CN108623488A - A kind of synthetic method of aminomethylbenzoic acid - Google Patents
A kind of synthetic method of aminomethylbenzoic acid Download PDFInfo
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- CN108623488A CN108623488A CN201810634724.XA CN201810634724A CN108623488A CN 108623488 A CN108623488 A CN 108623488A CN 201810634724 A CN201810634724 A CN 201810634724A CN 108623488 A CN108623488 A CN 108623488A
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- acid
- reaction
- synthetic method
- methyl
- aminomethylbenzoic acid
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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 34
- 229960003375 aminomethylbenzoic acid Drugs 0.000 title claims abstract description 34
- 238000010189 synthetic method Methods 0.000 title claims abstract description 18
- 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 38
- 239000007787 solid Substances 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000001816 cooling Methods 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 8
- -1 halogen methyl alkyl benzoates Chemical class 0.000 claims abstract description 8
- 238000001704 evaporation Methods 0.000 claims abstract description 7
- 230000008020 evaporation Effects 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 13
- 239000000908 ammonium hydroxide Substances 0.000 claims description 13
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- DLAHAXOYRFRPFQ-UHFFFAOYSA-N dodecyl benzoate Chemical compound CCCCCCCCCCCCOC(=O)C1=CC=CC=C1 DLAHAXOYRFRPFQ-UHFFFAOYSA-N 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- TWQLMAJROCNXEA-UHFFFAOYSA-N ethyl 4-(bromomethyl)benzoate Chemical class CCOC(=O)C1=CC=C(CBr)C=C1 TWQLMAJROCNXEA-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- NLWBJPPMPLPZIE-UHFFFAOYSA-N methyl 4-(bromomethyl)benzoate Chemical class COC(=O)C1=CC=C(CBr)C=C1 NLWBJPPMPLPZIE-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 1
- 239000005711 Benzoic acid Substances 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 14
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 238000007086 side reaction Methods 0.000 abstract description 8
- 238000012805 post-processing Methods 0.000 abstract description 7
- 238000003912 environmental pollution Methods 0.000 abstract description 6
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 238000012545 processing Methods 0.000 abstract description 3
- 150000004867 thiadiazoles Chemical class 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 27
- 239000000047 product Substances 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 208000032843 Hemorrhage Diseases 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- UBMPDLRSKDVIOD-UHFFFAOYSA-N ethyl 2-(aminomethyl)benzoate Chemical compound CCOC(=O)C1=CC=CC=C1CN UBMPDLRSKDVIOD-UHFFFAOYSA-N 0.000 description 4
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 4
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 4
- 229960004011 methenamine Drugs 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000034158 bleeding Diseases 0.000 description 3
- 231100000319 bleeding Toxicity 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
- RBTRYPAYLTVGDV-UHFFFAOYSA-N methyl 2-(aminomethyl)benzoate Chemical class COC(=O)C1=CC=CC=C1CN RBTRYPAYLTVGDV-UHFFFAOYSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000036632 reaction speed Effects 0.000 description 3
- WZSOEUAQKKEHFE-UHFFFAOYSA-N 2-chloro-2-phenylacetonitrile Chemical compound N#CC(Cl)C1=CC=CC=C1 WZSOEUAQKKEHFE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010054949 Metaplasia Diseases 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000015689 metaplastic ossification Effects 0.000 description 2
- ZOOQFAUFPWXUMI-UHFFFAOYSA-N methyl 3-amino-2-methylbenzoate Chemical class COC(=O)C1=CC=CC(N)=C1C ZOOQFAUFPWXUMI-UHFFFAOYSA-N 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- VWVZFHRDLPHBEG-UHFFFAOYSA-N 1-(chloromethyl)-4-methylsulfanylbenzene Chemical group CSC1=CC=C(CCl)C=C1 VWVZFHRDLPHBEG-UHFFFAOYSA-N 0.000 description 1
- CLTMYNWFSDZKKI-UHFFFAOYSA-N 2-(aminomethyl)benzoic acid Chemical class NCC1=CC=CC=C1C(O)=O CLTMYNWFSDZKKI-UHFFFAOYSA-N 0.000 description 1
- XQJMXPAEFMWDOZ-UHFFFAOYSA-N 3exo-benzoyloxy-tropane Natural products CN1C(C2)CCC1CC2OC(=O)C1=CC=CC=C1 XQJMXPAEFMWDOZ-UHFFFAOYSA-N 0.000 description 1
