CN108623488B - Synthetic method of aminomethylbenzoic acid - Google Patents
Synthetic method of aminomethylbenzoic acid Download PDFInfo
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- CN108623488B CN108623488B CN201810634724.XA CN201810634724A CN108623488B CN 108623488 B CN108623488 B CN 108623488B CN 201810634724 A CN201810634724 A CN 201810634724A CN 108623488 B CN108623488 B CN 108623488B
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- 229960003375 aminomethylbenzoic acid Drugs 0.000 title claims abstract description 28
- QCTBMLYLENLHLA-UHFFFAOYSA-N aminomethylbenzoic acid Chemical compound NCC1=CC=C(C(O)=O)C=C1 QCTBMLYLENLHLA-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 48
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 239000007787 solid Substances 0.000 claims abstract description 27
- HMPUHXCGUHDVBI-UHFFFAOYSA-N 5-methyl-1,3,4-thiadiazol-2-amine Chemical compound CC1=NN=C(N)S1 HMPUHXCGUHDVBI-UHFFFAOYSA-N 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000003756 stirring Methods 0.000 claims abstract description 20
- 238000001816 cooling Methods 0.000 claims abstract description 17
- 238000001035 drying Methods 0.000 claims abstract description 16
- 238000001914 filtration Methods 0.000 claims abstract description 16
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000001704 evaporation Methods 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 15
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 15
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 10
- 229940095102 methyl benzoate Drugs 0.000 claims description 10
- -1 4-chloromethyl methyl benzoate Chemical compound 0.000 claims description 8
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 8
- 230000001376 precipitating effect Effects 0.000 claims description 5
- TWQLMAJROCNXEA-UHFFFAOYSA-N ethyl 4-(bromomethyl)benzoate Chemical compound CCOC(=O)C1=CC=C(CBr)C=C1 TWQLMAJROCNXEA-UHFFFAOYSA-N 0.000 claims description 3
- 125000005907 alkyl ester group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 13
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 10
- 238000007086 side reaction Methods 0.000 abstract description 8
- 238000003912 environmental pollution Methods 0.000 abstract description 6
- 230000001988 toxicity Effects 0.000 abstract description 6
- 231100000419 toxicity Toxicity 0.000 abstract description 6
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 239000003513 alkali Substances 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 25
- 239000000047 product Substances 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 7
- 208000032843 Hemorrhage Diseases 0.000 description 5
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- JTTXRFNOFFGPFI-UHFFFAOYSA-N ethyl 4-(chloromethyl)benzoate Chemical compound CCOC(=O)C1=CC=C(CCl)C=C1 JTTXRFNOFFGPFI-UHFFFAOYSA-N 0.000 description 3
- 230000036632 reaction speed Effects 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- WCTQEHGXBKFLKG-UHFFFAOYSA-N ethyl 4-(aminomethyl)benzoate Chemical compound CCOC(=O)C1=CC=C(CN)C=C1 WCTQEHGXBKFLKG-UHFFFAOYSA-N 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 230000002439 hemostatic effect Effects 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- LFIWXXXFJFOECP-UHFFFAOYSA-N 4-(aminomethyl)benzonitrile Chemical compound NCC1=CC=C(C#N)C=C1 LFIWXXXFJFOECP-UHFFFAOYSA-N 0.000 description 1
- LOQLDQJTSMKBJU-UHFFFAOYSA-N 4-(chloromethyl)benzonitrile Chemical compound ClCC1=CC=C(C#N)C=C1 LOQLDQJTSMKBJU-UHFFFAOYSA-N 0.000 description 1
- 208000000616 Hemoptysis Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010051482 Prostatomegaly Diseases 0.000 description 1
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000024753 bloody sputum Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- DLAHAXOYRFRPFQ-UHFFFAOYSA-N dodecyl benzoate Chemical class CCCCCCCCCCCCOC(=O)C1=CC=CC=C1 DLAHAXOYRFRPFQ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- NLWBJPPMPLPZIE-UHFFFAOYSA-N methyl 4-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C=C1 NLWBJPPMPLPZIE-UHFFFAOYSA-N 0.000 description 1
- SATDLKYRVXFXRE-UHFFFAOYSA-N methyl 4-(chloromethyl)benzoate Chemical compound COC(=O)C1=CC=C(CCl)C=C1 SATDLKYRVXFXRE-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- 230000002087 whitening effect Effects 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
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
The invention discloses a synthetic method of aminomethylbenzoic acid, which comprises the following steps: adding 4-halomethyl alkyl benzoate and triethylamine, dropwise adding an ethanol-water solution dissolved with 2-amino-5-methyl-1, 3, 4-thiadiazole while stirring, after complete reaction, evaporating the solution until a large amount of solids are separated out, cooling, filtering and drying to obtain 4-aminomethyl alkyl benzoate; adding 4-aminomethyl alkyl benzoate into an acid solution, stirring for reaction, cooling, adding water, dropwise adding alkali until the solution becomes alkaline and a large amount of solids are separated out, filtering, washing and drying to obtain aminomethylbenzoic acid. The method has the advantages of mild reaction conditions, no use of-CN with strong toxicity and strong polluted organic solvent, cheap and easily obtained reaction raw materials, less side reactions, high yield, low cost, short reaction and post-treatment time, low energy consumption, high production efficiency, little environmental pollution, simple treatment of three wastes and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthetic method of aminomethylbenzoic acid.
