CN112920078A - Method for preparing 4-cyanobenzoic acid methyl ester and method for preparing 4-cyanobenzoic acid - Google Patents
Method for preparing 4-cyanobenzoic acid methyl ester and method for preparing 4-cyanobenzoic acid Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 47
- ADCUEPOHPCPMCE-UHFFFAOYSA-N 4-cyanobenzoic acid Chemical compound OC(=O)C1=CC=C(C#N)C=C1 ADCUEPOHPCPMCE-UHFFFAOYSA-N 0.000 title claims abstract description 26
- KKZMIDYKRKGJHG-UHFFFAOYSA-N methyl 4-cyanobenzoate Chemical compound COC(=O)C1=CC=C(C#N)C=C1 KKZMIDYKRKGJHG-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- 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 28
- 239000000126 substance Substances 0.000 claims abstract description 23
- REIDAMBAPLIATC-UHFFFAOYSA-M 4-methoxycarbonylbenzoate Chemical compound COC(=O)C1=CC=C(C([O-])=O)C=C1 REIDAMBAPLIATC-UHFFFAOYSA-M 0.000 claims abstract description 20
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 16
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229940095102 methyl benzoate Drugs 0.000 claims abstract description 11
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 8
- ADCUEPOHPCPMCE-UHFFFAOYSA-M 4-cyanobenzoate Chemical compound [O-]C(=O)C1=CC=C(C#N)C=C1 ADCUEPOHPCPMCE-UHFFFAOYSA-M 0.000 claims abstract description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 27
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- 239000012320 chlorinating reagent Substances 0.000 claims description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
- 229910021529 ammonia Inorganic materials 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- BAXOYLCGOYSPJH-UHFFFAOYSA-N methyl 4-carbamoylbenzoate Chemical compound COC(=O)C1=CC=C(C(N)=O)C=C1 BAXOYLCGOYSPJH-UHFFFAOYSA-N 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 5
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 239000012024 dehydrating agents Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 23
- 235000011114 ammonium hydroxide Nutrition 0.000 abstract description 6
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000005660 chlorination reaction Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 238000005580 one pot reaction Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000003912 environmental pollution Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- WWYFPDXEIFBNKE-UHFFFAOYSA-N 4-(hydroxymethyl)benzoic acid Chemical compound OCC1=CC=C(C(O)=O)C=C1 WWYFPDXEIFBNKE-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- XAASLEJRGFPHEV-UHFFFAOYSA-N 4-cyanobenzyl alcohol Chemical compound OCC1=CC=C(C#N)C=C1 XAASLEJRGFPHEV-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010014522 Embolism venous Diseases 0.000 description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- -1 aryl halogenated hydrocarbon Chemical class 0.000 description 2
- XHOLNRLADUSQLD-UHFFFAOYSA-N betrixaban Chemical compound C=1C=C(Cl)C=NC=1NC(=O)C1=CC(OC)=CC=C1NC(=O)C1=CC=C(C(=N)N(C)C)C=C1 XHOLNRLADUSQLD-UHFFFAOYSA-N 0.000 description 2
- 229950011103 betrixaban Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000007333 cyanation reaction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 208000004043 venous thromboembolism Diseases 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-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
- VCZNNAKNUVJVGX-UHFFFAOYSA-N 4-methylbenzonitrile Chemical compound CC1=CC=C(C#N)C=C1 VCZNNAKNUVJVGX-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000012769 display material Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- NJSUFZNXBBXAAC-UHFFFAOYSA-N ethanol;toluene Chemical compound CCO.CC1=CC=CC=C1 NJSUFZNXBBXAAC-UHFFFAOYSA-N 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000000988 hyperfibrinolytic effect Effects 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- BKBMACKZOSMMGT-UHFFFAOYSA-N methanol;toluene Chemical compound OC.CC1=CC=CC=C1 BKBMACKZOSMMGT-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/20—Preparation of carboxylic acid nitriles by dehydration of carboxylic acid amides
Abstract
The invention relates to the field of synthesis, and discloses a method for preparing 4-cyanobenzoic acid methyl ester and a method for preparing 4-cyanobenzoic acid, which comprise the following steps: (1) in the presence of a first alkaline substance, carrying out a first hydrolysis reaction on dimethyl terephthalate to obtain monomethyl terephthalate; (2) sequentially carrying out contact reaction on the monomethyl terephthalate with a chlorination reagent and ammonia water to obtain 4-carbamyl methyl benzoate; (3) and carrying out dehydration reaction on the 4-carbamyl methyl benzoate to obtain the 4-cyanobenzoate. The method for preparing the methyl 4-cyanobenzoate and the 4-cyanobenzoate has the advantages that the reaction raw materials are cheap and easy to obtain, and the target compound can be efficiently and environmentally-friendly prepared by the processes of hydrolyzing, ammoniating, dehydrating, optionally further hydrolyzing the raw materials.
