
Further, in the above technical solution, in the first step, the organic solvent is selected from isopropanol, dioxane, dimethyl sulfoxide or sulfolane.
Further, in the above technical solution, in the first step, the aqueous solution of potassium hydroxide is selected from a 30-50% aqueous solution of sodium hydroxide.
Further, in the above technical scheme, in the first step, 0.01-0.02eq antioxidant (such as sodium L-ascorbate or tea polyphenol) relative to the main raw material of 2-fluoro/chloro-6-nitrotoluene is additionally added for safe operation.
Further, in the above technical scheme, in the first step, the molar ratio of the 2-fluoro/chloro-6-nitrotoluene to the potassium hydroxide is 1:2.5-3.5.
Further, in the above technical solution, in the second step, the reducing agent is selected from iron powder or zinc powder.
Further, in the above technical solution, in the second step, the organic solvent is selected from acetic acid and/or ethanol.
Further, in the above technical solution, in the second step, the molar ratio of the 2-methyl-3-nitrophenol to the reducing agent is 1:3.5-4.5.
Further, in the above technical solution, in the third step, the quenching reagent is selected from urea or sulfamic acid.
Further, in the above technical solution, in the third step, the molar ratio of the 2-methyl-3-aminophenol, the sodium nitrite and the dilute sulfuric acid is 1:1.05-1.08:4.0-5.0.
Advantageous effects of the invention
A. The 2-halogen-6-nitrotoluene contains strong electron-withdrawing groups such as nitro, and the hydrolysis of halogen is a nucleophilic substitution reaction, so that the hydrolysis is relatively easier to perform, and the reaction has relatively low requirements on reaction temperature, does not need harsh conditions such as high pressure and has low requirements on equipment.
B. The method adopts iron powder or zinc powder for reduction, has high yield, simple and mature process, low requirement on equipment, good performability and no need of high-pressure reaction.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Synthesis of 2,6-dihydroxytoluene
Example 1
155g (1 mol) of 2-fluoro-6-nitrotoluene, 15.5g of tetrabutylammonium bromide, 2.0g (0.01 mol) of L-sodium ascorbate and 900mL of isopropanol are added into a reaction kettle and stirred uniformly, the temperature is raised to 60 ℃, 280.6g (2.5 mol) of 50% potassium hydroxide aqueous solution is added dropwise, the temperature is raised and the reflux is carried out for 8 hours after the dropwise addition is finished, the temperature is lowered to room temperature, 4mol/L hydrochloric acid aqueous solution is added to adjust the pH value to be =4-5, most of the isopropanol is evaporated through concentration under reduced pressure, a large amount of solid is separated out, the filtration is carried out, a filter cake is leached by water and n-heptane, and the 2-methyl-3-nitrophenol 137.2g is obtained after drying, the yield is 89.6% and the HPLC is 94.8%. 1 HNMR(400MHz,DMSO-d 6 )δ:10.29(s,1H),7.31-7.27(m,1H),7.22-7.17(m,1H),7.12-7.07(m,1H),2.23(s,2H).
Example 2
Adding 171.6g (1 mol) of 2-chloro-6-nitrotoluene, 2.8g (0.01 mol) of tea polyphenol and 850mL of sulfolane into a reaction kettle, uniformly stirring, heating to 60 ℃, dropwise adding 370.3g (3.3 mol) of 50% potassium hydroxide aqueous solution, heating to 130-135 ℃ after dropwise adding, reacting for 12 hours, cooling to room temperature, adding 0.5mol/L potassium bisulfate aqueous solution to adjust the pH to be =5-6, separating out a large amount of solids, filtering, leaching a filter cake with water and n-heptane, and drying to obtain 127.4g of 2-methyl-3-nitrophenol, wherein the yield is 83.2% and the HPLC is 96.5%.
Example 3
Under the protection of nitrogen, 122.5g (0.8 mol) of 2-methyl-3-nitrophenol, 144g (2.4 mol) of glacial acetic acid and 1200mL of 90% ethanol are added into a reaction kettle with strong stirring, after stirring and dissolving, the temperature is controlled to be 20-35 ℃, 178.7g (3.2 mol) of iron powder is added in batches, after the addition is finished, the reaction is carried out for 1h, the filtration is carried out, 1mol/L sodium hydroxide aqueous solution is added into the filtrate to adjust the pH to be =7.0, the ethanol is evaporated by decompression concentration, and dichloro-chlorine is addedStirring methane and water, layering, keeping an organic phase, washing the organic phase by using a saturated sodium chloride aqueous solution, concentrating the organic phase under reduced pressure, adding n-heptane to separate out a solid, filtering, and drying a filter cake to obtain 89.9g of 2-methyl-3-aminophenol, wherein HPLC97.5 percent and the yield is 91.2 percent. 1 HNMR(400MHz,CD 3 OD)δ:6.77-6.73(m,1H),6.28-6.26(m,1H),6.21-6.19(m,1H),2.01(s,3H).
