CN115611803B - Synthesis method of 2, 3-dichloropyridine - Google Patents
Synthesis method of 2, 3-dichloropyridine Download PDFInfo
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- MAKFMOSBBNKPMS-UHFFFAOYSA-N 2,3-dichloropyridine Chemical compound ClC1=CC=CN=C1Cl MAKFMOSBBNKPMS-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000001308 synthesis method Methods 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- 238000000034 method Methods 0.000 claims abstract description 42
- 238000003756 stirring Methods 0.000 claims abstract description 38
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 32
- PWRBCZZQRRPXAB-UHFFFAOYSA-N 3-chloropyridine Chemical compound ClC1=CC=CN=C1 PWRBCZZQRRPXAB-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003054 catalyst Substances 0.000 claims abstract description 24
- 239000000047 product Substances 0.000 claims abstract description 23
- 239000002585 base Substances 0.000 claims abstract description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000001914 filtration Methods 0.000 claims abstract description 20
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 18
- NEXUNCTUUDERGR-UHFFFAOYSA-N 3-chloro-1-oxidopyridin-1-ium Chemical compound [O-][N+]1=CC=CC(Cl)=C1 NEXUNCTUUDERGR-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000001816 cooling Methods 0.000 claims abstract description 15
- 238000010438 heat treatment Methods 0.000 claims abstract description 14
- 239000007787 solid Substances 0.000 claims abstract description 13
- 238000004321 preservation Methods 0.000 claims abstract description 12
- 238000002156 mixing Methods 0.000 claims abstract description 11
- 230000007062 hydrolysis Effects 0.000 claims abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 10
- 150000007530 organic bases Chemical class 0.000 claims abstract description 10
- 238000010992 reflux Methods 0.000 claims abstract description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000706 filtrate Substances 0.000 claims abstract description 7
- 239000005457 ice water Substances 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 239000000376 reactant Substances 0.000 claims abstract description 4
- 238000010189 synthetic method Methods 0.000 claims abstract description 4
- 230000008569 process Effects 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 18
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 10
- 235000010265 sodium sulphite Nutrition 0.000 claims description 9
- 238000005660 chlorination reaction Methods 0.000 claims description 8
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 7
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 7
- 229940045803 cuprous chloride Drugs 0.000 claims description 7
- 229960002089 ferrous chloride Drugs 0.000 claims description 7
- 229960001781 ferrous sulfate Drugs 0.000 claims description 7
- 239000011790 ferrous sulphate Substances 0.000 claims description 7
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 7
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 7
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 7
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 6
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 239000002808 molecular sieve Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 5
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 5
- 239000000920 calcium hydroxide Substances 0.000 claims description 5
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 5
- 239000008096 xylene Substances 0.000 claims description 5
- HYZQBNDRDQEWAN-LNTINUHCSA-N (z)-4-hydroxypent-3-en-2-one;manganese(3+) Chemical compound [Mn+3].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O HYZQBNDRDQEWAN-LNTINUHCSA-N 0.000 claims description 4
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims description 4
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 4
- FJDJVBXSSLDNJB-LNTINUHCSA-N cobalt;(z)-4-hydroxypent-3-en-2-one Chemical compound [Co].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FJDJVBXSSLDNJB-LNTINUHCSA-N 0.000 claims description 4
- 229910052750 molybdenum Inorganic materials 0.000 claims description 4
- 239000011733 molybdenum Substances 0.000 claims description 4
- YOBOXHGSEJBUPB-MTOQALJVSA-N (z)-4-hydroxypent-3-en-2-one;zirconium Chemical compound [Zr].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O YOBOXHGSEJBUPB-MTOQALJVSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 3
- 229960003280 cupric chloride Drugs 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 238000009776 industrial production Methods 0.000 abstract description 9
- 230000008901 benefit Effects 0.000 abstract description 6
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 26
- 239000002994 raw material Substances 0.000 description 16
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000005070 sampling Methods 0.000 description 5
- 239000002917 insecticide Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000005886 Chlorantraniliprole Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PSOVNZZNOMJUBI-UHFFFAOYSA-N chlorantraniliprole Chemical compound CNC(=O)C1=CC(Cl)=CC(C)=C1NC(=O)C1=CC(Br)=NN1C1=NC=CC=C1Cl PSOVNZZNOMJUBI-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229960003966 nicotinamide Drugs 0.000 description 3