Description
Technical Field
The invention relates to the field of synthesis, and particularly relates to a method for preparing 4-cyanobenzoic acid methyl ester and a method for preparing 4-cyanobenzoic acid.
Background
Methyl 4-cyanobenzoate is an important chemical raw material, is in the form of white flaky crystals, and can be hydrolyzed to obtain 4-cyanobenzoic acid. 4-Cyanobenzoic acid is a white leaf-like crystal with melting point 217-.
4-cyanobenzoic acid is used as an intermediate of the aromatic hemostatic acid, can be used for treating hemorrhage caused by hyperfibrinolytic process, is also an important intermediate for synthesizing oral highly selective coagulation factor Xa inhibitor Betrixaban (Betrixaban), and is currently used in phase III clinical tests for preventing and treating acute Venous Thromboembolism (VTE) of patients with high-risk acute internal medicine and clinical tests for preventing and treating Pulmonary Embolism (PE) in more than 50 countries such as the United states, the United kingdom and the like.
In addition, 4-cyanobenzoic acid is also an important raw material for synthesizing pyrimidine liquid crystal display materials, and the materials have the remarkable advantages of low starting voltage, wide nematic temperature, wider mesomorphic region and the like.
The existing synthesis method of 4-cyanobenzoic acid mainly comprises the following methods:
one is the Sandmeyer process, which uses p-aminobenzoic acid as raw material, K2Cu2(CN)4、Na2Cu2(CN)4The amino group is converted into a cyano group by Sandmeyer cyaniding reaction as a cyaniding reagent, but the method uses a highly toxic metal cyanide, so that great hidden danger exists in production and environmental pollution is serious.
Secondly, 4-chloromethyl benzonitrile is used as a raw material, concentrated nitric acid is used as an oxidant, and 4-cyanobenzoic acid is synthesized, although the synthesis route is simple, the byproducts are too many, the pollution is serious, the three wastes are not easy to treat, and the synthesis method is not suitable for industrial application;
thirdly, the 4-cyanobenzoic acid is prepared by oxidizing the p-4-methyl benzonitrile or 4-hydroxymethyl benzonitrile as the raw material. The synthetic route is simple, but the starting material 4-methyl benzonitrile or 4-hydroxymethyl benzonitrile is difficult to obtain, and potassium permanganate type strong oxidant is often needed in the oxidation process, so that the environmental pollution is serious.
Fourthly, p-hydroxymethylbenzoic acid is used as a raw material to synthesize 4-cyanobenzoic acid, but the p-hydroxymethylbenzoic acid serving as a starting material is difficult to obtain in a large amount, and formic acid is used in the synthesis method, so that the formic acid is high in corrosivity and is not suitable for working operation.
Fifthly, the ammoxidation method is adopted to prepare and synthesize the 4-cyanobenzoic acid, but the method has the biggest problems of harsh reaction conditions, high pressure and temperature required in the reaction process, increased equipment requirements of industrial production and unsuitability for industrial mass production.
