CN118546068A - Technological improvement method of mesalamine - Google Patents
Technological improvement method of mesalamine Download PDFInfo
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- CN118546068A CN118546068A CN202411019103.2A CN202411019103A CN118546068A CN 118546068 A CN118546068 A CN 118546068A CN 202411019103 A CN202411019103 A CN 202411019103A CN 118546068 A CN118546068 A CN 118546068A
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- 238000000034 method Methods 0.000 title claims abstract description 37
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229960004963 mesalazine Drugs 0.000 title claims abstract description 32
- 230000006872 improvement Effects 0.000 title claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910000570 Cupronickel Inorganic materials 0.000 claims abstract description 17
- YOCUPQPZWBBYIX-UHFFFAOYSA-N copper nickel Chemical compound [Ni].[Cu] YOCUPQPZWBBYIX-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229960004889 salicylic acid Drugs 0.000 claims abstract description 17
- 239000002608 ionic liquid Substances 0.000 claims abstract description 15
- 230000008569 process Effects 0.000 claims abstract description 13
- LODHFNUFVRVKTH-ZHACJKMWSA-N 2-hydroxy-n'-[(e)-3-phenylprop-2-enoyl]benzohydrazide Chemical compound OC1=CC=CC=C1C(=O)NNC(=O)\C=C\C1=CC=CC=C1 LODHFNUFVRVKTH-ZHACJKMWSA-N 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 10
- YCNIBOIOWCTRCL-UHFFFAOYSA-N azane;2,2,2-trifluoroacetic acid Chemical compound [NH4+].[O-]C(=O)C(F)(F)F YCNIBOIOWCTRCL-UHFFFAOYSA-N 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 230000009467 reduction Effects 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 7
- NQAOOXILUKVBAU-UHFFFAOYSA-N CO.[N+](=O)([O-])[O-].[Cu+2].[N+](=O)([O-])[O-] Chemical compound CO.[N+](=O)([O-])[O-].[Cu+2].[N+](=O)([O-])[O-] NQAOOXILUKVBAU-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- NGKWYRANVWGTGG-UHFFFAOYSA-N [Ni++].CO.[O-][N+]([O-])=O.[O-][N+]([O-])=O Chemical compound [Ni++].CO.[O-][N+]([O-])=O.[O-][N+]([O-])=O NGKWYRANVWGTGG-UHFFFAOYSA-N 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 230000001376 precipitating effect Effects 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 238000005303 weighing Methods 0.000 claims description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 238000011049 filling Methods 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000011403 purification operation Methods 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000006722 reduction reaction Methods 0.000 description 10
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000006396 nitration reaction Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- XVMIKRZPDSXBTP-UHFFFAOYSA-N 1,3-dibromobutan-2-one Chemical compound CC(Br)C(=O)CBr XVMIKRZPDSXBTP-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QUEKGYQTRJVEQC-UHFFFAOYSA-N 2516-96-3 Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl QUEKGYQTRJVEQC-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- ZUJURJDZOPMJPH-UHFFFAOYSA-N 5-diazocyclohexa-1,3-diene;hydrochloride Chemical compound Cl.[N-]=[N+]=C1CC=CC=C1 ZUJURJDZOPMJPH-UHFFFAOYSA-N 0.000 description 2
- -1 Benzene azo salicylic acid Chemical compound 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 210000004347 intestinal mucosa Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- 238000007065 Kolbe-Schmitt synthesis reaction Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- NESLWCLHZZISNB-UHFFFAOYSA-M sodium phenolate Chemical compound [Na+].[O-]C1=CC=CC=C1 NESLWCLHZZISNB-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
- B01J23/74—Iron group metals
- B01J23/755—Nickel
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0278—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre
- B01J31/0281—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member
- B01J31/0284—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member of an aromatic ring, e.g. pyridinium
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0298—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature the ionic liquids being characterised by the counter-anions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J35/00—Catalysts, in general, characterised by their form or physical properties
- B01J35/19—Catalysts containing parts with different compositions
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a process improvement method of mesalamine, which comprises the following reaction steps: 2-hydroxybenzoic acid and ammonium trifluoroacetate are used as raw materials, and react in the presence of a supported copper-nickel catalyst and ionic liquid to generate mesalamine. The method for preparing mesalamine has the advantages of easily available raw materials, short reaction steps and convenient and simple post-treatment and purification operation. In addition, the supported copper-nickel catalyst and the ionic liquid adopted by the invention can synergistically improve the yield and purity of the reaction, and have good industrial production application prospects.