- 235000005152 nicotinamide Nutrition 0.000 description 3
- 239000011570 nicotinamide Substances 0.000 description 3
- 238000007039 two-step reaction Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- GPAKJVMKNDXBHH-UHFFFAOYSA-N 2,3,6-trichloropyridine Chemical compound ClC1=CC=C(Cl)C(Cl)=N1 GPAKJVMKNDXBHH-UHFFFAOYSA-N 0.000 description 2
- GCTFDMFLLBCLPF-UHFFFAOYSA-N 2,5-dichloropyridine Chemical compound ClC1=CC=C(Cl)N=C1 GCTFDMFLLBCLPF-UHFFFAOYSA-N 0.000 description 2
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 2
- ZQZAHPFFZWEUCL-UHFFFAOYSA-N 2-chloropyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=C1Cl ZQZAHPFFZWEUCL-UHFFFAOYSA-N 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- 238000000297 Sandmeyer reaction Methods 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- MEQBJJUWDCYIAB-UHFFFAOYSA-N 2-chloropyridin-3-amine Chemical compound NC1=CC=CN=C1Cl MEQBJJUWDCYIAB-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000254173 Coleoptera Species 0.000 description 1
- 241000258937 Hemiptera Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- 241000255777 Lepidoptera Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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Abstract
The invention relates to a synthetic method of 2, 3-dichloropyridine, which comprises the following steps: uniformly mixing ethanol, 3-chloropyridine, a first catalyst and concentrated sulfuric acid, dropwise adding hydrogen peroxide, heating for reaction, cooling after the reaction is finished, dropwise adding a weak base solution, stirring and filtering, wherein the obtained solid is an intermediate: 3-chloropyridine-N-oxide; uniformly mixing the intermediate, the solvent, the second catalyst and the chlorinating agent, dropwise adding organic base, heating to reflux, carrying out heat preservation reaction, recovering the solvent and the chlorinating agent after the reaction is finished, cooling, pouring reactants into ice water, stirring for hydrolysis, adding the base to adjust the pH value, stirring, filtering, extracting the filtrate by dichloromethane, merging oil phases, carrying out desolventization, and obtaining a finished 2, 3-dichloropyridine product by rectification. The method has the advantages of short synthesis route, mild reaction conditions, total yield not lower than 90%, product purity over 99.0%, recyclable solvent and chlorinated reagent, environmental protection benefit and suitability for industrial production.
Description
Technical Field
The invention relates to a synthesis method of 2, 3-dichloropyridine, belonging to the technical field of compound preparation.
Background
2, 3-dichloropyridine is an important fine chemical intermediate, and the product CAS:2402-77-9, formula C 5 H 3 Cl 2 N is white or quasi-white crystal with molecular weight of 147.99 and difficult to dissolve in water; in the field of medicine, the compound is mainly used for synthesizing antibiotics and medicines for treating cardiovascular diseases, in the field of pesticide, the compound is mainly used for synthesizing insecticide, herbicide, bactericide and the like, and is an important intermediate of a novel insecticide, namely chlorantraniliprole.
The chlorantraniliprole is an excellent, efficient and broad-spectrum insecticide of lepidoptera, mainly beetles and whiteflies, has a brand-new action mechanism, is not easy to generate cross resistance with the existing insecticide, has low toxicity to fishes, bees, aquatic organisms, natural enemies and mammals, and is very environment-friendly. With the wide and large-scale use of chlorantraniliprole, the demand of 2, 3-dichloropyridine must be obviously increased, so the development of a synthetic process route suitable for industrial production has great social and economic benefits.
The existing synthetic methods for 2, 3-dichloropyridine are mainly as follows:
1. takes nicotinamide as a raw material, and obtains the 2, 3-dichloropyridine through Hofmann degradation, chlorination, diazotization and Sandmeyer reaction. In US2007/0161797, nicotinamide is used as a raw material, and 2, 3-dichloropyridine is prepared through Hofmann degradation, chlorination and diazonium salt Sandmeyer reaction. However, a large amount of acid-base substances are needed in the process, so that more industrial three wastes are generated, and the process is not environment-friendly. The process which takes 3-aminopyridine as raw material and the process which takes 2-chloro-3-aminopyridine as raw material are derived based on nicotinamide. The process routes are mature, but the process still needs to use a large amount of acid-base substances, so that more industrial three wastes are generated, the environmental pollution is serious, the industrial production scale of the product is restricted, and the requirements of energy conservation, emission reduction and green production in China are not met.