Sixthly, a catalytic aryl halogenated hydrocarbon cyanation method is adopted, and halogenated aromatic hydrocarbon is used as a raw material and is converted into aryl cyanides under catalysis, the method is high in yield and few in reaction steps, but expensive catalysts are required for reaction, and the used cyanation reagent has the problems of high toxicity, large environmental pollution, high price and the like, and is still in the laboratory research stage at present.
In conclusion, the existing method for synthesizing 4-cyanobenzoic acid has the limitations that the starting raw materials are expensive and are not easy to obtain, the byproducts in the reaction process are too many, a virulent cyaniding reagent is used or the corrosive property of the reagent is strong, the temperature and the pressure are high, and the like, and the existing method cannot meet the requirement of modern production of 4-cyanobenzoic acid.
Disclosure of Invention
The invention aims to solve the problems of low preparation yield of 4-cyanobenzoic acid, more byproducts, large three-waste pollution, difficult obtainment of raw materials and the like.
In order to achieve the above object, a first aspect of the present invention provides a method for preparing methyl 4-cyanobenzoate, which comprises:
(1) in the presence of a first alkaline substance, carrying out a first hydrolysis reaction on dimethyl terephthalate to obtain monomethyl terephthalate;
(2) sequentially carrying out contact reaction on the monomethyl terephthalate with a chlorinating agent and an ammonia-containing material flow to obtain 4-carbamyl methyl benzoate;
(3) and carrying out dehydration reaction on the 4-carbamyl methyl benzoate to obtain the 4-cyanobenzoate.
A second aspect of the present invention provides a method for preparing 4-cyanobenzoic acid, which comprises:
(a) preparing methyl 4-cyanobenzoate by the method of the first aspect of the invention;
(b) and carrying out a second hydrolysis reaction on the methyl 4-cyanobenzoate in the presence of a second alkaline substance to obtain the 4-cyanobenzoic acid.
The method for preparing the methyl 4-cyanobenzoate and the 4-cyanobenzoate has the advantages that the reaction raw materials are cheap and easy to obtain, and the target compound can be efficiently and environmentally-friendly prepared by the processes of hydrolyzing, ammoniating, dehydrating, optionally further hydrolyzing the raw materials.
The method also has the advantage of high purity of the target product, and the process provided by the invention has the advantages of simple post-treatment, high reaction yield, recyclable raw materials and less three-waste discharge. Therefore, the process of the invention is suitable for industrial production.
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
As previously mentioned, the first aspect of the present invention provides a process for the preparation of methyl 4-cyanobenzoate, which comprises:
(1) in the presence of a first alkaline substance, carrying out a first hydrolysis reaction on dimethyl terephthalate to obtain monomethyl terephthalate;
(2) sequentially carrying out contact reaction on the monomethyl terephthalate with a chlorinating agent and an ammonia-containing material flow to obtain 4-carbamyl methyl benzoate;
(3) and carrying out dehydration reaction on the 4-carbamyl methyl benzoate to obtain the 4-cyanobenzoate.
Preferably, in the step (1), the first basic substance is at least one selected from the group consisting of potassium hydroxide, sodium hydroxide, potassium carbonate and cesium carbonate; it is particularly preferred that the first alkaline substance is potassium hydroxide.
Preferably, in step (1), the molar ratio of the dimethyl terephthalate to the first basic substance is 1: (0.8-1.5).
Preferably, in step (1), the first hydrolysis reaction is carried out in the presence of a first solvent selected from at least one of methanol, ethanol, toluene and water. The first solvent in the present invention may be, for example, methanol, ethanol, methanol-toluene, ethanol-toluene, methanol-water, ethanol-water, or the like.
According to a preferred embodiment, in step (1), the molar ratio of the dimethyl terephthalate to the first solvent is 1: (10-100).
Preferably, in step (1), the temperature of the first hydrolysis reaction is 10 to 80 ℃.
The inventors of the present invention found that, in the step (1), by controlling the molar ratio of the dimethyl terephthalate to the first solvent to be 1: (10-100) and controlling the molar ratio of the dimethyl terephthalate to the first alkaline substance to be 1: (0.8-1.5), the one-step reaction yield of the step (1) can be more than 95%; and has the advantage of simple post-processing.