Background
Aminomethylbenzoic acid has a chemical name of 4-aminomethylbenzoic acid, and is a white flaky crystal or crystalline powder. It is slightly soluble in cold water, soluble in hot water, and hardly soluble in ethanol and chloroform.
Aminomethylbenzoic acid is a hemostatic used for various hemorrhages caused by primary hyperfibrino lysis, and is widely used in skin whitening and caring products because it can effectively prevent and improve pigmentation of skin color. Aminomethylbenzoic acid is widely used for hemorrhage caused by hyperfibrinolysis in operation and internal diseases, and is suitable for abnormal hemorrhage during operation of lung, liver, pancreas, prostate, thyroid gland, adrenal gland, etc., gynecological and puerperal hemorrhage, hemoptysis due to pulmonary tuberculosis, bloody sputum, hematuria, prostatomegaly hemorrhage, upper gastrointestinal hemorrhage, etc. Meanwhile, the compound is also a main raw material for preparing tranexamic acid which is another hemostatic with wider application, and the market demand is larger.
In the prior art, various methods for preparing aminomethylbenzoic acid exist, for example, in patent application No. CN102718673A, p-cyanobenzyl chloride is used as a raw material, and a product is obtained by acid hydrolysis and ammoniation. Patent application No. cn201510338012.x takes paracyano-chlorobenzyl as a raw material, and-CN is brought into a product in a reaction process, has strong toxicity and is not suitable for being used as a raw material for synthesizing a medical intermediate; and the organic solvent benzene used has larger toxicity and is easy to cause environmental pollution.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a synthetic method of aminomethylbenzoic acid.
The invention provides a synthetic method of aminomethylbenzoic acid, which comprises the following steps:
1) adding 4-halomethyl alkyl benzoate and triethylamine into a reaction container, then dropwise adding an ethanol-water solution dissolved with 2-amino-5-methyl-1, 3, 4-thiadiazole under stirring, after complete reaction, evaporating the solution until a large amount of solids are separated out, cooling, filtering and drying to obtain white solid 4-aminomethyl alkyl benzoate;
2) adding 4-aminomethyl alkyl benzoate into an acid solution, cooling after stirring reaction, adding water, then dropwise adding alkali under stirring until the solution becomes alkaline and a large amount of solid is separated out, filtering, washing and drying to obtain white solid aminomethylbenzoic acid.
Preferably, the 4-halomethyl alkyl benzoate is one of methyl 4-chloromethyl benzoate, ethyl 4-chloromethyl benzoate, methyl 4-bromomethylbenzoate and ethyl 4-bromomethylbenzoate.
Preferably, the temperature of the reaction in step 1) is 70-100 ℃.
Preferably, the molar ratio of 4-halomethylalkyl benzoate, triethylamine and 2-amino-5-methyl-1, 3, 4-thiadiazole in step 1) is 1: 1.2-2: 1.
preferably, the concentration of the ethanol-water solution dissolved with the 2-amino-5-methyl-1, 3, 4-thiadiazole in the step 1) is 2 mol/L.
Preferably, the mass ratio of ethanol to water in the ethanol-water solution dissolved with the 2-amino-5-methyl-1, 3, 4-thiadiazole in the step 1) is 10: 1.
