CN111574387A - P-aminomethyl benzoic acid and preparation method thereof - Google Patents
P-aminomethyl benzoic acid and preparation method thereof Download PDFInfo
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- QCTBMLYLENLHLA-UHFFFAOYSA-N aminomethylbenzoic acid Chemical compound NCC1=CC=C(C(O)=O)C=C1 QCTBMLYLENLHLA-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 229960003375 aminomethylbenzoic acid Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 33
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 22
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 22
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims abstract description 20
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 11
- 239000007788 liquid Substances 0.000 claims abstract description 3
- -1 saturated methyl chloride ethyl ether Chemical class 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- 239000000706 filtrate Substances 0.000 claims description 28
- 238000001914 filtration Methods 0.000 claims description 26
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 10
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 9
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 9
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 239000008367 deionised water Substances 0.000 claims description 7
- 229910021641 deionized water Inorganic materials 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- 150000008064 anhydrides Chemical group 0.000 abstract description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052794 bromium Inorganic materials 0.000 abstract description 2
- 125000001246 bromo group Chemical group Br* 0.000 abstract description 2
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 abstract description 2
- 229960000401 tranexamic acid Drugs 0.000 abstract description 2
- 238000006114 decarboxylation reaction Methods 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 239000012429 reaction media Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 230000002439 hemostatic effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012982 microporous membrane Substances 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- 229960002684 aminocaproic acid Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002008 hemorrhagic effect Effects 0.000 description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- JTTXRFNOFFGPFI-UHFFFAOYSA-N ethyl 4-(chloromethyl)benzoate Chemical compound CCOC(=O)C1=CC=C(CCl)C=C1 JTTXRFNOFFGPFI-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
-
- 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
-
- 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
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
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- 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 p-aminomethyl benzoic acid and a preparation method thereof, which comprises the steps of taking phthalic anhydride as a raw material, hydrolyzing under an alkaline condition to open the anhydride structure of the phthalic anhydride to prepare an intermediate 1, carrying out decarboxylation reaction on the intermediate 1 under the condition that high-temperature liquid water is taken as a reaction medium to prepare an intermediate 2, further converting the original dibasic acid of the intermediate 1 into monobasic acid, reacting the intermediate 2 with a saturated methyl chloride ethyl ether solution under the catalytic action of aluminum chloride to prepare an intermediate 3, carrying out bromine substitution reaction on the intermediate 3 and N-bromosuccinimide, and then carrying out ammoniation reaction under the action of triethylamine and potassium carbonate. And cyano with strong toxicity is not introduced, so that the production cost of tranexamic acid is greatly reduced.
Description
Technical Field
The invention belongs to the technical field of chemical medicine preparation, and particularly relates to p-aminomethyl benzoic acid and a preparation method thereof.
Background
The aminomethyl benzoic acid is a powerful and common hemostatic drug, has a fibrinolysis-resistant hemostatic effect, has the same action mechanism as aminocaproic acid, but is 4-5 times stronger than the aminocaproic acid, has an obvious hemostatic effect, slight toxic and side effects and high medication safety, is suitable for treating various hemorrhagic symptoms, can obviously reduce the harm of bleeding to a human body, even can save the life of a hemorrhagic patient, is a key intermediate for preparing another hemostatic tranexamic acid with wider application, and has a large market demand. After many years of intensive research, the product is successfully synthesized and prepared, and the yield and the quality are in the leading position from China to the world.
The p-aminomethyl benzoic acid prepared by the existing p-aminomethyl benzoic acid preparation process is low in yield, the price of raw materials for preparing p-aminomethyl benzoic acid is high, the preparation cost of p-aminomethyl benzoic acid is greatly improved, cyano groups are introduced into part of processes, the toxicity of the cyano groups is high, and further market popularization is not facilitated.
Disclosure of Invention
The invention aims to provide p-aminomethyl benzoic acid and a preparation method thereof.
The technical problems to be solved by the invention are as follows:
the p-aminomethyl benzoic acid prepared by the existing p-aminomethyl benzoic acid preparation process is low in yield, the price of raw materials for preparing p-aminomethyl benzoic acid is high, the preparation cost of p-aminomethyl benzoic acid is greatly improved, cyano groups are introduced into part of processes, the toxicity of the cyano groups is high, and further market popularization is not facilitated.