Preferably, in step (2), the contact reaction with the chlorinating reagent is a first contact reaction, and the temperature of the first contact reaction is 80-120 ℃.
Preferably, in the step (2), the mole ratio of the monomethyl terephthalate to the chlorinating agent is 1: (1.2-4).
Preferably, in step (2), the chlorinating agent is selected from at least one of triphosgene, thionyl chloride, phosphorus trichloride, phosphorus oxychloride and phosphorus pentachloride. It is particularly preferred that the chlorinating agent is thionyl chloride.
In a particularly preferred case, the solvent for the contact reaction of the step (2) in the present invention is toluene, and the solvent for the contact reaction of the step (2) may be, for example, benzene, dichloromethane, chloroform, 1, 2-dichloroethane, or the like.
According to a particularly preferred embodiment, the mixture obtained after the contact reaction of the monomethyl terephthalate with the chlorinating agent (i.e. the first contact reaction as defined above) is subjected to a solvent removal treatment before the contact reaction with the aqueous ammonia; then, the product obtained after the solvent removal treatment is subjected to a contact reaction with the aqueous ammonia (i.e., a second contact reaction defined later).
Preferably, in the step (2), the contact reaction with the aqueous ammonia is a second contact reaction, and the conditions of the second contact reaction include: the reaction temperature is-5 to 25 ℃, and the reaction time is 0.5 to 30 min.
Preferably, in step (2), the ammonia-containing stream is ammonia and/or ammonia gas.
Preferably, in step (2), the first contacting reaction is carried out in the presence of a catalyst, which is particularly preferably DMF (N, N-dimethylformamide). The amount of the catalyst is not particularly limited and can be selected by those skilled in the art in combination with the conventional amount of the catalyst.
Particularly preferably, the chlorinating agent used in the step (2) of the present invention enables the contact reaction of the step (2) to have the advantages of clean reaction, environmental protection, high efficiency and no by-product. The acid chloride obtained from the chlorinating agent used in step (2) of the present invention is subjected to a second contact reaction with an ammonia-containing stream (e.g., ammonia water and/or ammonia gas), wherein the second contact reaction is rapid, and usually only requires 5-10 min. The process can avoid the defects of more byproducts, low yield and even pressurized reaction caused by direct ammoniation by using dimethyl terephthalate in the prior art, and is suitable for industrial amplification.
Preferably, in the step (3), the dehydration reaction is carried out in the presence of at least one dehydrating agent selected from the group consisting of phosphorus pentoxide, phosphorus oxychloride, phosphorus trichloride and acetic anhydride.
Preferably, in the step (3), the weight ratio of the dehydrating agent to the methyl 4-carbamoylbenzoate is (3-10): 1.
preferably, in step (3), the dehydration reaction is performed under reflux.
As previously described, the second aspect of the present invention provides a method for producing 4-cyanobenzoic acid, which comprises:
(a) preparing methyl 4-cyanobenzoate by the method described in the first aspect of the invention;
(b) and carrying out a second hydrolysis reaction on the methyl 4-cyanobenzoate in the presence of a second alkaline substance to obtain the 4-cyanobenzoic acid.
In order to avoid repetition, the present invention will not be described in detail herein with respect to the process for the preparation of methyl 4-cyanobenzoate, and the features with respect to the process for the preparation of methyl 4-cyanobenzoate are the same as those described in the foregoing first aspect, and those skilled in the art should not be construed as limiting the present invention.
Preferably, in the step (b), the second basic substance is at least one selected from the group consisting of potassium hydroxide, sodium hydroxide, potassium carbonate and cesium carbonate.
In the present invention, the first basic substance and the second basic substance may be the same or different, and in the present invention, it is particularly preferable that the first basic substance and the second basic substance are the same.
Preferably, in the step (b), the molar ratio of the methyl 4-cyanobenzoate to the second basic substance is 1: (0.8-1.5).
