CN117843510A - Preparation method of aminomethylbenzoic acid - Google Patents
Preparation method of aminomethylbenzoic acid Download PDFInfo
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- CN117843510A CN117843510A CN202211206816.0A CN202211206816A CN117843510A CN 117843510 A CN117843510 A CN 117843510A CN 202211206816 A CN202211206816 A CN 202211206816A CN 117843510 A CN117843510 A CN 117843510A
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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 33
- 229960003375 aminomethylbenzoic acid Drugs 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 51
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 30
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000005711 Benzoic acid Substances 0.000 claims abstract description 25
- 235000010233 benzoic acid Nutrition 0.000 claims abstract description 25
- ADCUEPOHPCPMCE-UHFFFAOYSA-N 4-cyanobenzoic acid Chemical compound OC(=O)C1=CC=C(C#N)C=C1 ADCUEPOHPCPMCE-UHFFFAOYSA-N 0.000 claims abstract description 22
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims abstract description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 15
- WOZVHXUHUFLZGK-UHFFFAOYSA-N dimethyl terephthalate Chemical compound COC(=O)C1=CC=C(C(=O)OC)C=C1 WOZVHXUHUFLZGK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 8
- 230000001105 regulatory effect Effects 0.000 claims abstract description 8
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 7
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 19
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 15
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000010992 reflux Methods 0.000 claims description 9
- 229940103091 potassium benzoate Drugs 0.000 claims description 8
- 235000010235 potassium benzoate Nutrition 0.000 claims description 8
- 239000004300 potassium benzoate Substances 0.000 claims description 8
- 238000007112 amidation reaction Methods 0.000 claims description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 5
- MCDLETWIOVSGJT-UHFFFAOYSA-N acetic acid;iron Chemical compound [Fe].CC(O)=O.CC(O)=O MCDLETWIOVSGJT-UHFFFAOYSA-N 0.000 claims description 5
- 238000005984 hydrogenation reaction Methods 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 3
- 229940050390 benzoate Drugs 0.000 claims description 3
- UGKDIUIOSMUOAW-UHFFFAOYSA-N iron nickel Chemical group [Fe].[Ni] UGKDIUIOSMUOAW-UHFFFAOYSA-N 0.000 claims description 3
- BFDHFSHZJLFAMC-UHFFFAOYSA-L nickel(ii) hydroxide Chemical compound [OH-].[OH-].[Ni+2] BFDHFSHZJLFAMC-UHFFFAOYSA-L 0.000 claims description 3
- DBVJIZFBISXHET-UHFFFAOYSA-N C(CCCCCCCC)C(=O)[Fe]C(=O)CCCCCCCCC Chemical compound C(CCCCCCCC)C(=O)[Fe]C(=O)CCCCCCCCC DBVJIZFBISXHET-UHFFFAOYSA-N 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- HLYRMDDXFDINCB-UHFFFAOYSA-N carbon monoxide;iron Chemical compound [Fe].[Fe].[Fe].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] HLYRMDDXFDINCB-UHFFFAOYSA-N 0.000 claims description 2
- 229960002089 ferrous chloride Drugs 0.000 claims description 2
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 2
- 229910052759 nickel Inorganic materials 0.000 claims 1
- 239000000377 silicon dioxide Substances 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 8
- 239000000460 chlorine Substances 0.000 abstract description 8
- 229910052801 chlorine Inorganic materials 0.000 abstract description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 3
- 230000018044 dehydration Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 239000000376 reactant Substances 0.000 abstract 1
- 238000007086 side reaction Methods 0.000 abstract 1
- 239000002699 waste material Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- 238000003756 stirring Methods 0.000 description 15
- 238000001914 filtration Methods 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 238000004519 manufacturing process Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 239000008213 purified water Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 6
- 229960000401 tranexamic acid Drugs 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000005576 amination reaction Methods 0.000 description 4
- 238000010009 beating Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 208000032843 Hemorrhage Diseases 0.000 description 3