2. The 2,3, 6-trichloropyridine is used as a raw material to obtain the 2, 3-dichloropyridine through hydrogenation reduction, most of the process routes need high-pressure hydrogen introduction, the requirement on equipment is high, and the risk coefficient is high. Japanese patent JP1193246 adopts 2,3,6-trichloropyridine as material, pd/C as catalyst, acetic acid as solvent and sodium acetate as acid-binding agent, and through hydrogenation reaction at normal pressure to obtain 2,3-dichloropyridine. Although the process reduces the hydrogenation risk, the conversion rate is low, and the process is not suitable for industrial scale-up. For example, CN104529880A adopts an earlier developed process, but the conversion rate of each reaction step is still low, and a complicated separation and purification process is required.
3. 2-chloropyridine is used as a raw material to obtain a mixture of 2, 3-dichloropyridine and 2, 5-dichloropyridine through three-step reaction. For example, in patent US5380862, 2-chloropyridine is used as a raw material in the process to react to obtain a mixture of 2, 3-dichloropyridine and 2, 5-dichloropyridine, but the separation of the two is difficult, the total yield is low, and the process is not suitable for industrial production.
4. 2-chloro nicotinamide is used as a raw material, for example, in patent CN102086174, the method uses the 2-chloro nicotinamide as the raw material, avoids the problem of more side reactions caused by 2-site chlorination, but the raw material is not easy to obtain, the cost is higher, and the industrial production is difficult.
All the methods have defects, so that the industrial production difficulty is high and the cost is high.
The applicant has been working diligently in this respect, applying patent applications on 26.12.2017 (CN 107935921A) and on 3.12.2020 (CN 112194618B), respectively. The applicant has obtained different research results from the above technical solutions through further research, and has applied for the present invention patent.
Disclosure of Invention
The main purposes of the invention are: the method overcomes the problems in the prior art, is simple and convenient in process, high in yield and product purity, and is suitable for industrial production.
The technical scheme for solving the technical problems of the invention is as follows:
a synthetic method of 2, 3-dichloropyridine is characterized by comprising the following steps:
step one, uniformly mixing ethanol, 3-chloropyridine, a first catalyst and concentrated sulfuric acid, dropwise adding hydrogen peroxide, heating for reaction, cooling after the reaction is finished, dropwise adding a weak base solution, stirring and filtering, wherein the obtained solid is an intermediate shown in formula I: 3-chloropyridine-N-oxide;
and step two, uniformly mixing the intermediate, the solvent, the second catalyst and the chlorinating agent, dropwise adding organic base, heating to reflux, carrying out heat preservation reaction, recovering the solvent and the chlorinating agent after the reaction is finished, cooling, pouring the reactant into ice water, stirring for hydrolysis, adding the base to adjust the pH value to a preset range, stirring, filtering, extracting the filtrate with dichloromethane, combining oil phases, carrying out desolventization, and carrying out rectification to obtain the finished 2, 3-dichloropyridine product.
The method takes 3-chloropyridine as a raw material, and firstly carries out oxidation reaction to obtain an intermediate: 3-chloropyridine-N-oxide, and then carrying out chlorination reaction on the intermediate to obtain the 2, 3-dichloropyridine. The process route is simple to operate, raw materials are easy to obtain, chlorination selectivity is good, side reactions are few, reaction conditions are mild, the product yield is high, the product purity is high, the total yield is not lower than 90%, and the product purity is more than 99.0%; meanwhile, the solvent and the chlorination reagent can be recycled, so that the method has the advantages of less industrial three wastes and environmental friendliness; safe and simple operation, low requirement on equipment and suitability for industrial production.
The further improved technical scheme of the invention is as follows:
preferably, in the first step, the first catalyst is selected from one of manganese acetylacetonate, cobalt acetylacetonate, molybdenum acetylacetonate, zirconium acetylacetonate or a combination of at least two thereof; the weak base contained in the weak base solution is selected from one of sodium sulfite, sodium bicarbonate and sodium carbonate or the combination of at least two of the sodium sulfite, the sodium bicarbonate and the sodium carbonate.