Preferably, in step (b), the temperature of the second hydrolysis reaction is 10-80 ℃.
According to a particularly preferred embodiment, the present invention provides a process for preparing 4-cyanobenzoic acid, which comprises:
(a1) in the presence of a first alkaline substance, carrying out a first hydrolysis reaction on dimethyl terephthalate to obtain monomethyl terephthalate;
(a2) sequentially carrying out contact reaction on the monomethyl terephthalate with a chlorinating agent and an ammonia-containing material flow to obtain 4-carbamyl methyl benzoate;
(a3) carrying out dehydration reaction on the 4-carbamyl methyl benzoate to obtain the 4-cyanobenzoate;
(b) and carrying out a second hydrolysis reaction on the methyl 4-cyanobenzoate in the presence of a second alkaline substance to obtain the 4-cyanobenzoic acid.
In the present invention, unless otherwise specified, the solvent used may be an aqueous solvent (if aqueous, the water content may be a water content which is commercially available in the art) or may be an anhydrous solvent.
The preparation method of the present invention may further include various post-treatment steps conventionally used in the art, such as washing with water, filtering, evaporating, recrystallizing, stirring, adjusting pH, etc., which are not particularly limited in the present invention, and several specific post-treatment operations are provided in the examples of the present invention, which should not be construed as limiting the present invention by those skilled in the art.
The post-treatment step of step (1) of the present invention may be, for example: the mixture obtained after the first hydrolysis reaction is subjected to solvent recovery, and the remaining product obtained after solvent recovery is dissolved with water (or other soluble solvent), and after or without filtration, for example, hydrochloric acid (no particular requirement for concentration) is added to the solution to adjust the pH to an acidic value, for example, to a pH of about 4, to obtain the monomethyl terephthalate.
Likewise, the post-treatment step in the step (b) for the present invention may also employ an operation similar to the post-treatment step of the step (1).
The reaction time of each step is not particularly required in the present invention unless otherwise specified, and those skilled in the art can determine an appropriate reaction time by integrating the reaction conditions of the raw materials according to actual conditions, and those skilled in the art should not be construed as limiting the present invention.
Unless specifically stated otherwise, the terms "first," "second," and the like, as used herein, do not denote any order, but rather are used to clearly convey that the operation(s) described are two separate operations.
The present invention will be described in detail below by way of examples. In the following examples, the various starting materials used are all analytical commercially available products unless otherwise specified.
Example 1
(1) Preparation of monomethyl terephthalate
Adding 1.35L of methanol and 56g (1mol) of KOH into a reaction bottle, heating to completely dissolve the KOH, then adding 194.2g (1mol) of dimethyl terephthalate, continuously heating to reflux reaction (the temperature is 65 +/-1 ℃), monitoring the reaction process by TLC, keeping the temperature for reaction for 4 hours, and then distilling under reduced pressure to recover the methanol. The obtained white solid was dissolved in water, stirred for 30min and then filtered, and about 11g of unreacted raw material was recovered. The filtrate was acidified to pH 4 with hydrochloric acid (36 mass%), the product precipitated, filtered under stirring for 1h, and washed with water to give monomethyl terephthalate with a yield of 95.3% in one step (yield after removal of recovered raw materials) and a purity of 98.0%.
(2) Preparation of methyl 4-carbamoylbenzoate
Adding 40g (0.22mol) of monomethyl terephthalate, 200mL of toluene, 0.44mol of thionyl chloride and 0.5mL of DMF into a reaction bottle, heating to reflux for reaction for 2h, clarifying the reaction solution, cooling to 45 ℃ after the reaction is finished, evaporating the toluene under reduced pressure for recovery, slowly dripping acyl chloride into ammonia (136mL) cooled to 0 ℃, absorbing tail gas by dilute alkali liquor to generate white solid, reacting at 25 ℃ for 1h after dripping is finished, filtering to obtain the white solid, washing with water and drying to obtain the methyl 4-carbamoylbenzoate, wherein the purity is 98.0%, and the one-step reaction yield is 97.1%.