Example 4
Under the protection of nitrogen, 122.5g (0.8 mol) of 2-methyl-3-nitrophenol, 1000mL of glacial acetic acid and 200mL of water are added into a reaction kettle with strong stirring, after stirring and dissolving, the temperature is controlled to be 20-35 ℃, 198.8g (3.04 mol) of zinc powder is added in batches, after the addition, reaction is carried out for 2h, chlorobenzene is added for extraction, the extract is concentrated under reduced pressure to remove most of acetic acid, 1mol/L sodium hydroxide aqueous solution is used for adjusting the pH to be =7.0, dichloromethane and water are added for stirring, layering is carried out, an organic phase is reserved, the organic phase is washed by saturated sodium chloride aqueous solution, the organic phase is concentrated under reduced pressure, n-heptane is added for precipitating solids, filtration is carried out, and a filter cake is dried to obtain 84.4g of 2-methyl-3-aminophenol, HPLC95.7 percent and the yield is 85.7 percent.
Example 5
Adding 61.6g (0.5 mol) of 2-methyl-3-aminophenol and 882g (2.25 mol) of 25% sulfuric acid aqueous solution into a reaction kettle under the protection of nitrogen, mixing, cooling to 0 ℃, adding 200g of ice cream, adding 36.2g (0.525 mol) of sodium nitrite in batches, adding 2g of urea after the addition is finished and reacting for 1.5 hours, stirring for 10 minutes, adding 15g of 97% sulfuric acid, slowly heating to 85-90 ℃, reacting for 2 hours, detecting the completion of the reaction by TLC, cooling to room temperature, adding dichloromethane, layering, extracting an aqueous phase by using dichloromethane, combining organic phases, washing by using saturated sodium chloride aqueous solution, evaporating dichloromethane by using organic phase under pressure, adding 350mL of toluene, 0.5g of sodium thiosulfate, 1mL of concentrated hydrochloric acid and 5g of activated carbon, and heating to obtain the mixtureRefluxing at a high temperature for 1 hour, carrying out hot filtration, slowly cooling the filtrate to precipitate a large amount of product, filtering, and drying to obtain a white-like solid 2,6-dihydroxytoluene 52.1g, HPLC99.7% and a yield of 83.9%. 1 HNMR(400MHz,CDCl 3 )δ:9.41(s,2H),7.37-6.84(m,2H),6.45-6.13(m,1H),2.13(s,3H).
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered as the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (9)
1. A preparation method of 2,6-dihydroxytoluene is characterized by comprising the following steps:
a first step of hydrolysis reaction: mixing the 2-fluoro/chloro-6-nitrotoluene with an organic solvent, dropwise adding a potassium hydroxide aqueous solution, and reacting at a high temperature to obtain 2-methyl-3-nitrophenol;
and a second step of reduction reaction: mixing the 2-methyl-3-nitrophenol with an organic solvent, heating, and adding a reducing agent in batches for reaction to obtain 2-methyl-3-aminophenol;
thirdly, diazotization hydrolysis: mixing 2-methyl-3-aminophenol with dilute sulfuric acid, adding sodium nitrite in batches, adding a quenching reagent to quench redundant sodium nitrite, and adding concentrated sulfuric acid to raise the temperature and hydrolyze to obtain the 2, 6-dihydroxytoluene.
2. The process for producing 2,6-dihydroxytoluene according to claim 1, characterized in that: in the first step, the organic solvent is selected from isopropanol, dioxane, dimethyl sulfoxide or sulfolane.
3. The method of producing 2,6-dihydroxytoluene according to claim 1, wherein: in the first step, the aqueous potassium hydroxide solution is selected from 30-50% aqueous sodium hydroxide solution.
4. The method for producing 2,6-dihydroxytoluene according to claim 1, characterized in that: in the first step, the molar ratio of the 2-fluoro/chloro-6-nitrotoluene to the potassium hydroxide is 1:2.5-3.5.
5. The method for producing 2,6-dihydroxytoluene according to claim 1, characterized in that: in the second step, the reducing agent is selected from iron powder or zinc powder.
6. The process for producing 2,6-dihydroxytoluene according to claim 1, characterized in that: in the second step, the organic solvent is selected from acetic acid and/or ethanol.
7. The process for producing 2,6-dihydroxytoluene according to claim 1, characterized in that: in the second step, the molar ratio of the 2-methyl-3-nitrophenol to the reducing agent is 1:3.5-4.5.
8. The process for producing 2,6-dihydroxytoluene according to claim 1, characterized in that: in the third step, the quenching reagent is selected from urea or sulfamic acid.
9. The method for producing 2,6-dihydroxytoluene according to claim 1, characterized in that: in the third step, the molar ratio of the 2-methyl-3-aminophenol, the sodium nitrite and the dilute sulfuric acid is 1:1.05-1.08:4.0-5.0.
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