Preferably, in the first step, the equivalent ratio of the 3-chloropyridine to the hydrogen peroxide is 1:1.05 to 2; the weight ratio of the 3-chloropyridine to the first catalyst is 1:0.005 to 0.05.
More preferably, in the first step, the weight ratio of the ethanol to the 3-chloropyridine is 2 to 5:1; the weight ratio of the concentrated sulfuric acid to the 3-chloropyridine is 0.006 to 0.04:1; the weight ratio of weak base contained in the weak base solution to 3-chloropyridine is 0.02 to 0.2:1.
preferably, in the first step, before dropping the hydrogen peroxide, continuously stirring and mixing the reaction system, starting dropping the hydrogen peroxide when the temperature of the reaction system is raised to 55 +/-5 ℃ and finishing dropping within 1.5-3 hours, wherein the temperature of the reaction system is controlled to be 50-60 ℃ in the dropping process.
Preferably, in the first step, the reaction temperature is 60-150 ℃ and the reaction time is 2-10 hours during heating reaction; the reaction reached the end point when 3-chloropyridine <0.5% by HPLC; cooling to-10 ℃ to 0 ℃; stir for at least 30 minutes before filtration.
By adopting the preferable scheme, the specific technical characteristics of the first step can be further optimized.
Preferably, in the second step, the solvent is selected from one of toluene, xylene, chlorobenzene or a combination of at least two thereof; the second catalyst is prepared from metal salt and a Y-type molecular sieve according to the weight ratio of 1 +/-0.2: 1, wherein the metal salt is selected from one of ferrous chloride, cuprous chloride, ferrous sulfate, cupric chloride and cupric sulfate or the combination of at least two of the ferrous chloride, the cuprous chloride and the ferrous sulfate; the chlorination reagent is solid phosgene; the organic base is selected from one of triethylene diamine, tetramethyl ethylene diamine, N-dimethylformamide, N-dimethylacetamide and triethylamine or the combination of at least two of the triethylene diamine, the tetramethyl ethylene diamine and the N, N-dimethylformamide.
Preferably, in the second step, the equivalent ratio of said intermediate to chlorinating agent is 1:0.5 to 5; the equivalent ratio of the chlorinating agent to the organic base is 1 to 10:1; the weight ratio of the second catalyst to the intermediate is 0.005 to 0.1:1; the weight ratio of the solvent to the intermediate is 2 to 10:1.
preferably, in the second step, the alkali used in the addition of the alkali is selected from one of sodium hydroxide, potassium hydroxide, calcium hydroxide or a combination of at least two of the above, and the alkali is in the form of alkali solid or alkali solution; the preset range of the pH value is 1 to 5.
More preferably, in the second step, the reflux temperature is 80-160 ℃, and the time of the heat preservation reaction is 4-16 hours; the reaction reached the end point when HPLC detected <0.5% intermediate; cooling to 30-80 ℃; stirring for hydrolysis at 30-40 deg.C for 1-4 hr; the preset range of the pH value is 2.5 to 3.2; stir for at least 30 minutes before filtering.
By adopting the preferable scheme, the specific technical characteristics of the second step can be further optimized.
Compared with the prior art, the process route of the invention takes 3-chloropyridine as a raw material to prepare the intermediate 3-chloropyridine-N-oxide and then prepare the 2, 3-dichloropyridine. The process route has the advantages of short synthetic route, mild reaction conditions, total yield of not less than 90 percent, product purity of more than 99.0 percent, recyclable solvent and chlorinated reagent, environmental protection benefit and suitability for industrial production.
Drawings
FIG. 1 is a schematic diagram of the reaction of the present invention.
FIG. 2 shows the reaction of 2, 3-dichloropyridine obtained in example 2 of the present invention 1 H NMR chart.