(3) Preparation of methyl 4-cyanobenzoate
Adding 179.17g (1mol) of 4-carbamoylmethyl benzoate and 896g (5.8mol) of phosphorus oxychloride into a three-necked bottle, heating to reflux, carrying out TLC detection reaction until the raw materials disappear, carrying out reduced pressure distillation to recover the phosphorus oxychloride, pouring the residual liquid into 1L of ice water, continuously stirring for 30min, filtering, washing the filter cake twice, recrystallizing the obtained solid with methanol to obtain the 4-cyanobenzoic acid methyl ester, wherein the one-step reaction yield is 94.2%, and the HPLC detection purity is 99.0%.
(4) Preparation of 4-cyanobenzoic acid
161g (1mol) of methyl 4-cyanobenzoate and 1.9L of ethanol are added into a three-necked flask, the mixture is stirred for 30min, after all the raw materials are dissolved, 345mL of 2.9mol/L NaOH solution is slowly dripped at 25 ℃, the TLC is used for tracking reaction, and the reaction is finished after 2 h. And (3) carrying out rotary evaporation under reduced pressure to recover ethanol, adding water to dissolve the obtained solid sodium salt, washing the solution twice with dichloromethane, adjusting the pH value of a water phase to be about 4, separating out a solid, filtering, washing with water, and drying to obtain 144g of a target product, wherein the one-step reaction yield is 98.1%, and the HPLC purity is 99.0%.
Example 2
(1) Preparation of monomethyl terephthalate
Adding 40mol of ethanol and 1.1mol of KOH into a reaction bottle, heating to completely dissolve the KOH, then adding 1mol of dimethyl terephthalate, continuously heating to reflux reaction, monitoring the reaction process by TLC, keeping the temperature for reaction for 4.5h, and then carrying out reduced pressure distillation to recover the solvent. The obtained white solid was dissolved in water, stirred for 30min and then filtered, and about 10g of unreacted raw material was recovered. The filtrate was acidified to pH 4 with hydrochloric acid (36 mass%), the product precipitated, filtered under stirring for 1h, washed with water to give monomethyl terephthalate, in one step the yield was 95.5% (yield after removal of recovered starting material), with a purity of 98.1%.
(2) Preparation of methyl 4-carbamoylbenzoate
Adding 0.22mol of monomethyl terephthalate and 200mL of toluene into a reaction bottle, heating to 60 ℃, slowly adding 0.3mol of phosphorus trichloride into a reaction solution dropwise, heating to 80 ℃ for reaction for 2h, after the reaction is finished, evaporating toluene under reduced pressure for recovery, slowly adding the obtained acyl chloride dropwise into ammonia water (150mL) cooled to 0 ℃, absorbing tail gas by using dilute alkali liquor to generate white solid, reacting at 25 ℃ for 1h after the dropwise addition is finished, filtering to obtain the white solid, washing with water and drying to obtain the methyl 4-carbamoylbenzoate, wherein the purity is 98.1%, and the one-step reaction yield is 97.2%.
(3) Preparation of methyl 4-cyanobenzoate
Adding 179.17g (1mol) of 4-carbamyl methyl benzoate and 7.2mol of acetic anhydride into a three-necked bottle, heating to reflux, carrying out TLC detection reaction until the raw materials disappear, carrying out reduced pressure distillation to recover the acetic anhydride, pouring the residual liquid into 1L of ice water, continuously stirring for 30min, filtering, washing the filter cake twice, recrystallizing the obtained solid with methanol to obtain 4-cyano methyl benzoate, wherein the one-step reaction yield is 94.3%, and the HPLC detection purity is 99.0%.