Preferably, the acid in step 2) is one of concentrated sulfuric acid, phosphoric acid and nitric acid.
Preferably, the alkali in the step 2) is ammonia water.
Preferably, the molar ratio of the solute in the acid solution in the step 2) to the 4-aminomethyl alkyl benzoate is 1-3: 1.
Preferably, the temperature of the reaction in step 2) is 50-90 ℃.
The reaction time of the step 1) is 0.5-3h, and the reaction time of the step 2) is 0.5-1.5 h.
The ammonia concentration of the ammonia water is 25-28%.
The acid of the present invention is most preferably concentrated sulfuric acid, the concentration of which is 98%.
The principle of the method for synthesizing aminomethylbenzoic acid from 4-chloromethylated alkyl benzoate is as follows:
R＝CH3，CH2CH3
wherein R is CH3Or C2H5。
Compared with a comparison document CN201510338012.X in which p-cyanobenzyl halide is used, the method disclosed by the invention has the advantages that raw materials are simple and easy to obtain, the production process is safe, the introduction of-CN with strong toxicity is avoided, 4-halomethyl alkyl benzoate, triethylamine and 2-amino-5-methyl-1, 3, 4-thiadiazole are used as raw materials to obtain a 4-aminomethyl alkyl benzoate intermediate, compared with the comparison document, the reaction rate is accelerated, the reaction time is saved, the production efficiency is improved, the yield and purity of a product are improved, direct evaporation cooling is performed after the reaction is finished, the intermediate is obtained by filtering and drying, the post-treatment is simple, ammonia water is not required to be added in the process, the requirement on equipment is lower, the cost is lower, and the environmental pollution is less.
The 4-aminomethyl alkyl benzoate intermediate obtained by the invention is subjected to acid hydrolysis to obtain aminomethylbenzoic acid, compared with the aminomethylbenzoic acid obtained by the p-cyanobenzylamine in a comparison document which is subjected to acid hydrolysis, the intermediate obtained by the invention is directly cooled and added with water after reacting with acid, ammonia water is added for neutralization to obtain the aminomethylbenzoic acid, and the solid obtained by cooling needs to be subjected to layering and long-time reflux after hydrolysis in the comparison document to be neutralized again to obtain the aminomethylbenzoic acid; the synthesis method of the invention has the advantages of simplicity, less side reaction, simple post-treatment and high product purity.
The method has mild reaction conditions, does not use-CN with strong toxicity and organic solvent (such as benzene) with strong pollution, has cheap and easily obtained reaction raw materials, less side reactions, short reaction and post-treatment time, low energy consumption, high production efficiency, little environmental pollution and simple three-waste treatment, can obtain qualified products by washing reaction products, and is simple and convenient to operate and suitable for industrial production.
According to the invention, 2-amino-5-methyl-1, 3, 4-thiadiazole is dissolved in a mixed solvent with the mass ratio of ethanol to water being 10:1, compared with a solution containing 2-amino-5-methyl-1, 3, 4-thiadiazole obtained by dissolving in a single solvent of ethanol, the reaction efficiency of the system is higher, 2-amino-5-methyl-1, 3, 4-thiadiazole and triethylamine are used for replacing ammonia water and urotropine in a comparison document to carry out ammoniation reaction, so that side reactions are reduced, the reaction speed is obviously accelerated, the yield and purity of the product are improved, a large amount of ammonia gas is prevented from escaping to pollute the environment, the excessive ammonia water is prevented from being treated by a special device, and the production cost is reduced.
The invention has the beneficial effects that:
1. the method has the advantages of simple and easily obtained raw materials, safe production process, no introduction of strong-toxicity-CN, use of 4-halomethyl alkyl benzoate, triethylamine and 2-amino-5-methyl-1, 3, 4-thiadiazole as raw materials to obtain the 4-aminomethyl alkyl benzoate intermediate, accelerated reaction rate, reaction time saving, improved production efficiency, direct evaporation and cooling after the reaction, filtering and drying to obtain the intermediate, simple post-treatment, lower requirement on equipment, lower cost and less environmental pollution.
2. The method has mild reaction conditions, does not use-CN with strong toxicity and organic solvent (such as benzene) with strong pollution, has cheap and easily obtained reaction raw materials, less side reactions, short reaction and post-treatment time, low energy consumption, high production efficiency, little environmental pollution and simple three-waste treatment, can obtain qualified products by washing reaction products, and is simple and convenient to operate and suitable for industrial production.
