CN115784846B - Preparation method of 2,6-dihydroxytoluene - Google Patents
Preparation method of 2,6-dihydroxytoluene Download PDFInfo
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- nitrophenol
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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 26
- 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 29
- 238000000034 method Methods 0.000 claims abstract description 14
- 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
- FLROJJGKUKLCAE-UHFFFAOYSA-N 3-amino-2-methylphenol Chemical compound CC1=C(N)C=CC=C1O FLROJJGKUKLCAE-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 8
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 4
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 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
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 230000003301 hydrolyzing effect Effects 0.000 claims description 7
- 235000010288 sodium nitrite Nutrition 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- 235000013824 polyphenols Nutrition 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
- 230000000171 quenching effect Effects 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 241001122767 Theaceae Species 0.000 claims description 3
- 235000006708 antioxidants Nutrition 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 150000008442 polyphenolic compounds Chemical class 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
- 238000010438 heat treatment Methods 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
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 2
- 229960005055 sodium ascorbate Drugs 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 239000000047 product Substances 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
- 230000007062 hydrolysis Effects 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- -1 dyeing Substances 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
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 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
- 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 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 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
- DJSISFGPUUYILV-UHFFFAOYSA-N UNPD161792 Natural products O1C(C(O)=O)C(O)C(O)C(O)C1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC(O)=CC=1)O2 DJSISFGPUUYILV-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000003277 amino group Chemical group 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000001514 detection method 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
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000118 hair dye Substances 0.000 description 1
- 239000000463 material Substances 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
- 239000002861 polymer material Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 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
- 229920006395 saturated elastomer Polymers 0.000 description 1
- DJSISFGPUUYILV-ZFORQUDYSA-N scutellarin Chemical compound O1[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC(O)=CC=1)O2 DJSISFGPUUYILV-ZFORQUDYSA-N 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 239000011780 sodium chloride Substances 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
Abstract
The invention discloses a preparation method of 2,6-dihydroxytoluene, and belongs to the technical field of organic synthesis. The method takes 2-fluoro/chloro-6-nitrotoluene as raw material, hydrolyzes under the action of potassium hydroxide and antioxidant to obtain 2-methyl-3-nitrophenol, then reduces nitro group by adding reducing agent to obtain 2-methyl-3-aminophenol, and finally diazotizes and hydrolyzes 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: the 2,6-Dihydroxytoluene contains two meta-phenolic hydroxyl groups and one ortho-methyl group, can be modified differently, has special physicochemical 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, agrochemicals, catalysis application, photosensitive materials, explosive and the like. For example, 2,6-dihydroxytoluene and phthalic anhydride undergo a Friedel-crafts reaction to obtain anthraquinone compounds, and then hydroxyl and methyl groups of the anthraquinone compounds are modified to synthesize antitumor drugs of the breviscapine; for example, a series of phenyl porphyrin compounds applied to high polymer materials, molecular targeted drugs, chemical catalysis and the like are synthesized by taking 2,6-dihydroxytoluene as a raw material; derivatives such as 2,6-dihydroxytoluene are also used in a large amount 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, and is obtained by catalytic hydrogenation and dehydrogenation of Pd/C, the yield is 92%, the raw material is more expensive than the product, and the cost is too high due to the use of Pd/C as an expensive catalyst. The reaction equation is as follows:
at present, the relatively economical synthesis method comprises the steps of introducing phenolic hydroxyl groups (such as halogen high-temperature hydrolysis CN113698276,2021, A and the like or amino diazotization hydrolysis CN114085132,2022, A) or introducing methyl groups (such as methanol ammonium chloride high-temperature high-pressure methylation reaction CN106554255,2017, A), but the reaction is limited, the selectivity is poor, the yield is low, the purification is difficult, and the requirement on equipment is high.
Patent CN104341275,2016, B reports that 3-chloro-2-methylaniline is adopted as a raw material, one of phenolic hydroxyl groups is introduced by diazotizing and hydrolyzing the amino group, and the other phenolic hydroxyl group is introduced by hydrolyzing halogen with high temperature, so that the yield of the method is relatively high, the purity of the obtained product is high, but in the process of hydrolyzing the halogen with high temperature of 190-200 ℃ and high equipment requirement. The reaction equation is as follows:
in view of the above, it is necessary to provide a new process, which has relatively low reaction temperature, relatively safe operation, stable process, high product purity, and avoids the problems of poor reaction selectivity, high equipment requirement, and the like in the above problems, thereby meeting the increasing market demands.
