CN111672517A - Preparation method of X-CT contrast agent intermediate - Google Patents
Preparation method of X-CT contrast agent intermediate Download PDFInfo
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- CN111672517A CN111672517A CN202010690215.6A CN202010690215A CN111672517A CN 111672517 A CN111672517 A CN 111672517A CN 202010690215 A CN202010690215 A CN 202010690215A CN 111672517 A CN111672517 A CN 111672517A
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- reaction
- contrast agent
- benzenedicarboxamide
- dihydroxypropyl
- nitro
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- 239000002872 contrast media Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 17
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 17
- WGTJGVDPCKNNFQ-UHFFFAOYSA-N 3-n-(2,3-dihydroxypropyl)benzene-1,3-dicarboxamide Chemical compound NC(=O)C1=CC=CC(C(=O)NCC(O)CO)=C1 WGTJGVDPCKNNFQ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 11
- 229910044991 metal oxide Inorganic materials 0.000 claims abstract description 11
- 150000004706 metal oxides Chemical class 0.000 claims abstract description 11
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 9
- 239000012429 reaction media Substances 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 14
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 7
- 239000005751 Copper oxide Substances 0.000 claims description 7
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 7
- 229910000423 chromium oxide Inorganic materials 0.000 claims description 7
- 229910000431 copper oxide Inorganic materials 0.000 claims description 7
- 239000013078 crystal Substances 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 4
- SJLOMQIUPFZJAN-UHFFFAOYSA-N oxorhodium Chemical compound [Rh]=O SJLOMQIUPFZJAN-UHFFFAOYSA-N 0.000 claims description 4
- 229910003450 rhodium oxide Inorganic materials 0.000 claims description 4
- 229910000480 nickel oxide Inorganic materials 0.000 claims description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 3
- GNRSAWUEBMWBQH-UHFFFAOYSA-N oxonickel Chemical compound [Ni]=O GNRSAWUEBMWBQH-UHFFFAOYSA-N 0.000 claims description 3
- 229910001925 ruthenium oxide Inorganic materials 0.000 claims description 3
- WOCIAKWEIIZHES-UHFFFAOYSA-N ruthenium(iv) oxide Chemical compound O=[Ru]=O WOCIAKWEIIZHES-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- -1 N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide hydrochloride Chemical compound 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 229960004359 iodixanol Drugs 0.000 description 2
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 description 2
- 229960001025 iohexol Drugs 0.000 description 2
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- MQDLKAADJTYKRH-UHFFFAOYSA-N 1-aminopropane-1,2,3-triol Chemical compound NC(O)C(O)CO MQDLKAADJTYKRH-UHFFFAOYSA-N 0.000 description 1
- GNBBCFFLJFKAHB-UHFFFAOYSA-N 5-amino-1-n,3-n-bis(2,3-dihydroxypropyl)benzene-1,3-dicarboxamide;hydrochloride Chemical compound Cl.NC1=CC(C(=O)NCC(O)CO)=CC(C(=O)NCC(O)CO)=C1 GNBBCFFLJFKAHB-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- GGTSJKFPGKFLCZ-UHFFFAOYSA-N dimethyl 5-nitrobenzene-1,3-dicarboxylate Chemical compound COC(=O)C1=CC(C(=O)OC)=CC([N+]([O-])=O)=C1 GGTSJKFPGKFLCZ-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- 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
- B01J23/76—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper combined with metals, oxides or hydroxides provided for in groups B01J23/02 - B01J23/36
- B01J23/84—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper combined with metals, oxides or hydroxides provided for in groups B01J23/02 - B01J23/36 with arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
- B01J23/85—Chromium, molybdenum or tungsten
- B01J23/86—Chromium
- B01J23/868—Chromium copper and chromium
-
- 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
- B01J23/002—Mixed oxides other than spinels, e.g. perovskite
-
- 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
- B01J23/76—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper combined with metals, oxides or hydroxides provided for in groups B01J23/02 - B01J23/36
- B01J23/84—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper combined with metals, oxides or hydroxides provided for in groups B01J23/02 - B01J23/36 with arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
- B01J23/85—Chromium, molybdenum or tungsten
- B01J23/88—Molybdenum
- B01J23/887—Molybdenum containing in addition other metals, oxides or hydroxides provided for in groups B01J23/02 - B01J23/36
- B01J23/8878—Chromium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- 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
- B01J2523/00—Constitutive chemical elements of heterogeneous catalysts
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a preparation method of an X-CT contrast agent intermediate, which comprises the steps of taking 5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide as a raw material, hydrazine hydrate as a reducing agent, water and acetic acid as reaction media, metal oxide as a catalyst, and introducing hydrogen chloride after complete reaction to obtain a target product; hydrazine hydrate is used as a reducing agent, so that the storage is easy, the potential safety hazard in the production process is reduced, the metal oxide is used as a catalyst, the raw materials are cheap and easy to obtain, the catalytic effect is good, and the catalyst can be recycled and regenerated; the acetic acid aqueous solution is used as a water phase reaction medium, thereby avoiding the volatilization of the used organic solvent, reducing the influence on the environment and being suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of clean production, in particular to a preparation method of 5-amino-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide hydrochloride of an X-CT contrast agent intermediate.