Detailed Description
As shown in FIG. 1, the method for synthesizing 2, 3-dichloropyridine, which is specifically implemented by the invention, comprises the following steps:
step one, uniformly mixing ethanol, 3-chloropyridine, a first catalyst and concentrated sulfuric acid, dropwise adding hydrogen peroxide, heating for reaction, cooling after the reaction is finished, dropwise adding a weak base solution, stirring and filtering, wherein the obtained solid is an intermediate shown in formula I: 3-chloropyridine-N-oxide;
and step two, uniformly mixing the intermediate, the solvent, the second catalyst and the chlorinating agent, dropwise adding organic base, heating to reflux, carrying out heat preservation reaction, recovering the solvent and the chlorinating agent after the reaction is finished, cooling, pouring reactants into ice water, stirring for hydrolysis, adding the base to adjust the pH value to a preset range, stirring, filtering, extracting the filtrate by using dichloromethane, merging oil phases, carrying out desolventizing, and obtaining a finished product of the 2, 3-dichloropyridine by rectification.
Specifically, in the first step:
the first catalyst is selected from one of manganese acetylacetonate, cobalt acetylacetonate, molybdenum acetylacetonate and zirconium acetylacetonate or a combination of at least two of them; the weak base solution contains weak base selected from one of sodium sulfite, sodium bicarbonate and sodium carbonate or the combination of at least two of the sodium sulfite, the sodium bicarbonate and the sodium carbonate.
The equivalent ratio of the 3-chloropyridine to the hydrogen peroxide is 1:1.05 to 2; the weight ratio of the 3-chloropyridine to the first catalyst is 1:0.005 to 0.05. The weight ratio of the ethanol to the 3-chloropyridine is 2 to 5:1; the weight ratio of concentrated sulfuric acid to 3-chloropyridine is 0.006-0.04: 1; the weight ratio of weak base contained in the weak base solution to 3-chloropyridine is 0.02 to 0.2:1.
continuously stirring and mixing the reaction system before dropwise adding hydrogen peroxide, beginning dropwise adding hydrogen peroxide when the temperature of the reaction system is raised to 55 +/-5 ℃ and finishing dropwise adding within 1.5-3 hours, and controlling the temperature of the reaction system to be 50-60 ℃ in the dropwise adding process. Heating reaction at 60-150 deg.c for 2-10 hr; the reaction reached the end point when 3-chloropyridine <0.5% by HPLC; cooling to-10 ℃ to 0 ℃; stir for at least 30 minutes before filtration.
Specifically, in the second step:
the solvent is selected from one of toluene, xylene and chlorobenzene or the combination of at least two of the toluene, the xylene and the chlorobenzene; the second catalyst is prepared by mixing metal salt and a Y-type molecular sieve according to the weight ratio of 1 +/-0.2: 1, the metal salt is selected from one of ferrous chloride, cuprous chloride, ferrous sulfate, cupric chloride and cupric sulfate or the combination of at least two of the ferrous chloride, the cuprous chloride and the ferrous sulfate; the chlorinating agent is solid phosgene (i.e., triphosgene); the organic base is selected from one of triethylene diamine, tetramethyl ethylene diamine, N-dimethylformamide, N-dimethylacetamide and triethylamine or the combination of at least two of the triethylene diamine, the tetramethyl ethylene diamine and the N, N-dimethylformamide.
The equivalent ratio of the intermediate to the chlorinating agent is 1:0.5 to 5; the equivalent ratio of the chlorinating agent to the organic base is 1 to 10:1; the weight ratio of the second catalyst to the intermediate is 0.005 to 0.1:1; the weight ratio of the solvent to the intermediate is 2 to 10:1.
the alkali used in the alkali adding process is selected from one of sodium hydroxide, potassium hydroxide and calcium hydroxide or the combination of at least two of the sodium hydroxide, the potassium hydroxide and the calcium hydroxide, and the alkali is in the form of alkali solid or alkali solution; the predetermined range of pH is 1 to 5 (preferably 2.5 to 3.2).
The reflux temperature is 80-160 ℃, and the heat preservation reaction time is 4-16 hours; the reaction reached the end point when HPLC detected <0.5% intermediate; cooling to 30-80 ℃; stirring for hydrolysis at 30-40 deg.C for 1-4 hr; stir for at least 30 minutes before filtering.
The present invention will be described in further detail with reference to examples. The invention is not limited to the examples given.
Example 1
This example is to prepare intermediates: one specific example of 3-chloropyridine-N-oxide.
The basic process of this embodiment is the first step of the above-mentioned specific implementation scheme of the present invention.