The purpose of the invention can be realized by the following technical scheme:
p-aminomethyl benzoic acid, which is prepared by the following steps:
step S1: adding phthalic anhydride, sodium hydroxide and deionized water into a reaction kettle, stirring at the rotation speed of 200-85 ℃ for 300r/min until the phthalic anhydride and the sodium hydroxide are completely dissolved, heating to the temperature of 150-85 ℃ for 200 ℃, performing reflux reaction for 3-5h, filtering to obtain a filtrate, adding a hydrochloric acid solution into the filtrate until the pH value is 1-2, standing for 5-10min, and filtering to remove the filtrate to obtain an intermediate 1;
the reaction process is as follows:
step S2: adding the mixture of the intermediate 1 prepared in the step S1 and ammonia water into a reaction kettle, reacting for 1-1.5h at the rotation speed of 100-;
the reaction process is as follows:
step S3: adding the intermediate 2 and ether into a reaction kettle, stirring at the rotation speed of 200-300r/min until the intermediate 2 is completely dissolved, adding saturated methyl chloride ether solution and aluminum chloride, reacting for 1-1.5h at the temperature of 40-50 ℃, filtering to obtain filtrate, and distilling at the temperature of 50-60 ℃ to remove the solvent to obtain an intermediate 3;
the reaction process is as follows:
step S4: adding the intermediate 3 prepared in the step S3, N-bromosuccinimide, carbon tetrachloride and dibenzoyl peroxide into a reaction kettle, performing reflux reaction for 2-4h at the temperature of 80-90 ℃, adding triethylamine and potassium carbonate, and performing reaction for 4-5h at the rotation speed of 200-300r/min and the temperature of 25-30 ℃ to prepare p-aminomethyl benzoic acid.
The reaction process is as follows:
further, the amount ratio of phthalic anhydride to sodium hydroxide used in step S1 is 1: 2.
further, the dosage ratio of the intermediate 1 and the ammonia water mixture in the step S2 is 1 g: 3mL, mixing ammonia gas and high-temperature liquid water as an ammonia water mixture, wherein the volume fraction of the ammonia gas is 0.1-0.15%.
Further, the intermediate 2, the saturated methyl chloride ether solution, and the aluminum chloride in the step S3 are used in a ratio of 2 g: 3mL of: 0.1 g.
Further, the amount ratio of the intermediate 3, N-bromosuccinimide, carbon tetrachloride, dibenzoyl peroxide, triethylamine, and potassium carbonate described in step S4 is 2 g: 2.5 g: 5mL of: 0.5 g: 3mL of: 1g of the total weight of the composition.
Further, the preparation method of p-aminomethyl benzoic acid specifically comprises the following steps:
step S1: adding phthalic anhydride, sodium hydroxide and deionized water into a reaction kettle, stirring at the rotation speed of 200-85 ℃ for 300r/min until the phthalic anhydride and the sodium hydroxide are completely dissolved, heating to the temperature of 150-85 ℃ for 200 ℃, performing reflux reaction for 3-5h, filtering to obtain a filtrate, adding a hydrochloric acid solution into the filtrate until the pH value is 1-2, standing for 5-10min, and filtering to remove the filtrate to obtain an intermediate 1;
step S2: adding the mixture of the intermediate 1 prepared in the step S1 and ammonia water into a reaction kettle, reacting for 1-1.5h at the rotation speed of 100-;
step S3: adding the intermediate 2 and ether into a reaction kettle, stirring at the rotation speed of 200-300r/min until the intermediate 2 is completely dissolved, adding saturated methyl chloride ether solution and aluminum chloride, reacting for 1-1.5h at the temperature of 40-50 ℃, filtering to obtain filtrate, and distilling at the temperature of 50-60 ℃ to remove the solvent to obtain an intermediate 3;
step S4: adding the intermediate 3 prepared in the step S3, N-bromosuccinimide, carbon tetrachloride and dibenzoyl peroxide into a reaction kettle, performing reflux reaction for 2-4h at the temperature of 80-90 ℃, adding triethylamine and potassium carbonate, and performing reaction for 4-5h at the rotation speed of 200-300r/min and the temperature of 25-30 ℃ to prepare p-aminomethyl benzoic acid.
