CN117285420A - Preparation method of 3, 5-dichloro-4-methoxybenzoic acid - Google Patents
Preparation method of 3, 5-dichloro-4-methoxybenzoic acid Download PDFInfo
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- CN117285420A CN117285420A CN202311222945.3A CN202311222945A CN117285420A CN 117285420 A CN117285420 A CN 117285420A CN 202311222945 A CN202311222945 A CN 202311222945A CN 117285420 A CN117285420 A CN 117285420A
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- methoxybenzoic acid
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- hydrogen peroxide
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- XSYZTYQXKIXPRC-UHFFFAOYSA-N 3,5-dichloro-4-methoxybenzoic acid Chemical compound COC1=C(Cl)C=C(C(O)=O)C=C1Cl XSYZTYQXKIXPRC-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 claims abstract description 40
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 238000001953 recrystallisation Methods 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 12
- 239000007800 oxidant agent Substances 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000012320 chlorinating reagent Substances 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 201000005569 Gout Diseases 0.000 abstract description 2
- 201000001431 Hyperuricemia Diseases 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 230000001988 toxicity Effects 0.000 abstract 1
- 231100000419 toxicity Toxicity 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 20
- 239000000047 product Substances 0.000 description 15
- IBCQUQXCTOPJOD-UHFFFAOYSA-N 3-chloro-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1Cl IBCQUQXCTOPJOD-UHFFFAOYSA-N 0.000 description 14
- 239000012065 filter cake Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 230000001590 oxidative effect Effects 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VOFLAIHEELWYGO-UHFFFAOYSA-N (3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2h-1,3-benzothiazol-3-yl)methanone Chemical compound C1=C(Cl)C(O)=C(Cl)C=C1C(=O)N1C2=CC=CC=C2S(=O)(=O)C1 VOFLAIHEELWYGO-UHFFFAOYSA-N 0.000 description 1
- ASUMVAPLXCRBMA-UHFFFAOYSA-N (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydro-1,4-benzoxazin-4-yl)methanone Chemical compound C1=C(Cl)C(O)=C(Cl)C=C1C(=O)N1C2=CC=CC=C2OCC1 ASUMVAPLXCRBMA-UHFFFAOYSA-N 0.000 description 1
- AFYRKIAHDASULF-UHFFFAOYSA-N 3-chloro-4-methoxybenzenecarboperoxoic acid Chemical compound ClC1=CC(=CC=C1OC)C(=O)OO AFYRKIAHDASULF-UHFFFAOYSA-N 0.000 description 1
- 229940083914 URAT1 inhibitor Drugs 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940069601 dotinurad Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000004967 organic peroxy acids Chemical class 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 3, 5-dichloro-4-methoxybenzoic acid. Dorranolase is used to treat gout and hyperuricemia, and 3, 5-dichloro-4-methoxybenzoic acid is an important starting material for synthesizing dorranolase. In order to solve the problems of strong toxicity of raw materials, low preparation yield, complex post-synthesis treatment and the like in the prior art, the invention takes 4-methoxybenzoic acid as a substrate, concentrated hydrochloric acid and double salt water as a chlorinating agent and an oxidizing agent, and the equivalent of hydrogen peroxide is controlled to obtain the dichloro product 3, 5-dichloro-4-methoxybenzoic acid. After the reaction is finished, the product is treated by using a recrystallization solvent, so that the purity of the product is further improved, the final yield is up to more than 80%, and the purity of the recrystallized product is up to more than 99%.
Description
Technical Field
The invention relates to a preparation method of 3, 5-dichloro-4-methoxybenzoic acid, belonging to the field of synthesis of medical intermediates.
Background
Duotinolamine (Dotinurad) was approved for sale by PMDA in Japan at 23/1/2020 under the trade name ofThe medicine is developed by Fuji Yakuhin and Hospital field medicine (Mochida) in combination, is a URAT1 inhibitor on the market in the second lot in the global scope, and is used for treating gout and hyperuricemia. 3, 5-dichloro-4-methoxybenzoic acid is an important starting material for the synthesis of domenoramide.