(4) Preparation of 4-cyanobenzoic acid
161g (1mol) of methyl 4-cyanobenzoate and 1.9L of ethanol are added into a three-necked flask, the mixture is stirred for 30min, 380mL of 2.9mol/L NaOH solution is slowly dripped at 25 ℃ after the raw materials are dissolved, the TLC is used for tracking reaction, and the reaction is finished after 2 h. And (3) carrying out rotary evaporation under reduced pressure to recover ethanol, adding water to dissolve the obtained solid sodium salt, washing the solution twice with dichloromethane, adjusting the pH value of a water phase to be about 4, separating out a solid, filtering, washing with water, and drying to obtain 144g of a target product, wherein the one-step reaction yield is 98.0%, and the HPLC purity is 99.0%.
Therefore, the raw materials of the preparation method provided by the invention are cheap and easy to obtain, and the target compound can be efficiently and environmentally prepared by the processes of hydrolyzing, ammoniating, dehydrating and optionally further hydrolyzing the raw materials.
The method also has the advantage of high purity of the target product.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (10)
1. A method for preparing methyl 4-cyanobenzoate, comprising:
(1) in the presence of a first alkaline substance, carrying out a first hydrolysis reaction on dimethyl terephthalate to obtain monomethyl terephthalate;
(2) sequentially carrying out contact reaction on the monomethyl terephthalate with a chlorinating agent and an ammonia-containing material flow to obtain 4-carbamyl methyl benzoate;
(3) and carrying out dehydration reaction on the 4-carbamyl methyl benzoate to obtain the 4-cyanobenzoate.
2. The method according to claim 1, wherein, in step (1), the first basic substance is at least one selected from the group consisting of potassium hydroxide, sodium hydroxide, potassium carbonate, and cesium carbonate;
preferably, in step (1), the molar ratio of the dimethyl terephthalate to the first basic substance is 1: (0.8-1.5).
3. The process according to claim 1 or 2, wherein, in step (1), the first hydrolysis reaction is carried out in the presence of a first solvent selected from at least one of methanol, ethanol, toluene and water;
preferably, in the step (1), the molar ratio of the dimethyl terephthalate to the first solvent is 1: (10-100).
4. The process according to any one of claims 1 to 3, wherein in step (1), the temperature of the first hydrolysis reaction is 10 to 80 ℃.
5. The process of any one of claims 1 to 4, wherein, in step (2), the contact reaction with the chlorinating reagent is a first contact reaction, the temperature of the first contact reaction being 80-120 ℃;
preferably, in the step (2), the mole ratio of the monomethyl terephthalate to the chlorinating agent is 1: (1.2-4);
preferably, in step (2), the chlorinating agent is selected from at least one of triphosgene, thionyl chloride, phosphorus trichloride, phosphorus oxychloride and phosphorus pentachloride;
preferably, in step (2), the ammonia-containing stream is aqueous ammonia and/or ammonia gas.
6. The method according to any one of claims 1 to 5, wherein, in the step (2), the contact reaction with the aqueous ammonia is a second contact reaction, and conditions of the second contact reaction include: the reaction temperature is-5 to 25 ℃, and the reaction time is 0.5 to 30 min.
7. The process according to any one of claims 1 to 6, wherein, in step (3), the dehydration reaction is carried out in the presence of at least one dehydrating agent selected from phosphorus pentoxide, phosphorus oxychloride, phosphorus trichloride and acetic anhydride;
preferably, in the step (3), the weight ratio of the dehydrating agent to the methyl 4-carbamoylbenzoate is (3-10): 1.
8. the method according to any one of claims 1 to 7, wherein, in step (3), the dehydration reaction is carried out under reflux.
9. A method of preparing 4-cyanobenzoic acid, comprising:
(a) preparing methyl 4-cyanobenzoate by the method of any one of claims 1 to 8;
(b) and carrying out a second hydrolysis reaction on the methyl 4-cyanobenzoate in the presence of a second alkaline substance to obtain the 4-cyanobenzoic acid.
10. The method according to claim 9, wherein, in step (b), the second basic substance is selected from at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, and cesium carbonate;
preferably, in the step (b), the molar ratio of the methyl 4-cyanobenzoate to the second basic substance is 1: (0.8-1.5);
preferably, in step (b), the temperature of the second hydrolysis reaction is 10-80 ℃.
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