- BXDZOYLPNAIDOC-UHFFFAOYSA-N N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]-1-[2-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxoethyl]piperidine-4-carboxamide Chemical compound CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCN(CC(=O)NCCOCCOCCOCCNc4cccc5C(=O)N(C6CCC(=O)NC6=O)C(=O)c45)CC3)s2)o1 BXDZOYLPNAIDOC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000001502 supplementing effect Effects 0.000 description 3
- OITNBJHJJGMFBN-UHFFFAOYSA-N 4-(chloromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CCl)C=C1 OITNBJHJJGMFBN-UHFFFAOYSA-N 0.000 description 2
- -1 4-chloromethyl benzoic acid ester Chemical class 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- HMPUHXCGUHDVBI-UHFFFAOYSA-N 5-methyl-1,3,4-thiadiazol-2-amine Chemical compound CC1=NN=C(N)S1 HMPUHXCGUHDVBI-UHFFFAOYSA-N 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 208000000616 Hemoptysis Diseases 0.000 description 1
- 208000018525 Postpartum Hemorrhage Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- RPELOZWDWZQYDV-UHFFFAOYSA-N [Si]=O.[Ni] Chemical compound [Si]=O.[Ni] RPELOZWDWZQYDV-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940030225 antihemorrhagics Drugs 0.000 description 1
- ZXVOCOLRQJZVBW-UHFFFAOYSA-N azane;ethanol Chemical compound N.CCO ZXVOCOLRQJZVBW-UHFFFAOYSA-N 0.000 description 1
- OSOHBQZPFDDOMK-UHFFFAOYSA-N azane;propan-2-one Chemical compound N.CC(C)=O OSOHBQZPFDDOMK-UHFFFAOYSA-N 0.000 description 1
- 208000024753 bloody sputum Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 description 1
- 229960001826 dimethylphthalate Drugs 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 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
- 230000008020 evaporation Effects 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000000988 hyperfibrinolytic effect Effects 0.000 description 1
- 229940087654 iron carbonyl Drugs 0.000 description 1
- WXEICPMZIKLINJ-UHFFFAOYSA-L iron(2+) diacetate tetrahydrate Chemical compound O.O.O.O.[Fe+2].CC([O-])=O.CC([O-])=O WXEICPMZIKLINJ-UHFFFAOYSA-L 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of aminomethylbenzoic acid, which comprises the following steps: hydrolyzing dimethyl terephthalate with potassium hydroxide to obtain 4-methyl formate benzoate, then reacting at 90-110 ℃ in the presence of ammonia, regulating the pH of the reactant with hydrochloric acid to obtain 4-formamide benzoic acid, then carrying out catalytic dehydration in acetic anhydride to obtain 4-cyano benzoic acid, and finally carrying out palladium-carbon catalytic hydrogenation at 30-35 ℃ in the presence of an ammonia source to obtain the aminomethylbenzoic acid. The method has the advantages of low-cost and easily-obtained reaction raw materials, less side reaction, higher yield and low total cost, avoids using harmful substances such as chlorine and the like, can recycle and reuse waste ammonia, is environment-friendly, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of aminomethylbenzoic acid.
Background
The chemical name of the aminomethylbenzoic acid is 4-aminomethylbenzoic acid or p-aminomethylbenzoic acid, the English name is Aminomethylbenzoic Acid, and the molecular formula is C 8 H 9 NO 2 The chemical structural formula is as follows,
the aminomethylbenzoic acid is mainly used for treating or preventing hyperfibrinolytic hemorrhage caused by primary fibrinolysis, such as abnormal operation hemorrhage, postpartum hemorrhage, hemoptysis of pulmonary tuberculosis or bloody sputum, hematuria, prostatic hyperplasia hemorrhage, and the like, and is also a starting material for synthesizing the other hemostatic agent, such as the tranexamic acid. Because the tranexamic acid is not only applied to the medical market, the market demand of the tranexamic acid in the medical market is still quite large, so the total market demand of the tranexamic acid serving as a key material for synthesizing the tranexamic acid is quite high.
In recent years, the reported synthesis processes of aminomethylbenzoic acid include the following processes: 1. the p-toluic acid is used as raw material, and is subjected to chlorination and amination to finally synthesize the aminomethylbenzoic acid. The technology is one of the current mainstream production technologies, and because chlorine, urotropine and other materials are used, the production is dangerous, and the technology has great environmental challenges.