Description
Technical Field
The invention relates to the field of medicine synthesis, in particular to a process improvement method of mesalamine.
Background
Mesalamine, chemically named 5-aminosalicylic acid, is structurally: Is an organic compound widely applied to the field of medicine, has white to off-white powder appearance and has obvious anti-inflammatory effect. As a non-steroidal anti-inflammatory drug, mesalazine reduces prostaglandin synthesis in the body, mainly by inhibiting Cyclooxygenase (COX) activity, thus effectively alleviating inflammation and pain.
Mesalamine is developed and marketed by the company Boots Pharmaceutical in the united kingdom, and has excellent performance in the treatment of inflammatory diseases such as rheumatism and arthritis, and has an important role in the treatment of Inflammatory Bowel Diseases (IBD) such as Ulcerative Colitis (UC) and Crohn's Disease (CD). Mesalamine can remarkably inhibit intestinal wall inflammation, and inhibit biosynthesis and release of various inflammatory mediators by regulating local arachidonic acid metabolism of intestinal mucosa, so that the inflammatory state of the intestinal mucosa is effectively improved. In recent years, with the rising prevalence of IBD worldwide, mesalamine market demand has increased. Meanwhile, the continuous and deep development of the medicine promotes the innovation of new dosage forms and administration modes, and further improves the clinical application effect of mesalamine. Currently, mesalamine has become one of the important drugs for treating IBD, and has a broad market prospect, and is expected to keep a stable growth situation for the next few years. In the aspects of technical development and market expansion, various related enterprises are continuously increasing in investment so as to cope with the change and development of the market. The preparation method of mesalamine mainly comprises the following steps:
1) Salicylic acid nitration reduction method. The method takes salicylic acid as a raw material, synthesizes 5-nitrosalicylic acid through nitration reaction, and then reduces the 5-nitrosalicylic acid to obtain the 5-aminosalicylic acid. However, the method has the advantages of poor nitration reaction selectivity, low reaction yield, strong heat release and potential safety hazard. In addition, the pollution of the reduction reaction is serious, the production cost is higher, and the current industrial production requirement is not met.
2) Benzene azo salicylic acid reduction method. The method takes aniline as a raw material, diazobenzene chloride is synthesized through diazotization or directly takes the diazobenzene chloride as the raw material, then benzene azo salicylic acid is obtained through coupling with salicylic acid, and finally the target compound is synthesized through reduction. Although the method solves the problem of poor selectivity of salicylic acid nitration in the reduction method, the method has a plurality of reaction steps, needs to perform acid-base neutralization for many times, and is complex in operation. In addition, aniline is high in toxicity and serious in environmental pollution; the diazonium compound is unstable and easy to decompose when encountering light, and the dried diazonium salt can decompose and release nitrogen to explode, so that potential safety hazards exist.
3) Kolbe-Schmitt reaction method. The process is carried out on dried sodium phenolate or the like with carbon dioxide as electrophile, and carboxyl groups are finally formed on the aromatic ring. Or taking p-aminophenol as a raw material, and carrying out high-temperature high-pressure gas-solid reaction under the action of a catalyst to obtain the target compound. The method has short process route and high reaction yield. However, the reaction is sensitive to water, and even a small amount of water can significantly reduce the amount of product, and the anhydrous operation is highly required. And high temperature and high pressure are needed, the reaction conditions are harsh, and the operation is inconvenient. The toxicity of the raw materials is high, and the requirements of environmental protection and drug production are not met. Meanwhile, due to the positioning effect of-OH, -NH2 (or-NHCOCH 3) on the benzene ring, a certain amount of isomer still exists in the reaction, which brings trouble to post-treatment.
4) A halogenated aromatic hydrocarbon hydrolysis reduction method. The 5-nitro-o-chlorobenzoic acid is produced by nitration reaction by taking o-chlorobenzoic acid as a starting material, or the 5-nitro-o-chlorobenzoic acid is directly taken as the starting material, and is hydrolyzed under alkaline condition according to the hydrolysis principle of halogenated hydrocarbon to obtain 5-nitro-salicylic acid, and the 5-nitro-salicylic acid is reduced by zinc powder/hydrochloric acid to obtain a final product. The method has the advantages that the existence of electron-withdrawing groups, especially para-position nitro groups on the benzene ring, the hydrolysis reaction of the 5-nitro-o-chlorobenzoic acid is easy to carry out, and the reaction selectivity is good. However, halogenated aromatic hydrocarbon is an environment-friendly substance, and the problems of high cost, serious pollution and the like exist in the late reduction reaction.
