CN113717067A - Diiodoisophthaloyl chloride compound, preparation method and application thereof - Google Patents

Diiodoisophthaloyl chloride compound, preparation method and application thereof Download PDF

Info

Publication number
CN113717067A
CN113717067A CN202010446491.8A CN202010446491A CN113717067A CN 113717067 A CN113717067 A CN 113717067A CN 202010446491 A CN202010446491 A CN 202010446491A CN 113717067 A CN113717067 A CN 113717067A
Authority
CN
China
Prior art keywords
compound
chloride
under
amino
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202010446491.8A
Other languages
Chinese (zh)
Inventor
辛坤云
李壮
童耀
危军
吴灵静
王晶翼
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suzhou Kelun Pharmaceutical Research Co ltd
Original Assignee
Suzhou Kelun Pharmaceutical Research Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Suzhou Kelun Pharmaceutical Research Co ltd filed Critical Suzhou Kelun Pharmaceutical Research Co ltd
Priority to CN202010446491.8A priority Critical patent/CN113717067A/en
Publication of CN113717067A publication Critical patent/CN113717067A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/62—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino groups and at least two carboxyl groups bound to carbon atoms of the same six-membered aromatic ring
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to 5-amino-4-chloro-2, 6-diiodoisophthaloyl chloride and 5-amino-2-chloro-4, 6-diiodoisophthaloyl chloride, a preparation method thereof and application thereof in quality control of starting materials, namely 5-amino-2, 4, 6-triiodoisophthaloyl chloride and/or iopromide and other contrast agents. The method is favorable for further improving the medicine quality of the 5-amino-2, 4, 6-triiodo isophthalic acid chloride and subsequent final products thereof, reducing possible side effects and improving the medicine safety.

Description

Diiodoisophthaloyl chloride compound, preparation method and application thereof
Technical Field
The invention relates to a diiodoisophthaloyl chloride compound, a preparation method and application thereof.
Background
X-ray contrast agents are an important diagnostic agent in X-ray diagnostics. Wherein the non-ionic iodine contrast agent comprises: iopromide, iohexol, iopamidol, ioversol, iomeprol, iodixanol, etc. are widely used in diagnostic medicine due to their low osmotic pressure, high contrast density, low toxicity, etc. The non-ionic iodine contrast agent can be applied to contrast examination of a plurality of pathological changes in urinary tract, blood vessel, ventricle, lymphatic channel, gastrointestinal contrast agent and CT examination, and has good application prospect.
Figure BDA0002505896700000011
The structural general formula of the iodine contrast agent is as follows: the triiodobenzene ring is taken as a mother nucleus, carboxylic acid groups at 1 and 3 positions of the benzene ring are connected with two amino alcohols in an amido bond mode, and amino at 5 position is connected with an alkyl chain through alkylation reaction or amidation reaction.
Figure BDA0002505896700000021
The 5-amino-2, 4, 6-triiodoisophthaloyl chloride has a parent nucleus structure of the nonionic monomer type iodine contrast agent, and the synthesis of the nonionic type iodine contrast agent from the 5-amino-2, 4, 6-triiodoisophthaloyl chloride only needs to be subjected to subsequent functional group conversion, so the 5-amino-2, 4, 6-triiodoisophthaloyl chloride is often used as a key starting material for synthesizing the nonionic type iodine contrast agent. For example: the patent US4364921, a compound of iopromide original research corporation, discloses the synthesis of iopromide by 3-step amidation reaction using 5-amino-2, 4, 6-triiodoisophthaloyl chloride as starting material. In both Chinese patents CN201410155481.3 and CN201410157384.8, 5-amino-2, 4, 6-triiodoisophthaloyl chloride is used as a starting material for synthesizing iopromide. Furthermore, in the iopamidol synthesis method reported in british patent GB1472050, 5-amino-2, 4, 6-triiodoisophthaloyl chloride was also used as starting material; the synthesis of iohexol is also reported in US5705692 using 5-amino-2, 4, 6-triiodoisophthaloyl chloride as starting material.