CN105037186 a discloses a method for preparing aminomethylbenzoic acid, which takes p-cyanoborobenzyl as raw material, adopts urotropine and ammonia water for amination, and hydrolyzes in acid to obtain the aminomethylbenzoic acid.
CN108912002 a discloses a process for preparing aminomethylbenzoic acid, 4-chloromethylbenzoic acid is used as raw material, and ammonia water is used for amination to obtain the aminomethylbenzoic acid. The method for preparing the aminomethylbenzoic acid disclosed in CN108623488A takes 4-halomethyl alkyl benzoate as a raw material, and adopts 2-amino-5-methyl-1, 3, 4-thiadiazole for amination and then hydrolyzes to obtain the aminomethylbenzoic acid. CN113354550 a discloses a method that p-chloromethyl benzoic acid ethyl ester is used as a raw material, acetamide is used as a nitrogen source, p-acetamido methyl benzamide is synthesized, and the p-acetamido methyl benzamide is hydrolyzed to obtain aminomethylbenzoic acid. The method uses 4-chloromethyl benzoic acid or 4-chloromethyl benzoic acid ester as raw materials, and avoids using chlorine to react, but chlorine sources are still required to be introduced in the production process of the raw materials, so that the problem of environmental protection is not fundamentally solved, and the raw materials of the 4-chloromethyl benzoic acid ester are not easy to purchase.
The method of CN108484426A adopts p-aldehyde benzoic acid as a starting material, and the p-aldehyde benzoic acid is obtained through the reaction of ammonia gas and hydrogen gas. The chlorine-containing reaction is avoided, but ammonia and hydrogen are simultaneously used, and the reaction is carried out at high temperature and high pressure, so that the production is dangerous. The method of CN111574388A adopts various catalysts for catalytic reaction, has complex operation, uses high temperature and high pressure, adopts a solvent carbon tetrachloride and the like, and has higher industrialization difficulty.
Disclosure of Invention
The invention aims to provide a novel method for preparing aminomethylbenzoic acid, which has the advantages of low-cost and easily-obtained starting materials, low production cost, more environment-friendly production and more suitability for industrial production. More importantly, the method fundamentally avoids the use of a chlorine source in the prior art, and solves the problem of environmental protection.
For the purposes of the present invention, the following embodiments are provided:
in one embodiment, a method for preparing aminomethylbenzoic acid is provided, which comprises the following steps:
the method comprises the following steps:
(1) Dimethyl terephthalate is subjected to alkaline hydrolysis reaction in an organic solvent to obtain 4-methyl formate potassium benzoate;
(2) Carrying out amidation reaction on 4-methyl formate benzoate in a solvent, and regulating the pH value to be 1-6 to obtain 4-formamide benzoic acid;
(3) Carrying out dehydration reaction on 4-formamide benzoic acid in acetic anhydride to obtain 4-cyano benzoic acid;
(4) Dissolving 4-cyanobenzoic acid in ammonia water, and carrying out catalytic hydrogenation reaction to obtain the aminomethylbenzoic acid.
The hydrolysis reaction in the step 1) is carried out at a temperature of 5-75 ℃, preferably 40-45 ℃, the organic solvent is toluene and methanol, the volume ratio of toluene to methanol is 0.3-1.5, preferably 1.1-1.2, and the alkali is potassium hydroxide.
In the above preparation method of the present invention, in step 2), the amidation reaction temperature is 20 to 120 ℃, preferably 30 to 100 ℃, the ammonia source of the amidation reaction is ammonia gas, ammonia water, an ammonia methanol solution, an ammonia ethanol solution or an ammonia acetone solution, preferably ammonia gas, the solvent is water, methanol, ethanol or/and acetone, preferably methanol, and the pH is 3 to 4.