The invention has the beneficial effects that: the invention prepares the p-aminomethyl benzoic acid, which takes phthalic anhydride as a raw material to hydrolyze under alkaline condition so as to open the ring of the anhydride structure of the phthalic anhydride and prepare an intermediate 1,
and then the original dibasic acid of the intermediate 1 is converted into monobasic acid, the intermediate 2 takes ether as a solvent, and reacts with saturated methyl chloride ether solution under the catalytic action of aluminum chloride to prepare an intermediate 3, the intermediate 3 and N-bromosuccinimide undergo bromine substitution reaction, and then undergo ammoniation reaction under the action of triethylamine and potassium carbonate.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
P-aminomethyl benzoic acid, which is prepared by the following steps:
step S1: adding phthalic anhydride, sodium hydroxide and deionized water into a reaction kettle, stirring at the rotation speed of 200r/min and at the temperature of 80 ℃ until the phthalic anhydride and the sodium hydroxide are completely dissolved, heating to the temperature of 150 ℃, carrying out reflux reaction for 3 hours, filtering to obtain a filtrate, adding a hydrochloric acid solution into the filtrate until the pH value is 1, standing for 5 minutes, and filtering to remove the filtrate to obtain an intermediate 1;
step S2: adding the mixture of the intermediate 1 prepared in the step S1 and ammonia water into a reaction kettle, reacting for 1h at the rotation speed of 100r/min and the temperature of 180 ℃, cooling to room temperature, and filtering through a microporous membrane to obtain an intermediate 2;
step S3: adding the intermediate 2 and ether into a reaction kettle, stirring at the rotation speed of 200r/min until the intermediate 2 is completely dissolved, adding saturated methyl chloride ether solution and aluminum chloride, reacting for 1h at the temperature of 40 ℃, filtering to obtain filtrate, and distilling at the temperature of 50 ℃ to remove the solvent to obtain an intermediate 3;
step S4: and (3) adding the intermediate 3 prepared in the step (S3), N-bromosuccinimide, carbon tetrachloride and dibenzoyl peroxide into a reaction kettle, performing reflux reaction for 2 hours at the temperature of 80 ℃, adding triethylamine and potassium carbonate, and performing reaction for 4 hours at the rotation speed of 200r/min and the temperature of 25 ℃ to prepare p-aminomethyl benzoic acid.
Example 2
P-aminomethyl benzoic acid, which is prepared by the following steps:
step S1: adding phthalic anhydride, sodium hydroxide and deionized water into a reaction kettle, stirring at the rotation speed of 250r/min and at the temperature of 83 ℃ until the phthalic anhydride and the sodium hydroxide are completely dissolved, heating to the temperature of 180 ℃, performing reflux reaction for 4 hours, filtering to obtain a filtrate, adding a hydrochloric acid solution into the filtrate until the pH value is 1, standing for 8 minutes, and filtering to remove the filtrate to obtain an intermediate 1;
step S2: adding the mixture of the intermediate 1 prepared in the step S1 and ammonia water into a reaction kettle, reacting for 1.3h at the rotation speed of 150r/min and the temperature of 190 ℃, cooling to room temperature, and filtering through a microporous membrane to obtain an intermediate 2;
step S3: adding the intermediate 2 and ether into a reaction kettle, stirring at the rotation speed of 250r/min until the intermediate 2 is completely dissolved, adding saturated methyl chloride ether solution and aluminum chloride, reacting at 45 ℃ for 1.3h, filtering to obtain filtrate, and distilling at 55 ℃ to remove the solvent to obtain an intermediate 3;
step S4: and (3) adding the intermediate 3 prepared in the step (S3), N-bromosuccinimide, carbon tetrachloride and dibenzoyl peroxide into a reaction kettle, performing reflux reaction for 3 hours at the temperature of 85 ℃, adding triethylamine and potassium carbonate, and performing reaction for 4.5 hours at the rotation speed of 250r/min and the temperature of 28 ℃ to prepare p-aminomethyl benzoic acid.