At present, 5-amino-2, 4, 6-triiodo isophthaloyl chloride is generally synthesized by taking isophthalic acid as a starting material and carrying out nitration, reduction, iodination and acyl chlorination on the isophthalic acid. Iodine monochloride is mostly adopted as an iodine reagent in the iodination reaction, and the iodine monochloride and organic matters are subjected to iodination and chlorination at the same time, so that chlorinated compounds are inevitably generated, and the existence of the chlorinated compounds is detected in the research process. The main chlorinated compounds are 5-amino-4-chloro-2, 6-diiodoisophthaloyl chloride (compound 1) and 5-amino-2-chloro-4, 6-diiodoisophthaloyl chloride (compound 2).
Figure BDA0002505896700000022
Figure BDA0002505896700000031
The 5-amino-4-chloro-2, 6-diiodoisophthaloyl chloride (compound 1) and the 5-amino-2-chloro-4, 6-diiodoisophthaloyl chloride (compound 2) have similar structures and relatively similar chemical properties with the 5-amino-2, 4, 6-triiodoisophthaloyl chloride, are difficult to remove in the preparation and purification process, and can enter subsequent intermediate products and final products along with the flow of a process route, so that the quality of the final product is influenced, and even the clinical safety risk exists.
Taking the synthesis process of iopromide as an example, the method disclosed in patent US4364921 is usually adopted to synthesize iopromide, and the synthetic route is shown as follows:
Figure BDA0002505896700000032
the process route is that 5-amino-2, 4, 6-triiodoisophthaloyl chloride is used as a starting material to perform amidation reaction with methoxyacetyl chloride to generate an intermediate 1. And then, carrying out amidation reaction on the intermediate 1 and 2, 3-dihydroxypropylamine under the action of an acid-binding agent to obtain an intermediate 2. And finally, carrying out amidation reaction on the intermediate 2 and 3-methylamino-1, 2-propylene glycol under the action of an acid-binding agent to generate iopromide.
In the synthesis process of iopromide, corresponding side reactions of the compound 1 and the compound 2 in the starting material occur, and the side reactions remain in the subsequent intermediates and the final product along with the flow of the synthesis steps, and the impurity flows are as follows:
flow direction of compound 1:
Figure BDA0002505896700000041
the compound 1 reacts with methoxyacetyl chloride to generate an impurity A, then the impurity A and aminopropanediol undergo amidation reaction to generate an impurity B, and the impurity B reacts with methylaminopropanediol to generate an impurity C.
Compound 2 also undergoes the above reaction to form the corresponding impurity D, impurity E and impurity F, as shown in the following reaction:
Figure BDA0002505896700000042
furthermore, patent GB1472050 discloses a synthesis process for iopamidol, also starting from 5-amino-2, 4, 6-triiodoisophthaloyl chloride, the synthetic route of which is shown below:
Figure BDA0002505896700000051
the route starts from 5-amino-2, 4, 6-triiodoisophthaloyl chloride, and an intermediate 3 is obtained through amidation reaction with (L) -2-acetoxypropionyl chloride, and then the intermediate 3 is subjected to amidation reaction with 2-amino-1, 3-propylene glycol, and hydrolysis deprotection is carried out to obtain iopamidol.
In the synthesis process of iopamidol, the compound 1 and the compound 2 also have corresponding side reactions, which affect the quality safety of subsequent products and final products. In addition to the above-described process, other non-ionic iodine contrast agents prepared starting from 5-amino-2, 4, 6-triiodoisophthaloyl chloride also run the risk of remaining such material.
Therefore, it is necessary to provide a high-purity compound 1 and/or compound 2 as a reference substance by directional synthesis, which is used for qualitative and quantitative analysis of impurities in 5-amino-2, 4, 6-triiodoisophthaloyl chloride or subsequent bulk drugs, and has important significance for ensuring the quality safety and effectiveness of non-ionic iodine contrast agents such as iopromide and the like.
Disclosure of Invention
To this end, the present application provides, in a first aspect, compounds 1 and 2 of the formula,
Figure BDA0002505896700000052
the chemical name of the compound 1 is 5-amino-4-chloro-2, 6-diiodoisophthaloyl chloride; the chemical name of the compound 2 is 5-amino-2-chloro-4, 6-diiodoisophthaloyl chloride.