Some specific details of this embodiment are as follows:
400g of ethanol, 113.5g (1 mol) of 3-chloropyridine, 2g of manganese acetylacetonate and 2g of concentrated sulfuric acid are added into a 1000ml four-neck flask, stirring is started, when the temperature is raised to 55 ℃, 140g (1.441 mol) of 35% hydrogen peroxide is slowly dripped, the temperature in the dripping process is controlled to be 55-60 ℃, dripping is completed within about 2.5 hours, the temperature is continuously raised to 70-75 ℃, after heat preservation reaction is carried out for 3 hours, sampling HPLC detection is carried out, the content of the 3-chloropyridine as a central control raw material is 0.32%, the reaction is stopped, the temperature is started to be lowered to-10-0 ℃, 50g of 10% sodium sulfite solution is dripped, stirring is carried out for 30 minutes, then filtration is carried out, an obtained filter cake is dried, weighed and detected, the purity of the product is 99.72%, the product contains 128.5g of an intermediate 3-chloropyridine-N-oxide, and the yield is 99.23% (theoretical weight is 129.5 g).
Example 2
This example is a specific example of the preparation of 2, 3-dichloropyridine.
The basic process of this embodiment is the second step of the above-described embodiment of the present invention.
This example is based on example 1.
Some specific details of this embodiment are as follows:
into a 500ml four-necked flask were charged 64.7g (0.4996 mol) of the intermediate obtained in example 1, 200g of toluene, 180g (0.608 mol) of phosgene solid, catalyst: starting stirring 0.5g of cuprous chloride and 0.5g of Y-type molecular sieve, dropwise adding 35g (0.347 mol) of triethylamine, heating to the reflux temperature of 90-100 ℃, carrying out heat preservation reaction for 8 hours, sampling and carrying out HPLC (high performance liquid chromatography) detection, stopping the reaction until the content of 3-chloropyridine-N-oxide is 0.38%, starting recovering the solvent and the chlorinating agent, and then cooling to 30-40 ℃; pouring the reaction solution into ice water; controlling the hydrolysis temperature at 30-40 ℃, and stirring for 1 hour; adjusting the pH value to 2.5 to 2.6 by using liquid alkali, stirring for 30 minutes, filtering, extracting the filtrate for four times by using 200g of dichloromethane, combining oil phases for desolvation, rectifying in high vacuum to obtain a product 2, 3-dichloropyridine, weighing, detecting, wherein the purity of the obtained product is 99.31 percent, the content of the 2, 3-dichloropyridine is 67.7g, the yield is 91.49 percent (the theoretical weight is 74 g), and the product is prepared by using the method 1 The H NMR 300MHz DMSO results are shown in FIG. 2.
The total yield of the two-step reaction was 90.78%.
Example 3
This example is to prepare intermediates: one specific example of 3-chloropyridine-N-oxide.
The basic process of this embodiment is the first step of the above-mentioned specific implementation scheme of the present invention.
Some specific details of this embodiment are as follows:
400g of ethanol, 113.5g (1 mol) of 3-chloropyridine, 1.5g of cobalt acetylacetonate and 2g of concentrated sulfuric acid are added into a 1000ml four-neck flask, stirring is started, when the temperature is raised to 55 ℃, 120g (1.235 mol) of 35% hydrogen peroxide is slowly dripped, the temperature in the dripping process is controlled to be 55-60 ℃, the dripping is finished within about 2 hours, the temperature is continuously raised to 60-65 ℃, after the heat preservation reaction is carried out for 8 hours, the sample HPLC detection is carried out, the central control raw material 3-chloropyridine is 0.12%, the reaction is stopped, the temperature is started to be lowered to-10-0 ℃, 40g of 10% sodium sulfite solution is dripped, the stirring is carried out for 30 minutes, then the filtration is carried out, the obtained filter cake is dried, weighed and the product purity is detected to be 99.52%, 129g of intermediate 3-chloropyridine-N-oxide is contained, and the yield is 99.61% (the theoretical weight is 129.5 g).
Example 4
This example is a specific example of the preparation of 2, 3-dichloropyridine.
The basic process of this embodiment is the second step of the above-described embodiment of the present invention.
This example is based on example 3.