The preparation of 3, 5-dichloro-4-methoxybenzoic acid can be achieved by hydrolysis, alkylation or carboxylation using different starting materials, but these synthetic routes all suffer from the problem of insufficient material sources. In addition, 4-methoxybenzoic acid is used as a starting material, and a required product can be obtained through an oxidative chlorination reaction, wherein the oxidative chlorination reaction is realized through directly introducing chlorine or indirectly generating the chlorine in situ. Chlorine is a highly toxic gas and has great danger in industrial application. N-chlorosuccinimide is used as a chlorine source in CN115057768 to catalyze the p-toluenesulfonic acid to prepare a product, however, the preparation method has the problems of low yield, large required amount of the N-chlorosuccinimide, high price, complex post-treatment due to the large amount of the generated byproduct succinimide and the like. If CrO is used 3 HCl is used as an oxidizing and chlorinating agent, the yield is lower, and CrO 3 Has strong oxidizing property and is unsafe to use in industry. Therefore, no suitable industrial method for preparing 3, 5-dichloro-4-methoxybenzoic acid is reported at present, and no technology can realize kg-grade preparation of 3, 5-dichloro-4-methoxybenzoic acid.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of 3, 5-dichloro-4-methoxybenzoic acid, which uses hydrogen peroxide and hydrochloric acid as oxidizing/chlorinating agents, can simply and rapidly prepare the 3, 5-dichloro-4-methoxybenzoic acid with high yield and purity, and simultaneously realizes kg-grade supply, and comprises the following steps:
in an organic solvent, 4-methoxybenzoic acid reacts with concentrated hydrochloric acid and hydrogen peroxide at 50-100 ℃ to obtain 3, 5-dichloro-4-methoxybenzoic acid, wherein the molar ratio of 4-methoxybenzoic acid to hydrogen peroxide is 1: (3.0-5.0).
Preferably, the reaction temperature is 60-85 ℃.
Further, when the molar ratio of the 4-methoxybenzoic acid to the hydrogen peroxide is 1:1.0, obtaining the monochloro product 3-chloro-4-methoxybenzoic acid.
Further, hydrogen peroxide is added into the reaction system in a dropwise adding mode, so that the phenomenon that the reaction is too severe and the product generation is influenced is avoided.
Further, the feed ratio of the concentrated hydrochloric acid to the 4-methoxybenzoic acid is 3-5:1 (mL: g).
Preferably, the feed ratio of concentrated hydrochloric acid to 4-methoxybenzoic acid is 3.5:1 (mL: g).
Further, the organic solvent is one or more of acetic acid, propionic acid and acetonitrile.
Further, the ratio of the organic solvent to the 4-methoxybenzoic acid is 5-20:1 (mL: g), when the solvent content is too low, the solubility of the substrate is affected, the reaction system cannot reach a homogeneous state, and the substrate remains after the reaction is finished.
Preferably, the ratio of organic solvent to 4-methoxybenzoic acid is 15:1 (mL: g).
Further, the reaction time is 2 to 8 hours.
Preferably, the reaction time is 2 hours.
Further, after the reaction is finished, the product is subjected to recrystallization treatment, so that the purity of the product is improved.
Further, the temperature condition of the recrystallization step is 5-20 ℃.
Further, an aqueous solution of alcohol was used as a solvent in the recrystallization.
Further, the alcohol is methanol, ethanol or isopropanol.
Preferably, the alcohol is ethanol at a concentration of 95%.
Preferably, the ratio of 95% ethanol to water in the aqueous ethanol solution is 2:1.
The invention has the beneficial effects that:
adopts hydrogen peroxide as an oxidizing reagent, compared with CrO 3 The oxidant is safe to use and low in price; the preparation method is simple to operate, the purity of the obtained product reaches more than 98%, the yield reaches 80%, the kg-grade preparation is realized, and the method is suitable for industrial production. By controlling the equivalent of hydrogen peroxide, the invention can also prepare the monochloro product 3-chloro-4-methoxybenzoic acid. The product is an important pharmaceutical and chemical intermediate, and can be used for synthesizing organic peroxy acid 3-chloro-4-methoxy peroxy benzoic acid.
Drawings
FIG. 1 is a schematic diagram of the product 3, 5-dichloro-4-methoxybenzoic acid of example 1 1 H NMR chart;
FIG. 2 is an HPLC chart of the product 3, 5-dichloro-4-methoxybenzoic acid of example 1;
FIG. 3 is a schematic diagram of 3-chloro-4-methoxybenzoic acid as the product of comparative example 1 1 H NMR chart;
FIG. 4 is an HPLC chart of the product 3-chloro-4-methoxybenzoic acid of comparative example 1.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the invention and practice it.
The purity measurement method comprises the following steps: the purity was calculated by area normalization using a liquid chromatograph, wherein the detection solution was a solution prepared by dissolving and diluting an appropriate amount of solid with methanol to about 1 mg/mL.
Chromatographic column: c18 (250 mm. Times.4.6 mm,5 μm)
Mobile phase a is a 0.1% phosphoric acid solution; mobile phase B was acetonitrile.