In a second aspect, the present application provides a process for the preparation of compound 1, as follows:
Figure BDA0002505896700000061
wherein R is C1-4An alkyl group; preferably, R is selected from methyl, ethyl and n-propyl;
the method comprises the following steps:
dissolving a compound 3 in an alcohol solvent, and carrying out an esterification reaction under the catalysis of a catalyst to obtain a compound 4; alternatively, Compound 3 is reacted with C under basic conditions1-4Halogenated hydrocarbon or sulfate compound reacts to generate ester;
step b), dissolving the compound 4 in an organic solvent, and carrying out chlorination reaction under the action of a chlorination reagent to obtain a compound 5 and a compound 6;
step c), carrying out hydrolysis reaction on the compound 5 under an alkaline condition to obtain a compound 7;
step d), carrying out iodination reaction on the compound 7 under the action of an iodination reagent to obtain a compound 8;
and e), carrying out acyl chlorination reaction on the compound 8 under the action of an acyl chlorination reagent to generate a compound 1.
In some embodiments, the catalyst in step a) is an acid or a substance that can be hydrolyzed to an acid, preferably, the catalyst is selected from the group consisting of sulfuric acid, phosphorus trichloride, thionyl chloride, and the like;
in some embodiments, the alcoholic solvent in step a) is selected from methanol, ethanol, propanol and benzyl alcohol;
in some embodiments, the chlorinating agent in step b) is selected from the group consisting of N-chlorosuccinimide and chlorine gas;
in some embodiments, the base in step c) is selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide;
in some embodiments, the iodinating agent in step d) is selected from the group consisting of iodine monochloride, N-iodosuccinimide, elemental iodine, and a combination of potassium iodide and potassium iodate;
in some embodiments, the acid chloride reagent in step e) is selected from thionyl chloride, oxalyl chloride and phosphorus trichloride.
In some embodiments, the base in step a) is sodium bicarbonate, potassium bicarbonate, or triethylamine;
in some embodiments, said C in step a)1～4The halogenated hydrocarbon is selected from methyl iodide, ethyl iodide and propyl iodide;
in some embodiments, the sulfate-based compound in step a) is selected from the group consisting of dimethyl sulfate, diethyl sulfate, dipropyl sulfate, and dibutyl sulfate.
In a third aspect, the present application provides a process for the preparation of compound 2, as follows:
Figure BDA0002505896700000071
wherein the method comprises the following steps:
step f), hydrolyzing the compound 6 under an alkaline condition to obtain a compound 9;
step g), iodinating the compound 9 under the action of an iodinating reagent to obtain a compound 10;
and h) carrying out acyl chlorination on the compound 10 to generate a compound 2.
In some embodiments, the base in step f) is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like;
in some embodiments, the iodinating agent in step g) is selected from the group consisting of iodine monochloride, N-iodosuccinimide, elemental iodine, and a combination of potassium iodide and potassium iodate;
in some embodiments, the acid chloride reagent in step h) is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, and the like.
In a third aspect of the invention there is provided the use of compound 1 and/or compound 2 in the quality control of a non-ionic contrast agent and/or 5-amino-2, 4, 6-triiodoisophthaloyl chloride.
In some embodiments, the present application provides the use of compound 1 and/or compound 2 in the quality control of iopromide.
In some embodiments, the present application provides the use of compound 1 and/or compound 2 in the quality control of a compound as shown below:
Figure BDA0002505896700000081
the compound 1 and the compound 2 have potential health threat risks to organisms, and the compound 1 and the compound 2 are prepared and provided as reference substances, are applied to quality control of contrast agents or starting materials thereof, are beneficial to establishing more complete quality standards, can detect and control the content of the contrast agents in the whole preparation and purification process, and have important significance for further improving the quality of the raw material medicines and preparations thereof of the contrast agents and the medication safety.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the specific embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Various aspects of the invention are further illustrated by the following specific examples, and various advantages of the invention are shown by the following examples.
The English abbreviated compound of the invention corresponds to the Chinese name as follows:
DMSO, DMSO: dimethyl sulfoxide NCS: chlorosuccinimide
SOCl2: thionyl chloride (or thionyl chloride)
1. LC-MS liquid-mass spectrometry assay
The tests were carried out with high resolution mass spectrometry (Agilent Technologies 1260 Infinity II liquid chromatography) in positive and negative ion mode, ESI ionization source, scanning range 50-1000 m/z.
2、1H-NMR nuclear magnetic resonance measurement
The assay was carried out using a Qone-WNMR-I-AS400 NMR spectrometer, solvent d6-DMSO, at a test temperature of 28 ℃.