Aiming at the problems of long reaction step, high cost, high toxicity, serious pollution and the like in the prior art, the development of a process improvement method of mesalamine suitable for industrial production is needed.
Disclosure of Invention
The invention aims to provide a process improvement method of mesalamine, which aims to solve the problems of long reaction step, high cost, high toxicity, serious pollution and the like in the prior art.
In order to solve the technical problems, the invention provides the following technical scheme:
a technological improvement method of mesalamine is characterized in that: 2-hydroxybenzoic acid and ammonium trifluoroacetate are used as raw materials, and react in the presence of a supported copper-nickel catalyst and ionic liquid to generate mesalamine, wherein the reaction formula is as follows:
The preparation method of the supported copper-nickel catalyst comprises the following steps:
Accurately weighing a proper amount of active carbon carrier, sequentially adding copper nitrate methanol solution and nickel nitrate methanol solution, heating to 60-90 ℃ in a water bath for reflux, fully impregnating the solution into the carrier under the action of ultrasonic waves, and evaporating and drying; then filling the obtained catalyst into an activation furnace, and roasting in a nitrogen atmosphere; and finally, reducing the roasted catalyst in a hydrogen reduction furnace to obtain the supported copper-nickel catalyst.
In some embodiments, the method of preparing the supported copper nickel catalyst preferably is:
Accurately weighing 10g of active carbon carrier (particle size is 15 meshes, specific surface area is 1000m 2/g, pore volume is 1.0 mL/g), then sequentially adding 1.0 mol/L of copper nitrate methanol solution (100 mL) and 0.1 mol/L of nickel nitrate methanol solution (100 mL), heating to 80 ℃ in a water bath to reflux, fully impregnating the solution into the carrier under the action of ultrasonic waves, evaporating the residual liquid, and drying at 100 ℃ for 2h. The resulting catalyst was then loaded into an activation furnace and calcined at 350 ℃ under nitrogen atmosphere for 2h. And finally, placing the roasted catalyst into a hydrogen reduction furnace, and reducing for 2 hours at 200 ℃ to obtain the supported copper-nickel catalyst.
In some embodiments, the ionic liquid has a cation of [ HDBU ] +, which has the structure: The anion is [ HCOO ] -、[CH3COO]-、[C6H5COO]-、[C2H5COO]-、Cl-、HSO4-.
In some embodiments, the ionic liquid is [ HDBU ] [ HCOO ], [ HDBU ] [ OAc ], [ HDBU ] [ Cl ].
In some embodiments, the molar ratio of the 2-hydroxybenzoic acid to the ammonium trifluoroacetate is 1 (1.5-3); the molar ratio of the 2-hydroxybenzoic acid to the ionic liquid is 1 (0.5-1.0).
In some embodiments, the reaction temperature is 50-100 ℃ and the reaction time is 3-10 hours.
In some embodiments, the reaction solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, DMSO, and DMF.
In some embodiments, the concentration of the copper nitrate methanol solution is (1-2) mol/L, and the concentration of the nickel nitrate methanol solution is (0.1-0.2) mol/L.
In some embodiments, after the reaction is finished, filtering, decompressing and concentrating the filtrate, then dissolving the concentrate in hot water, regulating the pH of the solution to 2.0-3.0 by using hydrochloric acid, standing, cooling, precipitating crystals, carrying out suction filtration, washing a filter cake by using cold water, and carrying out vacuum drying to obtain mesalamine.