In the above preparation method of the present invention, in step 3), the dehydration reaction has a reaction temperature of 80 ℃ to a reflux temperature, preferably a reflux temperature, and further comprises a catalyst, wherein the amount of the catalyst added is 1% -10%, preferably 5%, of the molar amount of the 4-formamide benzoic acid, and the catalyst is an iron-nickel catalyst selected from the group consisting of: one or more of iron powder, nickel powder, ferrous acetate, ferrous chloride, ferric chloride, dinonylcarbonyl iron, carbonyl iron, dodecacarbonyl iron and nickel hydroxide, preferably ferrous acetate, is added in an amount of 3-10 times volume (ml), preferably 6 times volume, of the mass (g) of 4-formamide benzoic acid.
In the preparation method of the invention, in the step 4), the reaction temperature of the hydrogenation reaction is 25-45 ℃, preferably 30-35 ℃, the reaction pressure is 0.1Mpa-3.0Mpa, preferably 1.0Mpa, the catalytic hydrogenation is carried out, the feeding amount of the catalyst is 1% -30%, preferably 5% of the mass of the 4-cyanobenzoic acid, and the catalyst is selected from palladium carbon, nickel silicon oxide and Raney nickel, preferably palladium carbon.
In a specific embodiment, the preparation method of the aminomethylbenzoic acid comprises the following steps:
(1) Dissolving alkali in methanol, adding a proper amount of toluene, stirring uniformly, adding dimethyl phthalate (starting material SM 1) into the solution for hydrolysis reaction, evaporating the reaction solution to dryness after hydrolysis, pulping in dichloromethane, filtering and drying to obtain 4-methyl formate potassium benzoate (intermediate Z1);
(2) Adding 4-methyl formate potassium benzoate (intermediate Z1) and a proper amount of methanol into a high-pressure reaction kettle, introducing ammonia gas after nitrogen replacement, carrying out amidation reaction, regulating the pH value to 3-4 after the reaction is finished, filtering, and drying to obtain 4-formamide benzoic acid (intermediate Z2);
(3) Adding 4-formamide benzoic acid (intermediate Z2) into acetic anhydride, adding a dehydration catalyst for dehydration reaction, evaporating the reaction liquid after the reaction is finished, and adding purified water for washing to obtain 4-cyano benzoic acid (intermediate Z3);
(4) Dissolving 4-cyanobenzoic acid (intermediate Z3) in ammonia water, decoloring by using active carbon, carrying out hydrogenation reaction in the presence of palladium-carbon, concentrating, filtering and drying after the reaction is finished to obtain the aminomethylbenzoic acid.
In the above embodiment, in the method for producing aminomethylbenzoic acid according to the present invention, in step 1), the hydrolysis reaction temperature is preferably 40 to 45 ℃, the hydrolysis reaction time is 3 to 10 hours, preferably 6 hours, the volume of toluene and methanol is preferably 1.1 to 1.2, the methanol is fed in an amount of 5 to 15 times by volume (ml), preferably 10 times by volume (ml) of the mass (g) of dimethyl terephthalate, the molar equivalent of the base is 0.8 to 1.5 times, preferably 1.0 times, the equivalent of dimethyl terephthalate, and the base is potassium hydroxide.
In the above embodiment, in the method for producing aminomethylbenzoic acid according to the present invention, in step 2), the temperature of the reaction is preferably 30 to 100 ℃, the time of the reaction is preferably 10 to 16 hours, and the pressure of the reaction is 0.1Mpa to 10Mpa, preferably 1Mpa to 3Mpa, more preferably 1.5 to 2Mpa.
In the above specific embodiment, in the preparation method of the aminomethylbenzoic acid according to the present invention, in step 3), the reaction temperature is preferably reflux temperature, the reaction time is preferably 4 to 5 hours, the catalyst is an iron-nickel catalyst, preferably ferrous acetate, the amount of the catalyst to be fed is preferably 5% of the molar amount of 4-formamide benzoic acid, and the amount of the acetic anhydride to be fed is preferably 6 times by volume (ml) of the mass (g) of 4-formamide benzoic acid.
In the above specific embodiment, in the preparation method of the aminomethylbenzoic acid according to the present invention, in step 4), the reaction temperature is preferably 30 to 35 ℃, the reaction pressure is preferably 1.0Mpa, the palladium-carbon loading amount of the catalyst is 1% to 20%, preferably 5%, and the palladium-carbon loading amount of the catalyst is preferably 5% of the mass of 4-cyanobenzoic acid.