Flow rate: 1.0mL/min; sample injection amount: 20. Mu.L; wavelength: 274nm; column temperature: the gradient at 40℃is as follows:
example 1
To a 1L four-necked flask, acetic acid (342 mL), 4-methoxybenzoic acid (22.8 g,0.15mol,1.0 equivalent) and concentrated hydrochloric acid (80 mL) were added, followed by stirring and heating, and dropwise addition of 30% hydrogen peroxide (45 mL,0.45mol,3.0 equivalent) at an internal temperature of 60-65℃for about 1 hour. After the addition, stirring and reacting for 2 hours at 60-65 ℃, cooling to 15-20 ℃, and keeping the temperature and stirring for 2 hours. Suction filtration, washing with 50mL of water, drying the obtained filter cake at 60 ℃ for 8 hours to obtain 3, 5-dichloro-4-methoxybenzoic acid as a white solid, 28.4g; yield: 85%; purity: 98.4%. Recrystallizing with ethanol-water solution (95% ethanol: water ratio of 2:1) (200 mL), and drying the filter cake at 60deg.C for 8 hr to obtain 3, 5-dichloro-4-methoxybenzoic acid as a white solid, 27.1g; total yield: 81% of a glass fiber; purity: 99.9%. 1 H NMR(CDCl 3 )δ：8.04(s，2H)，7.26(s，2H)，3.98(s，3H)。
Example 2
To a 1L four-necked flask, acetic acid (342 mL), 4-methoxybenzoic acid (22.8 g,0.15mol,1.0 equivalent) and concentrated hydrochloric acid (80 mL) were added, followed by stirring and heating, and dropwise addition of 30% hydrogen peroxide (45 mL,0.45mol,3.0 equivalent) at an internal temperature of 70-75℃for about 1 hour. After the addition, stirring and reacting for 2 hours at 70-75 ℃, cooling to 15-20 ℃, and keeping the temperature and stirring for 2 hours. Suction filtration, washing with 50mL of water, drying the obtained filter cake at 60 ℃ for 8 hours to obtain 3, 5-dichloro-4-methoxybenzoic acid as a white solid, 27.8g; yield: 83%; purity: 98.8%.
Example 3
Acetonitrile (114 mL), 4-methoxybenzoic acid (22.8 g,0.15mol,1.0 equivalent) and concentrated hydrochloric acid (80 mL) were added to a 1L four-necked flask, stirred and warmed, and 30% hydrogen peroxide (45 mL,0.45mol,3.0 equivalent) was added dropwise, and the internal temperature was controlled at 80-85℃for about 1 hour. After the addition, stirring and reacting for 2 hours at 80-85 ℃, cooling to 15-20 ℃, and keeping the temperature and stirring for 2 hours. Suction filtration and washing with 50mL of water gave a filter cake which was dried at 60℃for 8 hours to give 28.0g of 3, 5-dichloro-4-methoxybenzoic acid as a white solid with a yield of 84% and a purity of 98.9%.
Example 4
To a 1L four-necked flask, propionic acid (342 mL), 4-methoxybenzoic acid (22.8 g,0.15mol,1.0 equivalent) and concentrated hydrochloric acid (80 mL) were added, followed by stirring and heating, and dropwise addition of 30% hydrogen peroxide (75 mL,0.75mol,5.0 equivalent) at an internal temperature of 80-85℃for about 1 hour. After the addition, stirring and reacting for 2 hours at 80-85 ℃, cooling to 15-20 ℃, and keeping the temperature and stirring for 2 hours. Suction filtration and washing with 50mL of water gave a filter cake which was dried at 60℃for 8 hours to give 27.2g of 3, 5-dichloro-4-methoxybenzoic acid as a white solid with a yield of 81% and a purity of 99.2%.
Example 5
To a 1L four-necked flask, propionic acid (456 mL), 4-methoxybenzoic acid (22.8 g,0.15mol,1.0 equivalent), concentrated hydrochloric acid (80 mL), stirring and heating were added dropwise 30% hydrogen peroxide (75 mL,0.75mol,5.0 equivalent), and the internal temperature was controlled at 80-85℃for about 1 hour. After the addition, stirring and reacting for 2 hours at 80-85 ℃, cooling to 5-10 ℃, and keeping the temperature and stirring for 2 hours. Suction filtration and washing with 50mL of water gave a filter cake which was dried at 60℃for 8 hours to give 27.4g of 3, 5-dichloro-4-methoxybenzoic acid as a white solid with a yield of 82% and a purity of 98.4%.