The invention has the following beneficial effects:
The method for preparing mesalamine has the advantages of easily available raw materials, short reaction steps and convenient and simple post-treatment and purification operation. In addition, the supported copper-nickel catalyst and the ionic liquid adopted by the invention can synergistically improve the yield and purity of the reaction, and have good industrial production application prospects.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
No endpoints of the ranges and any values recited herein are limited to the precise range or value, and such range or value should be understood to encompass values approaching those range or value. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
Preparation example 1 preparation of supported copper nickel catalyst:
Accurately weighing 10g of active carbon carrier (particle size is 15 meshes, specific surface area is 1000m 2/g, pore volume is 1.0 mL/g), then sequentially adding 1.0 mol/L of copper nitrate methanol solution (100 mL) and 0.1 mol/L of nickel nitrate methanol solution (100 mL), heating to 80 ℃ in a water bath to reflux, fully impregnating the solution into the carrier under the action of ultrasonic waves, evaporating the residual liquid, and drying at 100 ℃ for 2h. The resulting catalyst was then loaded into an activation furnace and calcined at 350 ℃ under nitrogen atmosphere for 2h. And finally, placing the roasted catalyst into a hydrogen reduction furnace, and reducing for 2 hours at 200 ℃ to obtain the supported copper-nickel catalyst.
Example 1 preparation of mesalamine
2-Hydroxybenzoic acid (13.8 g, 0.1 mol) was added to methanol (200 mL) under nitrogen, followed by ammonium trifluoroacetate (32.8 g, 0.25 mol), the supported copper-nickel catalyst (2.0 g) obtained in preparation example 1 and ionic liquid [ HDBU ] [ OAc ] (0.1 mol) were added in this order, and the mixture was heated to 70℃and stirred for 5 hours. After the reaction, filtering, concentrating the filtrate under reduced pressure, then dissolving the concentrate in hot water (60 ℃), regulating the pH of the solution to 3.0 by using hydrochloric acid, standing, cooling, precipitating crystals, carrying out suction filtration, washing a filter cake by using cold water, and carrying out vacuum drying to obtain 12.8 g-white solid mesalamine, wherein the yield is 83.7%, and the HPLC purity is 99.3%.
LC-MS (ESI): [M+H]+=154.1；
13CNMR （400MHz,DMSO-d6）：δ171.82，156.15，132.21，124.56，118.83，117.35，115.28；
1HNMR (400 MHz, DMSO-d6)：δ= 13.22 (s,1H), 7.61-7.52(m,1H), 7.26 (d,1H) , 7.13 (d,1H) ,6.85 (dd,2H), 5.34 (s,1H).
EXAMPLE 2 preparation of mesalamine
2-Hydroxybenzoic acid (13.8 g, 0.1 mol) was added to ethanol (200 mL) under nitrogen, followed by ammonium trifluoroacetate (26.2 g, 0.2 mol), the supported copper-nickel catalyst (3.0 g) obtained in preparation example 1, and ionic liquid [ HDBU ] [ HCOO ] (0.1 mol) were added in this order, and the mixture was heated to 80℃and stirred for 3 hours. After the reaction, filtering, concentrating the filtrate under reduced pressure, then dissolving the concentrate in hot water (60 ℃), regulating the pH of the solution to 2.5 by using hydrochloric acid, standing, cooling, precipitating crystals, carrying out suction filtration, washing a filter cake by using cold water, and carrying out vacuum drying to obtain 13.4 g white solid mesalamine, wherein the yield is 87.6%, and the HPLC purity is 99.2%.
LC-MS (ESI): [M+H]+=154.1；
13CNMR （400MHz,DMSO-d6）：δ171.82，156.15，132.21，124.56，118.83，117.35，115.28；
1HNMR (400 MHz, DMSO-d6)：δ= 13.22 (s,1H), 7.61-7.52(m,1H), 7.26 (d,1H) , 7.13 (d,1H) ,6.85 (dd,2H), 5.34 (s,1H).
EXAMPLE 3 preparation of mesalamine
2-Hydroxybenzoic acid (13.8 g, 0.1 mol) was added to isopropanol (200 mL) under nitrogen protection, followed by ammonium trifluoroacetate (32.8 g, 0.25 mol), the supported copper-nickel catalyst (2.5 g) obtained in preparation example 1 and ionic liquid [ HDBU ] [ Cl ] (0.1 mol) were added in sequence, and the temperature was raised to 70℃and stirred for 6 hours. After the reaction, filtering, concentrating the filtrate under reduced pressure, then dissolving the concentrate in hot water (60 ℃), regulating the pH of the solution to 3.0 by using hydrochloric acid, standing, cooling, precipitating crystals, carrying out suction filtration, washing a filter cake by using cold water, and carrying out vacuum drying to obtain 13.1 g-like white solid mesalamine, wherein the yield is 85.6%, and the HPLC purity is 99.3%.