Some specific details of this embodiment are as follows:
into a 1000ml four-necked flask were charged 64.7g (0.4996 mol) of the intermediate obtained in example 3, 500g of toluene, 300g (1.014 mol) of phosgene solid, a catalyst: 0.5g of ferrous chloride and 0.5g of Y-type molecular sieve, starting stirring, dropwise adding 80g (0.792 mol) of triethylamine, heating to a reflux temperature of 80-85 ℃, carrying out heat preservation reaction for 4 hours, then sampling and carrying out HPLC detection, wherein the content of 3-chloropyridine-N-oxide is 0.23%, stopping the reaction, recovering the solvent and the chlorinating reagent, then cooling to 30-40 ℃, pouring the reaction liquid into ice water, controlling the hydrolysis temperature to be 30-40 ℃, stirring for 2 hours, adjusting the pH value to 2.8-2.9 with liquid alkali, stirring for 30 minutes, filtering, extracting the filtrate for four times with 200g of dichloromethane, combining oil phases for desolventizing, carrying out high vacuum rectification to obtain a product 2, 3-dichloropyridine, weighing, detecting, wherein the purity of the obtained product is 99.06%, the content of 2, 3-dichloropyridine is 67g, and the yield is 90.54% (the theoretical weight is 74 g). The total yield of the two-step reaction was 90.19%.
Example 5
This example is to prepare intermediates: one specific example of 3-chloropyridine-N-oxide.
The basic process of this embodiment is the first step of the above-mentioned specific implementation scheme of the present invention.
Some specific details of this embodiment are as follows:
400g of ethanol, 113.5g (1 mol) of 3-chloropyridine, 1g of molybdenum acetylacetonate and 2g of concentrated sulfuric acid are added into a 1000ml four-neck flask, stirring is started, when the temperature is raised to 55 ℃, 110g (1.132 mol) of 35% hydrogen peroxide is slowly dripped, the temperature in the dripping process is controlled to be 55-60 ℃, dripping is completed within about 2 hours, the temperature is continuously raised to 75-80 ℃, the temperature is kept for reaction for 6 hours, sampling HPLC detection is carried out, the temperature is controlled to be 0.48% of 3-chloropyridine as a central control raw material, the reaction is stopped, the temperature is started to be lowered to-10-0 ℃, 50g of 10% sodium sulfite solution is dripped, stirring is carried out for 30 minutes, then filtering is carried out, and the obtained filter cake is dried, weighed and detected, the purity of the product is 99.61%, the intermediate 3-chloropyridine-N-oxide is 128.4g, and the yield is 99.15% (the theoretical weight is 129.5 g).
Example 6
This example is a specific example of the preparation of 2, 3-dichloropyridine.
The basic process of this embodiment is the second step of the above-mentioned embodiment of the present invention.
This example is based on example 5.
Some specific details of this embodiment are as follows:
a500 ml four-necked flask was charged with 64.7g (0.4996 mol) of the intermediate of example 5, 200g of toluene, 90g (0.304 mol) of phosgene solid, a catalyst: 1g of ferrous sulfate and 1g of Y-type molecular sieve, starting stirring, then dropwise adding 15g (0.149 mol) of triethylamine, heating to a reflux temperature of 100-110 ℃, carrying out heat preservation reaction for 12 hours, then sampling and carrying out HPLC (high performance liquid chromatography) detection, wherein the content of 3-chloropyridine-N-oxide is 0.42%, stopping the reaction, recovering a solvent and a chlorinating agent, then cooling to 70-80 ℃, pouring a reaction solution into ice water, controlling the hydrolysis temperature to be 30-40 ℃, stirring for 1 hour, adjusting the pH to 2.7-2.8 by liquid alkali, stirring for 30 minutes, filtering, extracting a filtrate for four times by using 200g of dichloromethane, combining oil phases for desolventizing, then carrying out high vacuum rectification to obtain a product 2, 3-dichloropyridine, weighing and detecting, wherein the purity of the obtained product is 99.34%, the content of 2, 3-dichloropyridine is 67.2g, and the yield is 90.81% (the theoretical weight is 74 g). The total yield of the two-step reaction was 90.04%.
In addition to the above embodiments, the present invention may have other embodiments. All technical solutions formed by adopting equivalent substitutions or equivalent transformations fall within the protection scope of the claims of the present invention.