Disclosure of Invention
In order to overcome the technical defects, the invention provides an improved preparation method of 2, 6-dihydroxytoluene. 2-fluoro/chloro-6-nitrotoluene is taken as a raw material, the raw material is hydrolyzed under the action of potassium hydroxide and an antioxidant to obtain 2-methyl-3-nitrophenol, then a reducing agent is added to reduce nitro to obtain 2-methyl-3-aminophenol, and finally diazotization and hydrolysis are carried out to obtain 2, 6-dihydroxytoluene.
The preparation method of the 2,6-dihydroxytoluene comprises the following steps:
the first step of hydrolysis reaction: mixing 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 step two, reduction reaction: mixing 2-methyl-3-nitrophenol with an organic solvent, and adding a reducing agent in batches at a temperature rise to react to obtain 2-methyl-3-aminophenol;
and thirdly, diazotizing and hydrolyzing: mixing 2-methyl-3-aminophenol with dilute sulfuric acid, adding sodium nitrite in batches, adding a quenching reagent to quench excess sodium nitrite, adding concentrated sulfuric acid, heating and hydrolyzing to obtain 2, 6-dihydroxytoluene.
Further, in the above technical scheme, in the first step, the organic solvent is selected from isopropanol, dioxane, dimethyl sulfoxide or sulfolane.
Further, in the above technical scheme, in the first step, the potassium hydroxide aqueous solution is selected from 30-50% sodium hydroxide aqueous solution.
Further, in the above technical scheme, in the first step, for the safety of the operation, 0.01-0.02eq of an antioxidant (e.g., sodium L-ascorbate or tea polyphenol) is additionally added relative to the main raw material 2-fluoro/chloro-6-nitrotoluene.
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 scheme, in the second step, the reducing agent is selected from iron powder or zinc powder.
Further, in the above technical scheme, in the second step, the organic solvent is selected from acetic acid and/or ethanol.
Further, in the above technical scheme, 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 scheme, in the third step, the quenching reagent is selected from urea or sulfamic acid.
Further, in the above technical scheme, in the third step, the molar ratio of the 2-methyl-3-aminophenol, sodium nitrite and 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 nucleophilic substitution reaction, so that the hydrolysis is relatively easier to carry out, the reaction has relatively low requirements on the reaction temperature, and the high-pressure harsh conditions are not needed, so that the requirement on equipment is low.
B. The method adopts iron powder or zinc powder for reduction, has high yield, simple and mature process, low equipment requirement and good performability, and does not need high-pressure reaction.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples should be construed as merely illustrative of the present invention and not limiting the scope of the present invention. Various changes and modifications to the present invention may be made by one skilled in the art after reading the description herein, and such equivalent changes and modifications are intended to fall within the scope of the present invention as defined in the appended 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, the mixture is stirred uniformly, the temperature is raised to 60 ℃, 280.6g (2.5 mol) of 50% potassium hydroxide aqueous solution is dropwise added, the mixture is heated and refluxed for 8 hours after the completion of the dropwise addition, the temperature is reduced to room temperature, 4mol/L of hydrochloric acid aqueous solution is added to adjust the pH to be 4-5, the mixture is concentrated under reduced pressure to evaporate most of the isopropanol, a large amount of solids are separated out, the mixture is filtered, a filter cake is leached by water and n-heptane, 137.2g of 2-methyl-3-nitrophenol is obtained after the 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
171.6g (1 mol) of 2-chloro-6-nitrotoluene, 2.8g (0.01 mol) of tea polyphenol and 850mL of sulfolane are added into a reaction kettle and evenly stirred, the temperature is raised to 60 ℃, 370.3g (3.3 mol) of 50% potassium hydroxide aqueous solution is added dropwise, the temperature is raised to 130-135 ℃ after the completion of the dropwise addition and reacted for 12 hours, the temperature is lowered to room temperature, 0.5mol/L potassium hydrogen sulfate aqueous solution is added to adjust the pH to be 5-6, a large amount of solids are separated out, the filtration is carried out, the filter cake is leached by water and n-heptane, 127.4g of 2-methyl-3-nitrophenol is obtained after drying, 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 clearing, 178.7g (3.2 mol) of iron powder is added in batches at the temperature of 20-35 ℃, 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 regulate pH to 7.0, the ethanol is evaporated by decompression concentration, methylene dichloride and water are added, stirring is carried out, 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 decompression, n-heptane is added to precipitate solids, the filtration is carried out, and a filter cake is dried to obtain 89.9g of 2-methyl-3-aminophenol, HPLC97.5% and the yield is 91.2%. 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 clearing, 198.8g (3.04 mol) of zinc powder is added in batches at a temperature of 20-35 ℃, after the reaction is finished, 2h of reaction is carried out, chlorobenzene is added for extraction, the extract is concentrated under reduced pressure to evaporate most of acetic acid, 1mol/L aqueous sodium hydroxide solution is used for adjusting pH to 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 aqueous sodium chloride solution, the organic phase is concentrated under reduced pressure, n-heptane is added for separating out solids, filtration and a filter cake is dried to obtain 84.4g of 2-methyl-3-aminophenol, HPLC95.7% and the yield is 85.7%.