LC-MS (ESI): [M+H]+=154.1；
13CNMR （400MHz,DMSO-d6）：δ171.82，156.15，132.21，124.56，118.83，117.35，115.28；
1HNMR (400 MHz, DMSO-d6)：δ= 13.22 (s,1H), 7.61-7.52(m,1H), 7.26 (d,1H) , 7.13 (d,1H) ,6.85 (dd,2H), 5.34 (s,1H).
Comparative example 1 the ionic liquid was omitted on the basis of example 1
2-Hydroxybenzoic acid (13.8 g, 0.1: 0.1 mol) was added to methanol (200: 200 mL) under nitrogen protection, followed by ammonium trifluoroacetate (32.8: 32.8 g, 0.25: 0.25 mol) and the supported copper-nickel catalyst (2.0 g) obtained in preparation example 1 were added in this order, and the mixture was stirred and reacted at a temperature of 70℃for 5 hours. After the reaction, filtering, concentrating the filtrate under reduced pressure, then dissolving the concentrate in hot water (60 ℃), regulating the pH of the solution to 3.0 by using hydrochloric acid, standing, cooling, precipitating crystals, carrying out suction filtration, washing a filter cake by using cold water, and carrying out vacuum drying to obtain 8.3 g-like white solid mesalamine, wherein the yield is 54.2%, and the HPLC purity is 95.5%.
LC-MS (ESI): [M+H]+=154.1；
The above examples are presented for clarity of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. And thus obvious variations or modifications to the disclosure are within the scope of the invention.
Claims (8)
1. A technological improvement method of mesalamine is characterized in that: 2-hydroxybenzoic acid and ammonium trifluoroacetate are used as raw materials, and react in the presence of a supported copper-nickel catalyst and ionic liquid to generate mesalamine, wherein the reaction formula is as follows:
；
The preparation method of the supported copper-nickel catalyst comprises the following steps:
Accurately weighing a proper amount of active carbon carrier, sequentially adding copper nitrate methanol solution and nickel nitrate methanol solution, heating to 60-90 ℃ in a water bath for reflux, fully impregnating the solution into the carrier under the action of ultrasonic waves, and evaporating and drying; then filling the obtained catalyst into an activation furnace, and roasting in a nitrogen atmosphere; and finally, reducing the roasted catalyst in a hydrogen reduction furnace to obtain the supported copper-nickel catalyst.
2. The process improvement according to claim 1 wherein the ionic liquid has a cation of [ HDBU ] + and has the structure: The anion is [ HCOO ] -、[CH3COO]-、[C6H5COO]-、[C2H5COO]-、Cl-、HSO4-.
3. The process improvement according to claim 1 wherein said ionic liquid is [ HDBU ] [ HCOO ], [ HDBU ] [ OAc ], [ HDBU ] [ Cl ].
4. The process improvement according to claim 1, wherein the molar ratio of 2-hydroxybenzoic acid to ammonium trifluoroacetate is 1 (1.5-3); the molar ratio of the 2-hydroxybenzoic acid to the ionic liquid is 1 (0.5-1.0).
5. The process improvement according to claim 1, wherein the reaction temperature is 50 to 100 ℃ and the reaction time is 3 to 10 hours.
6. The process improvement as claimed in claim 1 wherein the reaction solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, DMSO and DMF.
7. The process improvement according to claim 1, characterized in that the concentration of the copper nitrate methanol solution is (1-2) mol/L, and the concentration of the nickel nitrate methanol solution is (0.1-0.2) mol/L.
8. The process improvement method according to claim 1, wherein after the reaction is finished, filtering, concentrating the filtrate under reduced pressure, then dissolving the concentrate in hot water, adjusting the pH of the solution to 2.0-3.0 with hydrochloric acid, standing, cooling, precipitating crystals, filtering, washing the filter cake with cold water, and vacuum drying to obtain mesalamine.
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| WO2023144678A1 (en) * | 2022-01-25 | 2023-08-03 | Chemi S.P.A. | Process for the purification of 5-aminosalicylic acid |
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| WO2023144678A1 (en) * | 2022-01-25 | 2023-08-03 | Chemi S.P.A. | Process for the purification of 5-aminosalicylic acid |
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