- OITNBJHJJGMFBN-UHFFFAOYSA-N 4-(chloromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CCl)C=C1 OITNBJHJJGMFBN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000000616 Hemoptysis Diseases 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 description 1
- 208000018525 Postpartum Hemorrhage Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- QIZDQFOVGFDBKW-DHBOJHSNSA-N Pseudotropine Natural products OC1C[C@@H]2[N+](C)[C@H](C1)CC2 QIZDQFOVGFDBKW-DHBOJHSNSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 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
- 125000000217 alkyl group Chemical group 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- KHIHBOPGYSBYJJ-UHFFFAOYSA-N azane;toluene Chemical compound N.CC1=CC=CC=C1 KHIHBOPGYSBYJJ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- QIRSDXBXWUTMRE-UHFFFAOYSA-N benzylcyanamide Chemical compound N#CNCC1=CC=CC=C1 QIRSDXBXWUTMRE-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical class COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- CYHOMWAPJJPNMW-JIGDXULJSA-N tropine Chemical compound C1[C@@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-JIGDXULJSA-N 0.000 description 1
- 210000002700 urine Anatomy 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 kind of synthetic methods of aminomethylbenzoic acid, are as follows：4 halogen methyl alkyl benzoates and triethylamine is added, is added dropwise while stirring dissolved with 2 amino, 5 methyl 1,3, the ethanol water of 4 thiadiazoles, after the reaction was complete, for evaporation solution to there is a large amount of solids to be precipitated, cold filtration is dried to obtain 4 aminomethyl alkyl benzoates；4 aminomethyl alkyl benzoates are added in acid solution, are stirred to react, it is cooling, add water, then adds alkali to the aobvious alkalinity of solution dropwise, there are a large amount of solids to be precipitated, filter, wash, be dried to obtain aminomethylbenzoic acid.The reaction condition of the present invention is mild, the organic solvent do not used very supervirulent CN and polluted by force, reaction raw materials are cheap and easy to get, and side reaction is few, high income, at low cost, the time of reaction and post-processing is short, and low energy consumption, production efficiency is high, environmental pollution is small, and " three wastes " processing is simple, is suitble to industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of synthetic method of aminomethylbenzoic acid.
Background technology
The chemical name of aminomethylbenzoic acid is Aminomethylbenzoic Acid, is the crystallization of white flakes shape or crystalline powder.It is slightly molten
In cold water, hot water is dissolved in, is practically insoluble in ethyl alcohol, chloroform.
Aminomethylbenzoic acid is a kind of hemostatic of the various bleedings for primary fibrinolysis caused by hyperfunction, while by
In can effectively prevent and improve the pigment deposition of the colour of skin, therefore also it is widely used in Skin whitening care cosmetics.Aminomethylbenzoic acid is extensive
Applied to operation, the bleeding in internal disease caused by hyperfibrinolysis, be suitable for lung, liver, pancreas, prostate, thyroid gland,
The abnormal bleeding when operations such as adrenal gland, gynemetrics and postpartum haemorrhage and hemoptysis of pulmonary tuberculosis, blood-stained sputum, blood urine, prostate fertilizer
Massive haemorrhage, upper gastrointestinal bleeding etc..Meanwhile it is also to prepare another kind using the main of wider hemostatic-tranexamic acid
Raw material, market demand are larger.
There are many ways to preparing aminomethylbenzoic acid in the prior art, as in number of patent application CN102718673A with to cyano
Benzyl chloride is raw material, and product is obtained through sour water solution, ammonification, although the method route is short, hydrolysising by-product-benzyl is generated when hydrolyzing
Chlorine, and product crystal structure is variant.Number of patent application CN201510338012.X was as raw material, to react cyano benzyl chloride
Cheng Zhonghui brings-CN into the product, and-CN has very strong toxicity, is not suitable as the raw material of medicine intermediate synthesis；And
There is larger toxicity using organic solvent-benzene, be easy to cause environmental pollution.
Invention content
The purpose of the present invention is overcome the deficiencies of the prior art and provide a kind of synthetic method of aminomethylbenzoic acid.