The invention has the technical effects that: the method of the invention fundamentally and completely avoids chlorine sources, avoids the influence of chlorine on the environment, has less environmental pollution, obtains higher yield and purity, has the total molar yield of 70.24 percent and the total mass yield of 54.7 percent, has lower production cost and high safety, and is suitable for industrial mass production.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention to help understand the essence of the present invention. The examples should not be construed as limiting the scope of the invention.
Example 1
Synthesis of 4-methyl formate potassium benzoate
In a 10L three-necked flask, 4096mL of methanol and 115.6g of potassium hydroxide were put, and stirred and dissolved completely, 4588mL of toluene was added, and the temperature was raised to 40-45 ℃. 400.0g of dimethyl terephthalate was slowly charged and reacted at 40-45℃with stirring for 6 hours. Concentrating under reduced pressure to dryness, and recovering solvent. After cooling, 3200mL of dichloromethane was added, after stirring thoroughly, the filter cake was filtered, washed with 1600mL of dichloromethane and dried at 50 ℃ for 6 hours to give 440.5g of potassium 4-methylformate benzoate with a purity of 98.5% and a molar yield of 96.1%.
Example 2
Synthesis of 4-carboxamide benzoic acid
Adding 440g of 4-methyl formate potassium benzoate and 4400ml of methanol into a high-pressure reaction kettle, sealing, replacing 3 times with nitrogen, introducing ammonia gas, controlling the pressure to be about 0.5MPa, starting stirring and heating up simultaneously, heating up to 100 ℃, supplementing the ammonia gas pressure to 2.0MPa, continuously supplementing ammonia gas to 2.0MPa when the ammonia gas pressure is lower than 1.5MPa, sampling after continuing to react for 1h until the ammonia gas pressure is not reduced, and reacting for 12h. Cooling, evacuating, collecting excessive ammonia gas and replacing nitrogen for 3 times. Concentrating the reaction solution to half of the original volume, dropwise adding concentrated hydrochloric acid at room temperature, monitoring the pH value, regulating the pH value to be 3-4, stirring for 1h at room temperature, filtering, and drying the filter cake at 60 ℃ for 6h to obtain 320.1g of 4-formamide benzoic acid with the purity of 95.2% and the molar yield of 93.2%.
Example 3
Synthesis of 4-carboxamide benzoic acid
440g of 4-methyl formate potassium benzoate and 4400ml of methanolic ammonia solution are put into a high-pressure reaction kettle, after being sealed, nitrogen is replaced for 3 times, stirring is started, heating is carried out at the same time, the temperature is raised to 100 ℃, and the reaction is carried out for 12 hours. Cooling and evacuating. Concentrating the reaction solution to half of the original volume, dropwise adding concentrated hydrochloric acid at room temperature, regulating the pH value to be stable at 3-4, stirring at room temperature for 1h, filtering, and drying the filter cake at 60 ℃ for 6h to obtain 305.2g of 4-formamide benzoic acid with the purity of 96.3% and the molar yield of 88.3%.
Example 4
Synthesis of 4-carboxamide benzoic acid
440g of 4-methyl formate potassium benzoate and 2200ml of ammonia water solution are put into a reaction bottle, the temperature is raised to 30 ℃, and stirring is started to react for 24 hours. After the reaction is finished, dropwise adding concentrated hydrochloric acid at room temperature, regulating the pH value to be stable at 3-4, stirring at room temperature for 1h, filtering, and drying a filter cake at 105 ℃ for 12h to obtain 297.2g of 4-formamide benzoic acid, wherein the purity is 89.6%, and the molar yield is 80.0%.
Example 5
Synthesis of 4-cyanobenzoic acid
10g of 4-formamide benzoic acid and 62.5mL of acetic anhydride are put into a 100mL three-necked flask, nitrogen is replaced for 3 times, 0.84g of iron carbonyl is added, after nitrogen is replaced for 3 times again, reflux reaction is carried out for 5 hours at the temperature of 135 ℃ in an oil bath, vacuum concentration is carried out until the solution is dried, 80mL of purified water is added, stirring and beating are carried out, filtering and washing are carried out until the pH value of the washing solution is 4-5, drying is carried out for 12 hours at the temperature of 105 ℃, 8.6g of 4-cyano benzoic acid is obtained, the purity is 89.6%, and the molar yield is 86.5%.