Example 5
Under the protection of nitrogen, 61.6g (0.5 mol) of 2-methyl-3-aminophenol and 882g (2.25 mol) of 25% sulfuric acid aqueous solution are added into a reaction kettle and mixed, the temperature is reduced to 0 ℃, 200g of ice is added, 36.2g (0.525 mol) of sodium nitrite is added in batches, urea is added after the addition is completed for 1.5 hours, stirring is carried out for 10 minutes, 15g of 97% sulfuric acid is added, the temperature is slowly increased to 85-90 ℃ for 2 hours, TLC detection reaction is complete, the temperature is reduced to room temperature, dichloromethane is added, layering, aqueous phase is extracted by dichloromethane, organic phase is combined, the organic phase is washed by saturated sodium chloride aqueous solution, the dichloromethane is distilled off under reduced pressure, 350mL of toluene, 0.5g of sodium thiosulfate, 1mL of concentrated hydrochloric acid and 5g of active carbon are added, reflux is carried out for 1 hour, a great amount of product is separated out by slow temperature reduction of filtrate, and the product is filtered, and the product is dried to obtain white-like solid 2,6-dihydroxytoluene 52.1g, HPLC99.7%, the yield is 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 foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should be covered by the protection scope of the present invention by making equivalents and modifications to the technical solution and the inventive concept thereof.
Claims (8)
1. The preparation method of the 2,6-dihydroxytoluene is characterized by comprising the following steps:
the first step of hydrolysis reaction: mixing 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; in the step, 0.01-0.02eq of antioxidant L-sodium ascorbate or tea polyphenol relative to the main raw material 2-fluoro/chloro-6-nitrotoluene is additionally added;
and step two, reduction reaction: mixing 2-methyl-3-nitrophenol with an organic solvent, and adding a reducing agent in batches at a temperature rise to react to obtain 2-methyl-3-aminophenol; the reducing agent is selected from iron powder or zinc powder;
and thirdly, diazotizing and hydrolyzing: mixing 2-methyl-3-aminophenol with dilute sulfuric acid, adding sodium nitrite in batches, adding a quenching reagent to quench excess sodium nitrite, adding concentrated sulfuric acid, heating and hydrolyzing to obtain 2, 6-dihydroxytoluene.
2. The process for producing 2,6-dihydroxytoluene according to claim 1, wherein: in the first step, the organic solvent is selected from isopropanol, dioxane, dimethyl sulfoxide or sulfolane.
3. The process for producing 2,6-dihydroxytoluene according to claim 1, wherein: in the first step, the aqueous potassium hydroxide solution is selected from 30-50% aqueous potassium hydroxide solution.
4. The process for producing 2,6-dihydroxytoluene according to claim 1, wherein: in the first step, the molar ratio of the 2-fluorine/chlorine-6-nitrotoluene to the potassium hydroxide is 1:2.5-3.5.
5. The process for producing 2,6-dihydroxytoluene according to claim 1, wherein: in the second step, the organic solvent is selected from acetic acid and/or ethanol.
6. The process for producing 2,6-dihydroxytoluene according to claim 1, wherein: in the second step, the mol ratio of the 2-methyl-3-nitrophenol to the reducing agent is 1:3.5-4.5.
7. The process for producing 2,6-dihydroxytoluene according to claim 1, wherein: in a third step, the quenching agent is selected from urea or sulfamic acid.
8. The process for producing 2,6-dihydroxytoluene according to claim 1, wherein: in the third step, the molar ratio of the 2-methyl-3-aminophenol to the sodium nitrite to the dilute sulfuric acid is 1:1.05-1.08:4.0-5.0.
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