The present invention provides a kind of synthetic method of aminomethylbenzoic acid, and steps are as follows：
1) 4- halogen methyls alkyl benzoate and triethylamine are added into reaction vessel, then under stiring, be added dropwise dissolved with
2- amino -5- methyl-1s, the ethanol-water solution of 3,4- thiadiazoles, after the reaction was complete, evaporation solution to there is a large amount of solids to be precipitated,
Cooling, filtering is dried to obtain white solid 4- aminomethyl alkyl benzoates；
2) 4- aminomethyl alkyl benzoates are added in acid solution, it is cooling after being stirred to react, add water, then
Add alkali to the aobvious alkalinity of solution dropwise under stiring, there are a large amount of solids to be precipitated, filter, wash, be dried to obtain white solid ammonia toluene
Acid.
Preferably, the 4- halogen methyls alkyl benzoate is 4- chloromethyl benzoic acids methyl esters, 4- chloromethyl benzoic acid second
One kind in ester, 4- bromomethyl-benzoic acid methyl esters, 4- bromomethyl-benzoic acid ethyl esters.
Preferably, the temperature of the step 1) reaction is 70-100 DEG C.
Preferably, step 1) the 4- halogen methyls alkyl benzoate, triethylamine and 2- amino -5- methyl-1s, 3,4- thiophenes
Molar ratio between diazole is 1：1.2-2：1.
Preferably, step 1) is described dissolved with 2- amino -5- methyl-1s, the ethanol-water solution of 3,4- thiadiazoles it is a concentration of
2mol/L。
Preferably, step 1) is described dissolved with 2- amino -5- methyl-1s, in the ethanol-water solution of 3,4- thiadiazoles ethyl alcohol and
The mass ratio 10 of water:1.
Preferably, the step 2) acid is one kind in the concentrated sulfuric acid, phosphoric acid, nitric acid.
Preferably, the step 2) alkali is ammonium hydroxide.
Preferably, the molar ratio of the solute in the step 2) acid solution and 4- aminomethyl alkyl benzoates is 1-3:1.
Preferably, the temperature of the step 2) reaction is 50-90 DEG C.
The reaction time of step 1) of the present invention is 0.5-3h, and the reaction time of the step 2) is 0.5-1.5h.
A concentration of 25-28% of ammonia in ammonium hydroxide of the present invention.
The acid of the present invention most preferably concentrated sulfuric acid, a concentration of the 98% of the concentrated sulfuric acid.
The present invention is as follows with the principle of the method for 4- chloromethyl alkylbenzoic acid Lipase absobed aminomethylbenzoic acids：
R=CH3, CH2CH3
Wherein, R CH3Or C2H5。
The present invention prepares aminomethylbenzoic acid with 4- halogen methyl alkyl benzoates, and in documents CN201510338012.X
It is compared using to cyano halogen benzyl, raw material of the invention is simple and easy to get, and production process safety avoids introducing supervirulent-CN, and
Using 4- halogen methyls alkyl benzoate, triethylamine and 2- amino -5- methyl-1s, 3,4- thiadiazoles is that raw material obtains 4- aminomethyls
Alkyl benzoate intermediate, compared with documents, reaction rate is accelerated, and saves the reaction time, production efficiency is carried
Height, the yield and purity of product are improved, and reaction terminates direct evaporating-cooling, and filtration drying obtains intermediate, post-processing letter
It is single, ammonium hydroxide need not be added in this process, the requirement to equipment is relatively low, and cost is relatively low, and environmental pollution is small.
The 4- aminomethyl alkyl benzoate intermediates that the present invention obtains obtain aminomethylbenzoic acid by sour water solution, with comparison text
It aminomethylbenzoic acid is obtained by sour water solution to cyano benzylamine compares in part, intermediate of the invention and acid are directly cooling after react to be added
Water, then ammonium hydroxide neutralization is added to can be obtained aminomethylbenzoic acid, and needed after being hydrolyzed in documents by layering, it is prolonged to flow back,
Cooling obtained solid neutralizes again just obtains aminomethylbenzoic acid；Illustrate that the synthetic method of the present invention is simple, side reaction is few, post-processing letter
Single, the purity of product is high.
The reaction condition of the present invention is mild, the organic solvent (such as benzene) do not used very supervirulent-CN and polluted by force, instead
Answer raw material cheap and easy to get, side reaction is few, and reaction product can obtain certified products, easy to operate, high income, cost by washing
Low, the time of reaction and post-processing is short, and low energy consumption, and production efficiency is high, and environmental pollution is small, and " three wastes " processing is simple, is suitble to work
Industry metaplasia is produced.