Example 6
Acetic acid (1.7L), 4-methoxybenzoic acid (1.15 kg,7.5mol,1.0 equivalent) and concentrated hydrochloric acid (4L) are added into a 50L glass reaction kettle, stirred and heated, 30% hydrogen peroxide (375 mL,37.5mol,5.0 equivalent) is added dropwise, the internal temperature is controlled to be 80-85 ℃, and the addition is completed in about 4 hours. Stirring and reacting for 2 hours at 80-85 ℃ after the addition is finished; cooling to 15-20deg.C in ice-water bath, and stirring for 2 hr. Suction-filtering with a filter vat, washing with 2.5L of water for multiple times, and drying the obtained filter cake by blowing at 60 ℃ for 12 hours to obtain 1.3kg of white solid; the yield thereof was found to be 78% and the purity thereof was found to be 99.6%.
Comparative example 1
To a 1L four-necked flask, acetic acid (342 mL), 4-methoxybenzoic acid (22.8 g,0.15mol,1.0 equivalent) and concentrated hydrochloric acid (80 mL) were added, followed by stirring and heating, and dropwise addition of 30% hydrogen peroxide (15 mL,0.15mol,1.0 equivalent) at an internal temperature of 60-65℃for about 20 minutes. After the addition, the mixture is heated to 60-65 DEG CStirring and reacting for 2 hours; cooling to 15-20deg.C in ice-water bath, and stirring for 2 hr. Filtering, washing with 50mL of water, adding the obtained filter cake (wet product) into a reaction bottle, adding 200mL of 95% ethanol and 100mL of water, heating to 80-85 ℃ and stirring to dissolve, cooling to 15-20 ℃ and stirring for 2 hours. Suction filtration, washing with ethanol-water solution (95% ethanol: water/2:1) (200 mL) and drying the filter cake at 60℃for 8 hours gave 20.0g of 3-chloro-4-methoxybenzoic acid as a white solid in 71% yield and 98.8% purity. 1 H NMR(CDCl 3 ) Delta: 8.12 (s, 1H), 8.02 (d, 1H, j=8.0 Hz), 6.98 (d, 1H, j=8.0 Hz), 3.98 (s, 3H). The 3-chloro-4-methoxybenzoic acid as an organic compound has wide application in the fields of chemical industry, pesticide, medicine and the like, and is an important intermediate in the synthesis process of a plurality of chemicals. The report of the synthesis method of 3-chloro-4-methoxybenzoic acid is less at present, and the preparation method provided by the invention can prepare the product with high purity and yield in a simple and safe way.
The above-described embodiments are merely preferred embodiments for fully explaining the present invention, and the scope of the present invention is not limited thereto. Equivalent substitutions and modifications will occur to those skilled in the art based on the present invention, and are intended to be within the scope of the present invention. The protection scope of the invention is subject to the claims.
Claims (10)
1. The preparation method of the 3, 5-dichloro-4-methoxybenzoic acid is characterized by comprising the following steps:
in an organic solvent, 4-methoxybenzoic acid reacts with concentrated hydrochloric acid and hydrogen peroxide at 50-100 ℃ to obtain 3, 5-dichloro-4-methoxybenzoic acid, wherein the molar ratio of 4-methoxybenzoic acid to hydrogen peroxide is 1: (3.0-5.0).
2. The method according to claim 1, characterized in that: the hydrogen peroxide is added into the reaction system in a dropwise manner.
3. The method according to claim 1, characterized in that: the feeding ratio of the concentrated hydrochloric acid to the 4-methoxybenzoic acid is 3-5:1 (mL: g).
4. The method according to claim 1, characterized in that: the organic solvent is one or more of acetic acid, propionic acid and acetonitrile.
5. The method according to claim 1, characterized in that: the ratio of the organic solvent to the 4-methoxybenzoic acid is 5-20:1 (mL: g).
6. The method according to claim 1, characterized in that: the reaction temperature is 60-85 ℃.
7. The method according to claim 1, characterized in that: the reaction time is 2-8 hours.
8. The method according to claim 1, characterized in that: after the reaction is finished, the method also comprises the step of recrystallizing the product.
9. The method according to claim 7, wherein: the temperature of the recrystallization is 5-20 ℃.
10. The method according to claim 7, wherein: the recrystallization uses an aqueous solution of an alcohol, which is methanol, ethanol or isopropanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311222945.3A CN117285420A (en) | 2023-09-21 | 2023-09-21 | Preparation method of 3, 5-dichloro-4-methoxybenzoic acid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311222945.3A CN117285420A (en) | 2023-09-21 | 2023-09-21 | Preparation method of 3, 5-dichloro-4-methoxybenzoic acid |
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| Publication Number | Publication Date |
|---|---|
| CN117285420A true CN117285420A (en) | 2023-12-26 |
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| CN202311222945.3A Pending CN117285420A (en) | 2023-09-21 | 2023-09-21 | Preparation method of 3, 5-dichloro-4-methoxybenzoic acid |
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