3. The detection method of the compounds 1 and 2 in the 5-amino-2, 4, 6-triiodoisophthaloyl chloride comprises the following steps:
detecting a compound 1 and a compound 2 in 5-amino-2, 4, 6-triiodo isophthalic acid chloride serving as a starting material by an HPLC (high performance liquid chromatography) method, wherein the specific detection method comprises the following steps:
Figure BDA0002505896700000091
example 1: synthesis of dimethyl 5-aminoisophthalate (Compound 4A)
Figure BDA0002505896700000092
Weighing 5-aminoisophthalic acid (15.00g,82.64mmol) in a reaction bottle, adding 75mL of methanol for dissolving, slowly dropwise adding thionyl chloride (24.57g,206.61mmol) into the system under stirring, heating the system to 65 ℃ after the completion of the addition, carrying out reflux reaction for 7h until the raw material is completely converted. Cooling the reaction solution to room temperature, adding 500mL of water, stirring for dissolving, adjusting the pH value to 8 by using a saturated sodium bicarbonate solution, precipitating a large amount of solid in the system, stirring for 0.5h, filtering, washing a filter cake by using 20mL of water, and drying in a 50 ℃ forced air drying oven to obtain a compound 4A, 15.76g of white solid, wherein the yield is as follows: 91%, LCMS [ M + H ]+]+:210.05。
Example 2: synthesis of 5-amino-4-chloroisophthalic acid dimethyl ester (Compound 5A) and 5-amino-2-chloroisophthalic acid dimethyl ester (Compound 6A)
Figure BDA0002505896700000093
Adding 5-aminoisophthalic acid dimethyl ester (15.76g,75.41mmol) into a reaction bottle, adding 200mL of acetonitrile, stirring to dissolve, adding chlorosuccinimide (10.07g,75.41mmol) into the system in three batches, and reacting for 3 hours at room temperature until the raw materials are basically unchanged. Cooling the reaction solution to room temperature, adding 500mL of ethyl acetate and 500mL of water, stirring uniformly, standing for layering, concentrating the organic phase, separating the obtained crude product by using a preparative chromatographic column (the elution system is 30% of water and acetonitrile), and obtaining 7.93g (yield: 43%) of a light yellow solid of the compound 5A and 2.07g (yield: 11%) of a light yellow solid of the compound 6A;
compound 5A:
LCMS[M+H+]+:244.1,
1H NMR(400MHz,CDCl3)δ7.78(d,J＝2.0Hz,1H),7.54(d,J＝2.0Hz,1H),4.44(s,2H),3.91(s,3H),3.88(s,3H).
compound 6A:
LCMS[M+H+]+:243.95.
1H NMR(400MHz,CDCl3)δ7.06(s,2H),3.90(s,6H).
example 3: synthesis of 5-amino-4-chloroisophthalic acid (Compound 7)
Figure BDA0002505896700000101
5-amino-4-chloroisophthalic acid dimethyl ester (2.50g,10.28mmol) is put into a reaction bottle, 20mL of methanol and 5mL of water are added for dissolution, and after sodium hydroxide (1.60g,41.10mmol) is added, the reaction is carried out for 4h at room temperature until the conversion of the raw material is complete. The methanol was removed by rotary evaporation, the residue was cooled in an ice water bath, 2N HCl was added dropwise to adjust the pH to 3, after stirring for 0.5 hour, suction filtration was carried out, and the obtained solid was dried to obtain compound 7 in a yield of 84% as a white solid, 1.87 g. LCMS [ M-H ]+]-:213.95.
Example 4: synthesis of 5-amino-4-chloro-2, 6-diiodoisophthalic acid (Compound 8)
Figure BDA0002505896700000102
Iodine chloride (4.03g,24.69mmol) and potassium chloride (5.75g,39.50mmol) were placed in a reaction flask, dissolved in 12mL of water, stirred for 5min and filtered to obtain the filtrate for use. Adding 5-amino-4-chloroisophthalic acid into a reaction bottle, adding 30mL of 1mol/L hydrochloric acid for dissolving, slowly dripping the filtrate obtained by filtering into a reaction system for 1 hour, completely dripping, heating to 60 ℃, and reacting for 3 days until the raw materials are completely converted. Cooling at room temperature, cooling to 0 ℃ in an ice water bath, stirring for 0.5h, performing suction filtration, washing a filter cake with 10mL of water, and drying to obtain a compound 8, 3.70g of yellow solid, wherein the yield is as follows: 96 percent. LCMS [ M + NH ]4 +]+:484.7.