For the present invention by 2- amino -5- methyl-1s, the mass ratio that 3,4- thiadiazoles is dissolved in second alcohol and water is 10:1 mixing
In solvent, compared to being dissolved in -5- the methyl-1s of amino containing 2- obtained in the single solvent of ethyl alcohol, the solution of 3,4- thiadiazoles,
The reaction efficiency higher of this system, with 2- amino -5- methyl-1s, 3,4- thiadiazoles and triethylamine replace the ammonium hydroxide in documents
Aminating reaction is carried out with methenamine, so that side reaction is reduced, reaction speed is obviously accelerated, and the yield and purity of product are carried
Height avoids a large amount of ammonia effusion and pollutes environment, and also avoiding excessive ammonia needs special device to be handled, and reduces
Production cost.
The beneficial effects of the invention are as follows：
1, raw material of the invention is simple and easy to get, production process safety, avoids introducing supervirulent-CN, and use 4- halogen
Methyl alkyl benzoic ether, triethylamine and 2- amino -5- methyl-1s, 3,4- thiadiazoles are that raw material obtains 4- aminomethyl alkylbenzene first
Acid esters intermediate, reaction rate are accelerated, and the reaction time is saved, and production efficiency is improved, and reaction terminates direct evaporating-cooling,
Filtration drying obtains intermediate, and post-processing is simple, and the requirement to equipment is relatively low, and cost is relatively low, and environmental pollution is small.
2, reaction condition of the invention is mild, the organic solvent (such as benzene) do not used very supervirulent-CN and polluted by force,
Reaction raw materials are cheap and easy to get, and side reaction is few, and reaction product can obtain certified products, easy to operate, high income, cost by washing
Low, the time of reaction and post-processing is short, and low energy consumption, and production efficiency is high, and environmental pollution is small, and " three wastes " processing is simple, is suitble to work
Industry metaplasia is produced.
3, for the present invention by 2- amino -5- methyl-1s, the mass ratio that 3,4- thiadiazoles is dissolved in second alcohol and water is 10:1 it is mixed
In bonding solvent, compared to being dissolved in -5- the methyl-1s of amino containing 2- obtained in the single solvent of ethyl alcohol, 3,4- thiadiazoles it is molten
Liquid, the reaction efficiency higher of this system.
4, the present invention uses 2- amino -5- methyl-1s, 3,4- thiadiazoles and triethylamine replace ammonium hydroxide in documents and
Methenamine carries out aminating reaction, and side reaction is made to reduce, and reaction speed is obviously accelerated, and the yield and purity of product are improved,
It avoids a large amount of ammonia effusion and pollutes environment, also avoiding excessive ammonia needs special device to be handled, and reduces
Production cost.
5, for the present invention with 2- amino -5- methyl-1s, 3,4- thiadiazoles are raw material, provide amino, the yield of products obtained therefrom and
Purity is all higher, and production efficiency is high.
Specific implementation mode
The specific implementation mode of the present invention is described further with reference to embodiment, is not therefore limited the invention to
Within the scope of the embodiment described.
Embodiment 1
1) 4- chloromethyl benzoic acids methyl esters and triethylamine are added into reaction vessel, then under stiring, 2mol/L is added dropwise
Dissolved with 2- amino -5- methyl-1s, the ethanol-water solution (mass ratio 10 of second alcohol and water of 3,4- thiadiazoles:1), at 100 DEG C
0.5h is reacted, after the reaction was complete, evaporation solution is to there are a large amount of solids to be precipitated, and cooling, filtering is dried to obtain white solid 4- ammonia first
Yl benzoic acid methyl esters；Wherein, 4- chloromethyl benzoic acids methyl esters, triethylamine and 2- amino -5- methyl-1s, between 3,4- thiadiazoles
Molar ratio is 1：1.2：1；
2) Aminomethylbenzoic Acid methyl esters is added in concentrated sulfuric acid solution, sulfuric acid and 4- aminomethyl alkyl benzoates
Molar ratio is 1:1, it is stirred to react 1.5h at 50 DEG C, after reaction, is cooled to room temperature, water is added, and (amount of the substance of water is
20 times of the amount of Aminomethylbenzoic Acid methyl esters substance), sodium hydroxide solution to solution is then added dropwise under stiring and shows alkali
Property, there are a large amount of solids to be precipitated, filter, washing is dried to obtain white solid aminomethylbenzoic acid.