3. According to the invention, 2-amino-5-methyl-1, 3, 4-thiadiazole is dissolved in a mixed solvent with the mass ratio of ethanol to water being 10:1, and the reaction efficiency of the system is higher compared with that of a solution containing 2-amino-5-methyl-1, 3, 4-thiadiazole obtained by dissolving the thiadiazole in a single solvent of ethanol.
4. According to the invention, 2-amino-5-methyl-1, 3, 4-thiadiazole and triethylamine are used for replacing ammonia water and urotropine in a comparison document to carry out ammoniation reaction, so that side reactions are reduced, the reaction speed is obviously accelerated, the yield and purity of the product are improved, the phenomenon that a large amount of ammonia gas escapes to pollute the environment is avoided, the phenomenon that excessive ammonia water needs to be treated by a special device is also avoided, and the production cost is reduced.
5. The invention takes 2-amino-5-methyl-1, 3, 4-thiadiazole as a raw material to provide amino, and the obtained product has high yield and purity and high production efficiency.
Detailed Description
The following examples are presented to further illustrate the embodiments of the present invention and are not intended to limit the invention thereto.
Example 1
1) Adding 4-chloromethyl methyl benzoate and triethylamine into a reaction vessel, then dropwise adding 2mol/L ethanol-water solution (the mass ratio of ethanol to water is 10:1) dissolved with 2-amino-5-methyl-1, 3, 4-thiadiazole under stirring, reacting for 0.5h at 100 ℃, evaporating the solution after complete reaction until a large amount of solid is separated out, cooling, filtering and drying to obtain white solid 4-aminomethyl methyl benzoate; wherein the molar ratio of 4-chloromethyl methyl benzoate, triethylamine and 2-amino-5-methyl-1, 3, 4-thiadiazole is 1: 1.2: 1;
2) adding 4-aminomethyl methyl benzoate into concentrated sulfuric acid solution, wherein the molar ratio of sulfuric acid to 4-aminomethyl alkyl benzoate is 1:1, stirring and reacting at 50 ℃ for 1.5h, 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), dropwise adding sodium hydroxide solution under stirring until the solution becomes alkaline, and precipitating a large amount of solids, filtering, washing and drying to obtain white solid aminomethylbenzoic acid.
Example 2
1) Adding 4-chloromethyl ethyl benzoate and triethylamine into a reaction container, then dropwise adding 2mol/L ethanol-water solution (the mass ratio of ethanol to water is 10:1) dissolved with 2-amino-5-methyl-1, 3, 4-thiadiazole under stirring, reacting for 1.5h at 80 ℃, evaporating the solution after complete reaction until a large amount of solid is separated out, cooling, filtering and drying to obtain white solid ethyl 4-aminomethyl benzoate; wherein the molar ratio of ethyl 4-chloromethyl benzoate to triethylamine to 2-amino-5-methyl-1, 3, 4-thiadiazole is 1: 1.5: 1;
2) adding 4-aminomethyl ethyl benzoate into a concentrated sulfuric acid solution, stirring and reacting at 80 ℃ for 1h with the molar ratio of sulfuric acid to 4-aminomethyl alkyl benzoate being 2:1, 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 aminomethylbenzoic acid.
Example 3
1) Adding 4-bromoethyl methyl benzoate and triethylamine into a reaction container, then dropwise adding 2mol/L ethanol-water solution (the mass ratio of ethanol to water is 10:1) dissolved with 2-amino-5-methyl-1, 3, 4-thiadiazole under stirring, reacting for 3 hours at 70 ℃, after the reaction is completed, evaporating the solution until a large amount of solid is separated out, cooling, filtering and drying to obtain white solid ethyl 4-aminomethyl benzoate; wherein the molar ratio of ethyl 4-bromomethylbenzoate to triethylamine to 2-amino-5-methyl-1, 3, 4-thiadiazole is 1: 2: 1;
2) adding 4-aminomethyl ethyl benzoate into a concentrated sulfuric acid solution, stirring and reacting for 0.5h at 90 ℃ with the molar ratio of sulfuric acid to 4-aminomethyl alkyl benzoate being 3:1, 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 aminomethylbenzoic acid.