Claims (5)
1. A synthetic method of 2, 3-dichloropyridine is characterized by comprising the following steps:
step one, uniformly mixing ethanol, 3-chloropyridine, a first catalyst and concentrated sulfuric acid, dropwise adding hydrogen peroxide, heating for reaction, cooling after the reaction is finished, dropwise adding a weak base solution, stirring and filtering, wherein the obtained solid is an intermediate shown in formula I: 3-chloropyridine-N-oxide;
wherein, the first catalyst is selected from one of manganese acetylacetonate, cobalt acetylacetonate, molybdenum acetylacetonate and zirconium acetylacetonate or the combination of at least two of them; the weak base contained in the weak base solution is selected from one of sodium sulfite, sodium bicarbonate and sodium carbonate or the combination of at least two of the sodium sulfite, the sodium bicarbonate and the sodium carbonate;
the equivalent ratio of the 3-chloropyridine to the hydrogen peroxide is 1:1.05 to 2; the weight ratio of the 3-chloropyridine to the first catalyst is 1:0.005 to 0.05;
heating reaction at 60-150 deg.c for 2-10 hr; the reaction reached the end point when 3-chloropyridine <0.5% by HPLC;
step two, uniformly mixing the intermediate, the solvent, the second catalyst and the chlorinating agent, dropwise adding organic base, heating to reflux, carrying out heat preservation reaction, recovering the solvent and the chlorinating agent after the reaction is finished, cooling, pouring reactants into ice water, stirring for hydrolysis, adding the base to adjust the pH value to a preset range, stirring, filtering, extracting the filtrate with dichloromethane, combining oil phases, carrying out desolventization, and obtaining a finished 2, 3-dichloropyridine product through rectification;
wherein the solvent is selected from one of toluene, xylene and chlorobenzene or the combination of at least two of the toluene, the xylene and the chlorobenzene; the second catalyst is prepared from metal salt and a Y-type molecular sieve according to the weight ratio of 1 +/-0.2: 1, the metal salt is selected from one of ferrous chloride, cuprous chloride, ferrous sulfate, cupric chloride and cupric sulfate or the combination of at least two of the ferrous chloride, the cuprous chloride and the ferrous sulfate; the chlorination reagent is solid phosgene; the organic base is selected from one of triethylene diamine, tetramethyl ethylene diamine, N-dimethylformamide, N-dimethylacetamide and triethylamine or a combination of at least two of the triethylene diamine, the tetramethyl ethylene diamine and the N, N-dimethylformamide;
the equivalent ratio of the intermediate to the chlorinating agent is 1:0.5 to 5; the equivalent ratio of the chlorinating agent to the organic base is 1 to 10:1; the weight ratio of the second catalyst to the intermediate is 0.005 to 0.1:1; the weight ratio of the solvent to the intermediate is 2 to 10:1; when adding alkali, the alkali is selected from one of sodium hydroxide, potassium hydroxide and calcium hydroxide or the combination of at least two of the sodium hydroxide, the potassium hydroxide and the calcium hydroxide, and the alkali is in the form of alkali solid or alkali solution; the preset range of the pH value is 1 to 5;
the reflux temperature is 80-160 ℃, and the heat preservation reaction time is 4-16 hours; the reaction reached the end point when the intermediate was <0.5% by HPLC.
2. The method for synthesizing 2, 3-dichloropyridine according to claim 1, wherein in the first step, the weight ratio of the ethanol to the 3-chloropyridine is 2-5: 1; the weight ratio of the concentrated sulfuric acid to the 3-chloropyridine is 0.006 to 0.04:1; the weight ratio of weak base contained in the weak base solution to 3-chloropyridine is 0.02 to 0.2:1.
3. the method for synthesizing 2, 3-dichloropyridine according to claim 1, wherein in the first step, the reaction system is continuously stirred and mixed before the hydrogen peroxide is added, the hydrogen peroxide is added when the temperature of the reaction system is raised to 55 ℃ +/-5 ℃ and is added within 1.5-3 hours, and the temperature of the reaction system is controlled to be 50-60 ℃ in the adding process.
4. The method for synthesizing 2, 3-dichloropyridine according to claim 1, wherein in the first step, the temperature is reduced to-10 ℃ to 0 ℃; stir for at least 30 minutes before filtration.
5. The method for synthesizing 2, 3-dichloropyridine according to claim 1, wherein in the second step, the temperature is reduced to 30-80 ℃; stirring for hydrolysis at 30-40 deg.C for 1-4 hr; the preset range of the pH value is 2.5 to 3.2; stir for at least 30 minutes before filtration.
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