Embodiment 2
1) 4- chloromethyl benzoic acids ethyl ester and triethylamine are added into reaction vessel, then under stiring, 2mol/L is added dropwise
Dissolved with 2- amino -5- methyl-1s, the ethanol-water solution (mass ratio 10 of second alcohol and water of 3,4- thiadiazoles:1), at 80 DEG C
1.5h is reacted, after the reaction was complete, evaporation solution is to there are a large amount of solids to be precipitated, and cooling, filtering is dried to obtain white solid 4- ammonia first
Yl benzoic acid ethyl ester；Wherein, 4- chloromethyl benzoic acids ethyl ester, triethylamine and 2- amino -5- methyl-1s, between 3,4- thiadiazoles
Molar ratio is 1：1.5：1；
2) Aminomethylbenzoic Acid ethyl ester is added in concentrated sulfuric acid solution, sulfuric acid and 4- aminomethyl alkyl benzoates
Molar ratio is 2:1, it is stirred to react 1h at 80 DEG C, after reaction, is cooled to room temperature, water is added, and (amount of the substance of water is 4-
20 times of the amount of amino-methyl benzoic acid methyl esters substance), ammonium hydroxide is then added dropwise under stiring to the aobvious alkalinity of solution, has a large amount of solid
Body is precipitated, and filters, and washing is dried to obtain white solid aminomethylbenzoic acid.
Embodiment 3
1) 4- bromomethyl-benzoic acid ethyl esters and triethylamine are added into reaction vessel, then under stiring, 2mol/L is added dropwise
Dissolved with 2- amino -5- methyl-1s, the ethanol-water solution (mass ratio 10 of second alcohol and water of 3,4- thiadiazoles:1), at 70 DEG C
3h is reacted, after the reaction was complete, evaporation solution is to there are a large amount of solids to be precipitated, and cooling, filtering is dried to obtain white solid 4- aminomethyls
Ethyl benzoate；Wherein, 4- bromomethyl-benzoic acid ethyl esters, triethylamine and 2- amino -5- methyl-1s, rubbing between 3,4- thiadiazoles
You are than being 1：2：1；
2) Aminomethylbenzoic Acid ethyl ester is added in concentrated sulfuric acid solution, sulfuric acid and 4- aminomethyl alkyl benzoates
Molar ratio is 3:1, it is stirred to react 0.5h at 90 DEG C, after reaction, is cooled to room temperature, water is added, and (amount of the substance of water is
20 times of the amount of Aminomethylbenzoic Acid methyl esters substance), ammonium hydroxide is then added dropwise under stiring to the aobvious alkalinity of solution, has a large amount of
Solid is precipitated, and filters, and washing is dried to obtain white solid aminomethylbenzoic acid.
Comparative example 1
1) 4- chloromethyl benzoic acids ethyl ester and ammonium hydroxide are added into reaction vessel, then under stiring, is added dropwise dissolved with black Lip river
The aqueous solution of tropine reacts 1.5h at 80 DEG C, and after the reaction was complete, evaporation solution to there is a large amount of solids to be precipitated, filter by cooling,
It is dried to obtain white solid Aminomethylbenzoic Acid ethyl ester；Wherein, between 4- chloromethyl benzoic acids ethyl ester, methenamine and ammonium hydroxide
Molar ratio be 1：1.5：1；
2) Aminomethylbenzoic Acid ethyl ester is added in concentrated sulfuric acid solution, sulfuric acid and 4- aminomethyl alkyl benzoates
Molar ratio is 2:1, it is stirred to react 1h at 80 DEG C, after reaction, is cooled to room temperature, water is added, and (amount of the substance of water is 4-
20 times of the amount of amino-methyl benzoic acid methyl esters substance), ammonium hydroxide is then added dropwise under stiring to the aobvious alkalinity of solution, has a large amount of solid
Body is precipitated, and filters, and washing is dried to obtain white solid aminomethylbenzoic acid.
Comparative example 2
Using the raw material and method synthesis aminomethylbenzoic acid in number of patent application CN201510338012.X.
The yield and purity of embodiment 1-3 and comparative example 1-2 products obtained therefroms are calculated, as a result such as the following table 1.