Comparative example 1
1) 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;
2) adding 4-aminomethyl ethyl benzoate into a concentrated sulfuric acid solution, stirring and reacting at 80 ℃ for 1h with the molar ratio of sulfuric acid to 4-aminomethyl alkyl benzoate being 2:1, 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 aminomethylbenzoic acid.
Comparative example 2
Aminomethylbenzoic acid was synthesized using the materials and methods described in patent application No. cn201510338012.
The yields and purities of the products obtained in examples 1 to 3 and comparative examples 1 to 2 were calculated, and the results are shown in table 1 below.
TABLE 1 yield and purity of the product
| Examples | Yield of product (%) | Purity of the product (%) |
| Example 1 | 87 | 98 |
| Example 2 | 91 | 99 |
| Example 3 | 85 | 94 |
| Comparative example 1 | 78 | 98 |
| Comparative example 2 | 65 | 98 |
From the data in the above table, it can be seen that the yield and purity of aminomethylbenzoic acid synthesized by the method and the raw material of the present invention are high, respectively 85% and 94% or more. Compared with the comparative example 1, the yield of the product is improved, which shows that the 2-amino-5-methyl-1, 3, 4-thiadiazole and triethylamine are used for replacing ammonia water and urotropine to carry out ammoniation reaction, so that the side reaction is reduced, the reaction speed is obviously accelerated, and the yield and the purity of the product are improved; compared with the comparative example 2, the yield of the product is improved, which shows that the synthesis method of the invention is simple, the side reaction is less, the post-treatment is simple, and the yield and the purity of the product are high.
Claims (1)
1. A synthetic method of aminomethylbenzoic acid is characterized by comprising the following steps:
1) adding 4-halogenated methyl benzoic acid alkyl ester and triethylamine into a reaction container, wherein the 4-halogenated methyl benzoic acid alkyl ester is one of 4-chloromethyl methyl benzoate, 4-chloromethyl ethyl benzoate, 4-bromomethyl benzoate and 4-bromomethyl ethyl benzoate, then dropwise adding an ethanol-water solution dissolved with 2-amino-5-methyl-1, 3, 4-thiadiazole under stirring, after complete reaction, evaporating the solution until a large amount of solids are separated out, cooling, filtering and drying to obtain white solid 4-aminomethyl benzoic acid alkyl ester;
the reaction temperature in the step 1) is 70-100 ℃, and the molar ratio of the 4-halomethylbenzoic acid alkyl ester, the triethylamine and the 2-amino-5-methyl-1, 3, 4-thiadiazole in the step 1) is 1: 1.2-2: 1, the concentration of the ethanol-water solution dissolved with the 2-amino-5-methyl-1, 3, 4-thiadiazole in the step 1) is 2mol/L, and the mass ratio of ethanol to water in the ethanol-water solution dissolved with the 2-amino-5-methyl-1, 3, 4-thiadiazole in the step 1) is 10: 1;
2) adding 4-aminomethyl benzoic acid alkyl ester into concentrated sulfuric acid solution, cooling after stirring reaction, adding water, then dropwise adding ammonia water under stirring until the solution is alkaline, precipitating a large amount of solids, filtering, washing and drying to obtain white solid aminomethylbenzoic acid; the molar ratio of the solute of the acid solution in the step 2) to the alkyl 4-aminomethyl benzoate is 1-3:1, and the reaction temperature in the step 2) is 50-90 ℃.
Priority Applications (1)
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| JPS4931632A (en) * | 1972-07-28 | 1974-03-22 | ||
| CN1939892A (en) * | 2005-09-28 | 2007-04-04 | 索尔蒂格有限责任公司 | Process for preparing methyl 4-aminomethylbenzoate |
| CN102791677A (en) * | 2010-01-14 | 2012-11-21 | Naf株式会社 | Preparation method of 4-aminomethylbenzoic acid |
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| GB760086A (en) * | 1953-12-01 | 1956-10-31 | Glanzstoff Ag | Process for the production of ú-aminomethyl benzoic acid esters |
| SU390080A1 (en) * | 1971-02-08 | 1973-07-11 | , М. М. Пешкова Институт биофизики | UNIVERSAL |
| JPS4931632A (en) * | 1972-07-28 | 1974-03-22 | ||
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