Example 3
P-aminomethyl benzoic acid, which is prepared by the following steps:
step S1: adding phthalic anhydride, sodium hydroxide and deionized water into a reaction kettle, stirring at the rotation speed of 300r/min and at the temperature of 85 ℃ until the phthalic anhydride and the sodium hydroxide are completely dissolved, heating to the temperature of 200 ℃, carrying out reflux reaction for 5 hours, filtering to obtain a filtrate, adding a hydrochloric acid solution into the filtrate until the pH value is 2, standing for 10 minutes, and filtering to remove the filtrate to obtain an intermediate 1;
step S2: adding the mixture of the intermediate 1 prepared in the step S1 and ammonia water into a reaction kettle, reacting for 1.5h at the rotation speed of 200r/min and the temperature of 200 ℃, cooling to room temperature, and filtering through a microporous membrane to obtain an intermediate 2;
step S3: adding the intermediate 2 and ether into a reaction kettle, stirring at the rotation speed of 300r/min until the intermediate 2 is completely dissolved, adding saturated methyl chloride ether solution and aluminum chloride, reacting at the temperature of 50 ℃ for 1.5h, filtering to obtain filtrate, and distilling at the temperature of 60 ℃ to remove the solvent to obtain an intermediate 3;
step S4: and (3) adding the intermediate 3 prepared in the step (S3), N-bromosuccinimide, carbon tetrachloride and dibenzoyl peroxide into a reaction kettle, performing reflux reaction for 4 hours at the temperature of 90 ℃, adding triethylamine and potassium carbonate, and performing reaction for 5 hours at the rotation speed of 300r/min and the temperature of 30 ℃ to prepare p-aminomethyl benzoic acid.
Comparative example 1
The comparative example is a production method of p-aminomethyl benzoic acid on the market, and the specific steps are as follows:
step S1: adding 4-chloromethyl ethyl benzoate and ammonia water into a reaction vessel, then dropwise adding an aqueous solution dissolved with urotropine under stirring, reacting for 1.5h at 80 ℃, evaporating the solution after the reaction is completed until a large amount of solid is separated out, cooling, filtering and drying to obtain white solid 4-aminomethyl ethyl benzoate; wherein the molar ratio of ethyl 4-chloromethyl benzoate to urotropine to ammonia water is 1: 1.5: 1;
step S2: adding 4-aminomethyl ethyl benzoate into a concentrated sulfuric acid solution, stirring sulfuric acid and 4-aminomethyl alkyl benzoate at a molar ratio of 2:1 at 80 ℃ for reaction for 1h, cooling to room temperature after the reaction is finished, adding water (the amount of water is 20 times of that of 4-aminomethyl methyl benzoate), then dropwise adding ammonia water while stirring until the solution becomes alkaline, precipitating a large amount of solids, filtering, washing, and drying to obtain white solid p-aminomethyl benzoic acid.
The method for preparing p-aminomethylbenzoic acid according to the above-mentioned examples 1 to 3 and comparative example 1 was conducted in accordance with the yield test, and the test results are shown in the following Table 1;
TABLE 1
| Example 1 | Example 2 | Example 3 | Comparative example 1 | |
| Yield of | 95.32 | 91.85％ | 93.88％ | 78.35％ |
As can be seen from Table 1 above, the p-aminomethyl benzoic acid prepared by the method for preparing p-aminomethyl benzoic acid according to examples 1-3 has a yield of 91.85-95.32%, while the p-aminomethyl benzoic acid prepared by the method for preparing p-aminomethyl benzoic acid according to comparative example 1 has a yield of 78.35%, which indicates that the p-aminomethyl benzoic acid prepared by the method according to the invention has a yield far higher than that of comparative example 1, and the method uses lower-priced raw materials without introducing cyano groups with stronger toxicity, thereby greatly reducing the production cost of p-aminomethyl benzoic acid.
The foregoing is merely exemplary and illustrative of the principles of the present invention and various modifications, additions and substitutions of the specific embodiments described herein may be made by those skilled in the art without departing from the principles of the present invention or exceeding the scope of the claims set forth herein.