Background
Contrast agents are drugs that clearly observe different organ and tissue types or body cavities of the human body during medical imaging. 5-amino-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide hydrochloride is an important intermediate for producing iohexol and iodixanol X-CT contrast agents. In recent years, X-ray contrast agents made of iohexol and iodixanol account for over thirty percent of the global market share. At present, the synthesis process route of 5-amino-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide hydrochloride is mainly prepared by using dimethyl 5-nitroisophthalate as a starting material through acylation and nitro reduction. In the acylation step, the ester group of the carbamate is substituted by the amino group of the amino glycerol; in the nitro reduction procedure, catalytic hydrogenation reduction is generally adopted, or iron powder or sulfide is utilized for reduction to prepare amino, and finally hydrogen chloride is introduced for salification, and a target product is prepared through crystallization, centrifugation and drying. In recent years, as the safety production requirement and the environmental protection standard are improved, the safety requirement of a hydrogenation workshop is met by adopting hydrogenation reduction, and a hydrogenation catalyst is flammable and has large potential safety hazard; the reduction by using iron powder or sulfide and other chemical methods needs to ensure the standard reaching of the three wastes.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of an X-CT contrast agent intermediate, in particular to a method for preparing a 5-amino-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide hydrochloride product by directly utilizing hydrazine to replace hydrogen to reduce nitro functional groups. The method overcomes the potential safety hazard and the influence on the environment in the prior preparation technology.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a preparation method of an X-CT contrast agent intermediate comprises the steps of taking 5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide as a raw material, hydrazine hydrate as a reducing agent, water and acetic acid as reaction media, metal oxide as a catalyst, cooling after complete reaction, slowly introducing hydrogen chloride, crystallizing, and centrifuging to obtain a white crystal target product (I);
further, the reactor used in the reaction is a high-pressure reaction kettle, the reaction temperature is 10-100 ℃ in the reaction process, and the pressure in the reactor is kept at 0.01-1.00 MPa.
Further, the molar ratio of the hydrogen chloride to the 5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide in the reaction is 1: 1.
Furthermore, the reducing agent is hydrazine hydrate aqueous solution with the hydrazine hydrate content of 30-95%, and the molar ratio of the hydrazine hydrate aqueous solution to the 5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide is 1-5: 1.
further, the weight percentage of acetic acid in water in the reaction medium is 1-30%, preferably 1-10%, and the dosage of acetic acid is 1-3 times of the weight of the reaction system.
The weight of the reaction system refers to the sum of the weight of 5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide, hydrazine hydrate and the catalyst.
Furthermore, the dosage of the metal oxide catalyst is 1-15% of the weight of 5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide. The metal oxide catalyst is selected from two or more of copper oxide, chromium oxide, nickel oxide, ruthenium oxide, rhodium oxide and aluminum oxide, wherein the proportion of each metal oxide is any weight ratio.
Compared with the prior art, the invention has the beneficial effects that:
1. the reducing agent is different, the existing reducing nitro compound generally uses hydrogen as the reducing agent, the hydrogen is flammable and explosive, has corrosion effect on metal, and the solubility of the hydrogen in an organic solvent is extremely low, so that the reaction is slow, generally requiring 24 hours, the invention adopts hydrazine hydrate as the reducing agent, is easy to store, has no danger of flammability and explosion and the like, reduces the potential safety hazard in the production process, and is extremely convenient to operate;
2. the catalysts are different, and the common catalyst uses expensive metal palladium, is loaded on activated carbon after being activated, is expensive, is easy to spontaneously combust after reaction and has potential safety hazard. The invention uses metal oxide as catalyst, not only the raw material is cheap and easy to get, but also the catalytic effect is good, the catalyst can be recycled and regenerated, and the production cost is reduced;
3. the method has the advantages that the acetic acid aqueous solution is used as the aqueous phase reaction medium, so that the volatilization of the used organic solvent is avoided, the influence on the environment is reduced, and the method is suitable for large-scale industrial production;
4. the reaction time is different, the hydrogen reduction time is long, and the reaction time of the invention can be basically controlled within 5 hours.
Detailed Description
The technical solution of the present invention is illustrated by the following specific examples, but the scope of the present invention is not limited thereto:
example 1
5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide 71.4 g (0.2 mol), 30% hydrazine hydrate 22 g (0.2 mol), copper oxide 0.36 g, chromium oxide 0.36 g and 1% acetic acid water solution 200 g are added into a high-pressure reaction kettle, the pressure in the reactor is kept 0.01MPa at 10 ℃, the reaction is carried out for 5 hours, the reaction is completed, the reaction is cooled, 7.3 g of gaseous hydrogen chloride is slowly introduced, crystallization is carried out for 3 hours, and centrifugation is carried out to obtain 69 g of white crystals, the yield is 95%, and the purity is more than or equal to 98%. MS (m/z): 363.8.