Example 6
Synthesis of 4-cyanobenzoic acid
10g of 4-formamide benzoic acid and 62.5mL of acetic anhydride are put into a 100mL three-necked flask, nitrogen is replaced for 3 times, 0.56g of iron powder is added, after nitrogen is replaced for 3 times again, reflux reaction is carried out for 5 hours at the temperature of 135 ℃ in an oil bath, vacuum concentration is carried out until the mixture is dried, 80mL of purified water is added, stirring and beating are carried out, filtration and washing with water are carried out until the pH value of the washing liquid is 4-5, drying is carried out for 12 hours at the temperature of 105 ℃, 7.2g of 4-cyano benzoic acid with the purity of 81.7% and the molar yield of 66.0% are obtained.
Example 7
Synthesis of 4-cyanobenzoic acid
60g of 4-formamide benzoic acid and 360ml of acetic anhydride are put into a 1L three-mouth bottle, nitrogen is replaced for 3 times, 0.6g of nickel hydroxide is added, after nitrogen is replaced for 3 times again, reflux reaction is carried out for 5 hours at the temperature of 145 ℃ of an oil bath, decompression concentration is carried out until the mixture is dried, 480ml of purified water is added, stirring and beating are carried out, filtration and water washing are carried out until the pH value of washing liquid is 4-5, and a wet 4-cyano benzoic acid product is obtained. Adding the wet 4-cyanobenzoic acid product into 3000ml of water, dropwise adding 20% sodium hydroxide, adjusting the pH to 10.5, stirring until the material is completely decomposed, and filtering. 2g of disodium ethylenediamine tetraacetate is added, stirred, 1g of active carbon is added, stirred for 30min, and filtered by a filter membrane until the mixture is clear. Concentrated hydrochloric acid was added dropwise to ph=4, filtered, and dried at 105 ℃ for 6 hours to give 52.1g of 4-cyanobenzoic acid with a purity of 86.0% and a molar yield of 83.7%.
Example 8
Synthesis of 4-cyanobenzoic acid
320g of 4-formamide benzoic acid in example 2, 1920ml of acetic anhydride are put into a 5L three-necked flask, nitrogen is replaced for 3 times, 22.6g of ferrous acetate tetrahydrate is added, nitrogen is replaced for 3 times again, reflux reaction is carried out for 6 hours at the temperature of 140 ℃ in an oil bath, decompression concentration is carried out to dryness, 2560ml of purified water is added, stirring beating is carried out, filtration is carried out, washing is carried out until the pH of washing liquid is 4-5, filtration is carried out, drying is carried out for 6 hours at 105 ℃ to obtain 265.8g of 4-cyanobenzoic acid, the purity is 96.3%, and the molar yield is 94.8%, thus obtaining 4-cyanobenzoic acid wet product.
Example 9
Synthesis of aminomethylbenzoic acid
265g of 4-cyanobenzoic acid of example 8, 2250ml of purified water and 750ml of ammonia water were added to a 5L three-necked flask, and the mixture was stirred to dissolve, 30g of activated carbon was added, stirred for 30 minutes, and then filtered. Adding the filtrate into a high-pressure hydrogenation kettle, adding 37.5g palladium carbon (palladium content 5%, water content 65%) into the kettle, replacing nitrogen for 3 times, supplementing hydrogen to 1.0Mpa, starting the reaction at about 30 ℃, keeping the temperature for continuous reaction for 1h after the hydrogen pressure is not reduced, stopping the reaction, and collecting the hydrogenated liquid. The hydrogenated solution was filtered, and after evaporation of ammonia gas, hydrochloric acid was added dropwise to a ph=3-4, 30g of activated carbon was added, stirred, and filtered. Concentrating to half of original volume, adding dropwise concentrated ammonia water into the hot concentrated solution, adjusting pH=7.5-8, cooling, standing for crystallization for 8h, filtering, drying at 105deg.C for 6h to obtain 240.9g of crude product of aminomethylbenzoic acid with purity of 98.2% and molar yield of 90.22%.