Claims (6)
1. A p-aminomethyl benzoic acid, characterized by: the method comprises the following steps:
step S1: adding phthalic anhydride, sodium hydroxide and deionized water into a reaction kettle, stirring at the rotation speed of 200-85 ℃ for 300r/min until the phthalic anhydride and the sodium hydroxide are completely dissolved, heating to the temperature of 150-85 ℃ for 200 ℃, performing reflux reaction for 3-5h, filtering to obtain a filtrate, adding a hydrochloric acid solution into the filtrate until the pH value is 1-2, standing for 5-10min, and filtering to remove the filtrate to obtain an intermediate 1;
step S2: adding the mixture of the intermediate 1 prepared in the step S1 and ammonia water into a reaction kettle, reacting for 1-1.5h at the rotation speed of 100-;
step S3: adding the intermediate 2 and ether into a reaction kettle, stirring at the rotation speed of 200-300r/min until the intermediate 2 is completely dissolved, adding saturated methyl chloride ether solution and aluminum chloride, reacting for 1-1.5h at the temperature of 40-50 ℃, filtering to obtain filtrate, and distilling at the temperature of 50-60 ℃ to remove the solvent to obtain an intermediate 3;
step S4: adding the intermediate 3 prepared in the step S3, N-bromosuccinimide, carbon tetrachloride and dibenzoyl peroxide into a reaction kettle, performing reflux reaction for 2-4h at the temperature of 80-90 ℃, adding triethylamine and potassium carbonate, and performing reaction for 4-5h at the rotation speed of 200-300r/min and the temperature of 25-30 ℃ to prepare p-aminomethyl benzoic acid.
2. P-aminomethylbenzoic acid according to claim 1, wherein: the dosage amount ratio of phthalic anhydride and sodium hydroxide in the step S1 is 1: 2.
3. p-aminomethylbenzoic acid according to claim 1, wherein: the dosage ratio of the intermediate 1 and the ammonia water mixture in the step S2 is 1 g: 3mL, mixing ammonia gas and high-temperature liquid water as an ammonia water mixture, wherein the volume fraction of the ammonia gas is 0.1-0.15%.
4. P-aminomethylbenzoic acid according to claim 1, wherein: the using amount ratio of the intermediate 2, the saturated monochloromethane ethyl ether solution and the aluminum chloride in the step S3 is 2 g: 3mL of: 0.1 g.
5. P-aminomethylbenzoic acid according to claim 1, wherein: the dosage ratio of the intermediate 3, the N-bromosuccinimide, the carbon tetrachloride, the dibenzoyl peroxide, the triethylamine and the potassium carbonate in the step S4 is 2 g: 2.5 g: 5mL of: 0.5 g: 3mL of: 1g of the total weight of the composition.
6. The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: the method specifically comprises the following steps: step S1: adding phthalic anhydride, sodium hydroxide and deionized water into a reaction kettle, stirring at the rotation speed of 200-85 ℃ for 300r/min until the phthalic anhydride and the sodium hydroxide are completely dissolved, heating to the temperature of 150-85 ℃ for 200 ℃, performing reflux reaction for 3-5h, filtering to obtain a filtrate, adding a hydrochloric acid solution into the filtrate until the pH value is 1-2, standing for 5-10min, and filtering to remove the filtrate to obtain an intermediate 1;
step S2: adding the mixture of the intermediate 1 prepared in the step S1 and ammonia water into a reaction kettle, reacting for 1-1.5h at the rotation speed of 100-;
step S3: adding the intermediate 2 and ether into a reaction kettle, stirring at the rotation speed of 200-300r/min until the intermediate 2 is completely dissolved, adding saturated methyl chloride ether solution and aluminum chloride, reacting for 1-1.5h at the temperature of 40-50 ℃, filtering to obtain filtrate, and distilling at the temperature of 50-60 ℃ to remove the solvent to obtain an intermediate 3;
step S4: adding the intermediate 3 prepared in the step S3, N-bromosuccinimide, carbon tetrachloride and dibenzoyl peroxide into a reaction kettle, performing reflux reaction for 2-4h at the temperature of 80-90 ℃, adding triethylamine and potassium carbonate, and performing reaction for 4-5h at the rotation speed of 200-300r/min and the temperature of 25-30 ℃ to prepare p-aminomethyl benzoic acid.
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| FUJII, AKIRA ETAL: "Probiotics: antistaphylococcal activity of 4-aminocyclohexanecarboxylic acid, aminobenzoic acid, and their derivatives and structure-activity relations", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
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| CN113354550A (en) * | 2021-05-28 | 2021-09-07 | 吉林大学 | Novel preparation method of aminomethylbenzoic acid |
| CN113354550B (en) * | 2021-05-28 | 2023-04-11 | 吉林大学 | Preparation method of aminomethylbenzoic acid |
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