Example 2
5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide 71.4 g (0.2 mol), 50% hydrazine hydrate 13 g (0.2 mol), copper oxide 0.36 g, chromium oxide 0.36 g, aluminum oxide 0.1 g, 10% acetic acid water solution 90 g, maintaining the pressure in a reactor at 1.00MPa, reacting for 5 hours at 10 ℃, cooling, slowly introducing gas hydrogen chloride 7.3 g, crystallizing for 3 hours, centrifuging to obtain white crystals 71 g, wherein the yield is 97%, and the purity is more than or equal to 98%. MS (m/z): 363.8.
Example 3
In a high-pressure reaction kettle, 71.4 g (0.2 mol) of 5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide, 11 g (0.3 mol) of 95% hydrazine hydrate, 3 g of copper oxide, 3 g of chromium oxide, 1 g of nickel oxide, 3 g of ruthenium oxide and 276 g of 30% acetic acid aqueous solution are added, the pressure in a reactor is maintained at 0.05MPa, the reaction is carried out for 1 hour at 100 ℃, the mixture is cooled, 7.3 g of gaseous hydrogen chloride is slowly introduced, crystallization is carried out for 3 hours, and centrifugation is carried out to obtain 69.8 g of white crystals, wherein the yield is 96%. The purity is more than or equal to 98 percent. MS (m/z): 363.8.
Example 4
5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide 71.4 g (0.2 mol), 50% hydrazine hydrate 64 g (1 mol), copper oxide 3.6 g, chromium oxide 3.6 g, rhodium oxide 2 g, 1 g of 1% acetic acid water solution 200 g are added into a high-pressure reaction kettle, the pressure in the reactor is kept at 10 ℃ and 0.08MPa, the reaction is carried out for 3 hours, the reaction product is cooled, gas hydrogen chloride is slowly introduced into the reaction product for 7.3 g, crystallization is carried out for 3 hours, and centrifugation is carried out to obtain white crystals 69 g, the yield is 95%, and the purity is more than or equal to 98%. MS (m/z): 363.8.
Example 5
5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide 71.4 g (0.2 mol), 50% hydrazine hydrate 64 g (1 mol), copper oxide 4 g, chromium oxide 4 g, rhodium oxide 2 g, alumina 0.7 g, 5% acetic acid water solution 300 g, keeping the pressure in a reactor at 10 ℃ at 1.00MPa, reacting for 2 hours, cooling, slowly introducing gas hydrogen chloride 7.3 g, crystallizing for 3 hours, centrifuging to obtain white crystals 71 g, wherein the yield is 97%, and the purity is more than or equal to 98%. MS (m/z): 363.8.
Claims (8)
1. A preparation method of an X-CT contrast agent intermediate is characterized by comprising the steps of taking 5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide as a raw material, hydrazine hydrate as a reducing agent, water and acetic acid as reaction media, metal oxide as a catalyst, cooling after complete reaction, slowly introducing hydrogen chloride, crystallizing, and centrifuging to obtain a white crystal target product (I);
2. the method for preparing the intermediate of the X-CT contrast agent according to claim 1, wherein the reactor is a high-pressure reaction kettle, the reaction temperature is 10-100 ℃ in the reaction process, and the pressure in the reactor is kept at 0.01-1.00 MPa.
3. The method of claim 1, wherein the molar ratio of hydrogen chloride to 5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide is 1: 1.
4. The method for preparing the intermediate of the X-CT contrast agent according to claim 1, wherein the molar ratio of the aqueous solution of hydrazine hydrate containing 30-95% of hydrazine hydrate as a reducing agent to 5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide is 1-5: 1.
5. the method for preparing an intermediate of an X-CT contrast agent according to claim 1, wherein the weight percentage of acetic acid in water in the reaction medium is 1-30%, and the dosage of acetic acid is 1-3 times of the weight of the reaction system.
6. The method for preparing an intermediate of X-CT contrast agent according to claim 1, characterized in that the weight of the reaction system is the sum of the weight of 5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide, hydrazine hydrate and catalyst.
7. The method for preparing an intermediate of an X-CT contrast agent according to claim 1, wherein the mass usage amount of the metal oxide catalyst is 1-15% of the weight of 5-nitro-N, N' - (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.
8. The method for preparing an intermediate of an X-CT contrast agent according to claim 7, wherein the metal oxide catalyst is selected from the group consisting of copper oxide, chromium oxide, nickel oxide, ruthenium oxide, rhodium oxide, and aluminum oxide, and the ratio of the metal oxides is any weight ratio.
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Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
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