Adding the crude product of the aminomethylbenzoic acid into 960ml of purified water and 240ml of concentrated ammonia water, heating, stirring, dissolving, introducing vacuum, evaporating residual ammonia, regulating pH to 7.5-8.0 with hydrochloric acid, standing, crystallizing for 8h, and filtering. The wet product is dried for 6 hours at 105 ℃ to obtain 218.7g of refined tranexamic acid with the purity of 99.8 percent and the molar yield of 90.6 percent.
Claims (17)
1. A preparation method of the aminomethylbenzoic acid comprises the following reaction routes:
the method comprises the following steps:
(1) Dimethyl terephthalate is subjected to alkaline hydrolysis reaction in an organic solvent to obtain 4-methyl formate potassium benzoate;
(2) Carrying out amidation reaction on 4-methyl formate benzoate in a solvent, and regulating the pH value to be 1-6 to obtain 4-formamide benzoic acid;
(3) Carrying out dehydration reaction on 4-formamide benzoic acid in acetic anhydride to obtain 4-cyano benzoic acid;
(4) Dissolving 4-cyanobenzoic acid in ammonia water, and carrying out catalytic hydrogenation reaction to obtain the aminomethylbenzoic acid.
2. The process according to claim 1, wherein the hydrolysis reaction in step 1) is carried out at a temperature of 5-75deg.C, preferably 40-45deg.C.
3. The process according to claim 1, wherein the organic solvent in step 1) is toluene or methanol.
4. A process according to claim 3, wherein the volume ratio of toluene to methanol is from 0.3 to 1.5, preferably from 1.1 to 1.2.
5. The process of claim 1, wherein the base in step 1) is potassium hydroxide.
6. The process according to claim 1, wherein the amidation reaction temperature in step 2) is 20 to 120 ℃, preferably 30 to 100 ℃.
7. The preparation process as claimed in claim 1, wherein the amidation reaction in step 2) is carried out with ammonia as ammonia gas, aqueous ammonia, methanolic ammonia solution, ethanolic ammonia solution or ethanolic ammonia solution, preferably ammonia gas.
8. The process according to claim 1, wherein the solvent in step 2) is water, methanol, ethanol or/and acetone, preferably methanol.
9. The process according to claim 1, wherein the pH in step 2) is 3 to 4.
10. The process according to claim 1, wherein the dehydration reaction in step 3) is carried out at a reaction temperature of 80 ℃ to reflux temperature, preferably reflux temperature.
11. The process according to claim 1, wherein the dehydration reaction in step 3) further comprises a catalyst,
the catalyst is an iron-nickel catalyst selected from the group consisting of: one or more of iron powder, nickel powder, ferrous acetate, ferrous chloride, ferric chloride, dinonylcarbonyl iron, carbonyl iron, dodecacarbonyl iron and nickel hydroxide, preferably ferrous acetate.
12. The process according to claim 11, wherein the catalyst is fed in an amount of 1-10%, preferably 5% of the molar amount of 4-formamide benzoic acid.
13. The process according to claim 1, wherein the acetic anhydride is fed in an amount of 3 to 10 volumes, preferably 6 volumes, based on the mass of 4-formamide benzoic acid in step 3).
14. The process according to claim 1, wherein the hydrogenation reaction in step 4) is carried out at a reaction temperature of 25-45 ℃, preferably 30-35 ℃.
15. The process according to claim 1, wherein the hydrogenation reaction in step 4) is carried out at a reaction pressure of 0.1Mpa to 3.0Mpa, preferably 1.0Mpa.
16. The process according to claim 1, wherein the catalytic hydrogenation is carried out in step 4) with a catalyst selected from palladium on carbon, nickel silica and Raney nickel, preferably palladium on carbon.
17. The process according to claim 16, wherein the catalyst is fed in an amount of 1% to 30%, preferably 5% by mass of 4-cyanobenzoic acid.
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