The yield and purity of 1 product of table
| Embodiment | The yield (%) of product | The purity (%) of product |
| Embodiment 1 | 87 | 98 |
| Embodiment 2 | 91 | 99 |
| Embodiment 3 | 85 | 94 |
| Comparative example 1 | 78 | 98 |
| Comparative example 2 | 65 | 98 |
From the data in upper table it is found that raw material using the present invention and method synthesis aminomethylbenzoic acid yield and purity all compared with
Height, respectively 85% and 94% or more.Compared with comparative example 1, the yield of product of the present invention improves, and illustrates with 2- amino -5- first
Base -1,3,4- thiadiazoles and triethylamine replace ammonium hydroxide and methenamine to carry out aminating reaction, so that side reaction is reduced, reaction speed is bright
Aobvious to accelerate, the yield and purity of product are improved；Compared with comparative example 2, the yield of product of the present invention improves, and illustrates the present invention
Synthetic method is simple, side reaction is few, post-processing is simple, and the yield and purity of product are high.
Claims (10)
1. a kind of synthetic method of aminomethylbenzoic acid, which is characterized in that steps are as follows：
1) 4- halogen methyls alkyl benzoate and triethylamine are added into reaction vessel, then under stiring, is added dropwise dissolved with 2- ammonia
Base -5- methyl-1s, the ethanol-water solution of 3,4- thiadiazoles, after the reaction was complete, evaporation solution is cooled down to there is a large amount of solids to be precipitated,
Filtering, is dried to obtain white solid 4- aminomethyl alkyl benzoates；
2) 4- aminomethyl alkyl benzoates are added in acid solution, it is cooling after being stirred to react, add water, is then stirring
It mixes down dropwise plus alkali is to the aobvious alkalinity of solution, there are a large amount of solids to be precipitated, filter, washing is dried to obtain white solid aminomethylbenzoic acid.
2. the synthetic method of aminomethylbenzoic acid as described in claim 1, which is characterized in that the 4- halogen methyls alkyl benzoate
For 4- chloromethyl benzoic acids methyl esters, 4- chloromethyl benzoic acids ethyl ester, 4- bromomethyl-benzoic acid methyl esters, 4- bromomethyl-benzoic acid ethyl esters
In one kind.
3. the synthetic method of aminomethylbenzoic acid as claimed in claim 1 or 2, which is characterized in that the temperature of the step 1) reaction
It is 70-100 DEG C.
4. the synthetic method of aminomethylbenzoic acid as claimed in claim 1 or 2, which is characterized in that step 1) the 4- halogen methyls alkane
Yl benzoic acid ester, triethylamine and 2- amino -5- methyl-1s, the molar ratio between 3,4- thiadiazoles are 1：1.2-2：1.
5. the synthetic method of aminomethylbenzoic acid as claimed in claim 1 or 2, which is characterized in that step 1) is described dissolved with 2- amino-
5- methyl-1s, a concentration of 2mol/L of the ethanol-water solution of 3,4- thiadiazoles.
6. the synthetic method of aminomethylbenzoic acid as claimed in claim 1 or 2, which is characterized in that step 1) is described dissolved with 2- amino-
5- methyl-1s, the mass ratio 10 of second alcohol and water in the ethanol-water solution of 3,4- thiadiazoles:1.
7. the synthetic method of aminomethylbenzoic acid as claimed in claim 1 or 2, which is characterized in that step 2) it is described acid be the concentrated sulfuric acid,
One kind in phosphoric acid, nitric acid.
8. the synthetic method of aminomethylbenzoic acid as claimed in claim 1 or 2, which is characterized in that the step 2) alkali is ammonium hydroxide.
9. the synthetic method of aminomethylbenzoic acid as claimed in claim 1 or 2, which is characterized in that the step 2) acid solution it is molten
Matter and the molar ratio of 4- aminomethyl alkyl benzoates are 1-3:1.
10. the synthetic method of aminomethylbenzoic acid as claimed in claim 1 or 2, which is characterized in that the temperature of the step 2) reaction
It is 50-90 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109879769A (en) * | 2019-03-22 | 2019-06-14 | 邯郸市赵都精细化工有限公司 | A kind of bromo element recycles the method for preparing aminomethylbenzoic acid |
| CN115925566A (en) * | 2022-11-10 | 2023-04-07 | 山东龙立恒医药有限公司 | Preparation method of 3-amino-4-alkylbenzoic acid |
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| CN109879769A (en) * | 2019-03-22 | 2019-06-14 | 邯郸市赵都精细化工有限公司 | A kind of bromo element recycles the method for preparing aminomethylbenzoic acid |
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