Example 5: synthesis of 5-amino-4-chloro-2, 6-diiodoisophthaloyl chloride (Compound 1)
Figure BDA0002505896700000111
5-amino-4-chloro-2, 6-diiodoisophthalic acid (0.74g,1.59mmol) is weighed into a reaction bottle, 7.4mL of thionyl chloride is added, and the mixture is heated to 80 ℃ for reflux reaction for 5 hours until the reaction is complete. Cooling to room temperature, removing thionyl chloride by rotary evaporation, adding 20mL of ethyl acetate to dissolve, washing with 15mL of saturated sodium bicarbonate and 15mL of saturated sodium chloride solution in sequence, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain compound 1, 0.77g of yellow solid, yield: 96% and purity 96.18%.
LCMS[M-H+]-:501.5,
13C NMR(100MHz,DMSO-d6)δ169.89,167.17,147.48,145.69,142.03,112.70,78.64,68.87.
Example 6: synthesis of 5-amino-2-chloro-4, 6-diiodoisophthalic acid (Compound 10)
Figure BDA0002505896700000112
5-amino-2-chloroisophthalic acid dimethyl ester (0.77g,3.16mmol) is put into a reaction bottle, 6.2mL of methanol and 1.5mL of water are added for dissolution, sodium hydroxide (0.51g,12.66mmol) is added for reaction at room temperature for 3h until the conversion of the raw material is complete. The pH was adjusted to 3 with 1N HCl and concentrated, and the crude product was used for the next reaction without further treatment.
Iodine chloride (1.55g,9.48mmol) and potassium chloride (2.21g,15.17mmol) are put into a reaction bottle, 5mL of water is added for dissolving, the mixture is stirred for 5min and then filtered, and the filtrate is taken for standby. And (3) adding 10mL of 1N HCl into the crude product to dissolve the crude product, and heating to 60 ℃ to react for 45 hours until the raw material is completely converted. Cooling the reaction solution to room temperature, transferring to ice water bath for cooling, filtering after 0.5H, oven drying to obtain compound 10, 1.00g gray solid (two-step yield: 68%), LCMS [2M-H ]+]-:932.45.
Example 7: synthesis of 5-amino-2-chloro-4, 6-diiodoisophthaloyl chloride (Compound 2)
Figure BDA0002505896700000121
Weighing 5-amino-2-chloro-4, 6-diiodoisophthalic acid (1.00g,2.14mmol) into a reaction bottle, adding 10mL of thionyl chloride, heating to 80 ℃ after the addition, and carrying out reflux reaction for 8h until the reaction is complete. Cooling to room temperature, removing thionyl chloride by rotary evaporation, adding 25mL of ethyl acetate to dissolve, washing with 20mL of saturated sodium bicarbonate and 20mL of saturated sodium chloride solution in sequence, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain compound 2, 1.05g of yellow solid, yield: 98%, purity: 92.83 percent.
LCMS[M-H+]-:501.5.
13C NMR(100MHz,DMSO-d6)δ167.12(2C),143.55,143.10(2C),121.78,98.44(2C).
Test example 1 detection of Compound 1 and Compound 2 in starting Material
Starting materials (5-amino-2, 4, 6-triiodoisophthaloyl chloride) of 5 different manufacturers are purchased respectively, the content of the compound 1 and the compound 2 in the starting materials is detected by an HPLC method, the purity of the starting materials and the content of the compound 1 and the compound 2 are calculated by an area normalization method, and the measurement results are shown in the following table 1.
TABLE 1 initial Material test results
Manufacturer of the product Purity of 5-amino-2, 4, 6-triiodo isophthaloyl chloride% Content of Compound No. 1% Content of Compound 2%
A 96.05 0.21 0.07
B 93.72 0.34 0.33
C 94.93 0.43 0.08
D 96.12 0.53 0.09
F 95.45 0.25 0.12
As can be seen from the data in the table above, the starting material 5-amino-2, 4, 6-triiodoisophthaloyl chloride contains a large amount of compound 1 and compound 2, and has quality safety risk for subsequent products.
Test example 2 Ames experiment (bacterial reverse mutation experiment)
Standard Ames experiments were performed on Compound 1 prepared in example 5, as follows:
1) preparation of bacterial liquid
After the frozen strains are melted in water bath at 37 ℃, 50 mu l of frozen strain liquid is inoculated into 5ml of nutrient broth culture solution, and the mixture is subjected to 120rpm dark shaking culture for about 16 to 18 hours.
2) Experimental procedure
Adopting a pre-culture method, wherein 0.5ml of S9 mixed solution is added under the condition of metabolic activation, 0.5ml of phosphate buffer solution (0.2mol/L, pH 7.2-7.4) is added under the condition of non-metabolic activation, and 0.1ml of bacterial solution, 0.1ml of test solution or solvent reference solution, or 0.1ml of positive reference solution are respectively added into a centrifuge tube, and after being uniformly mixed, the mixture is cultured for 20min at 37 ℃.
After the culture is finished, adding about 2ml of top-layer culture medium into the centrifuge tube, after the top-layer culture medium is fully and uniformly mixed, quickly pouring the top-layer culture medium onto the bottom-layer culture medium, rotating the plate to uniformly distribute the top-layer culture medium on the bottom layer, inverting the culture dish after the culture dish is flatly placed and solidified, carrying out shading culture at 37 ℃ for 48-72 h, and counting the number of retrogradation colonies of each dish.
3) Results of the experiment
The experimental result shows that the compound has mutation-causing effect on TA97a, TA98, TA100 and TA1535 strains under the condition of existence or nonexistence of a metabolic activation system, and the experimental result is positive.

Claims (9)

1. A compound represented by the structure selected from:
Figure FDA0002505896690000011
2. a process for the preparation of compound 1 according to claim 1, which process is carried out according to the following reaction scheme:
Figure FDA0002505896690000012
wherein R is C1-4An alkyl group; preferably, R is selected from methyl, ethyl and n-propyl;
the method comprises the following steps:
dissolving a compound 3 in an alcohol solvent, and carrying out an esterification reaction under the catalysis of a catalyst to obtain a compound 4; alternatively, Compound 3 is reacted with C under basic conditions1-4Halogenated hydrocarbon or sulfate compound reacts to generate ester;
step b), dissolving the compound 4 in an organic solvent, and carrying out chlorination reaction under the action of a chlorination reagent to obtain a compound 5 and a compound 6;
step c), carrying out hydrolysis reaction on the compound 5 under an alkaline condition to obtain a compound 7;
step d), carrying out iodination reaction on the compound 7 under the action of an iodination reagent to obtain a compound 8;
and e), carrying out acyl chlorination reaction on the compound 8 under the action of an acyl chlorination reagent to generate a compound 1.
3. The process of claim 2, wherein the catalyst in step a) is an acid or a substance that can be hydrolyzed to an acid; preferably, the catalyst is selected from the group consisting of sulfuric acid, phosphorus trichloride and thionyl chloride;
the chlorinating agent in step b) is selected from N-chlorosuccinimide and chlorine;
the base in step c) is selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide;
the iodinating reagent in step d) is selected from the group consisting of iodine monochloride, N-iodosuccinimide, elemental iodine and a combination of potassium iodide and potassium iodate;
in step e) the acylchlorinating reagent is selected from thionyl chloride, oxalyl chloride and phosphorus trichloride.
4. The process according to claim 2, wherein the base in step a) is sodium bicarbonate, potassium bicarbonate or triethylamine;
said C is1～4The halogenated hydrocarbon is selected from methyl iodide, ethyl iodide and propyl iodide;
the sulfate compound is selected from dimethyl sulfate, diethyl sulfate, dipropyl sulfate and dibutyl sulfate.
5. A process for the preparation of compound 2 according to claim 1, which process is carried out according to the following reaction scheme:
Figure FDA0002505896690000021
wherein the method comprises the following steps:
step f), hydrolyzing the compound 6 under an alkaline condition to obtain a compound 9;
step g), iodinating the compound 9 under the action of an iodinating reagent to obtain a compound 10;
and h) carrying out acyl chlorination on the compound 10 to generate a compound 2.
6. The process according to claim 5, wherein the base in step f) is selected from lithium hydroxide, sodium hydroxide and potassium hydroxide;
the iodinating reagent in step g) is selected from the group consisting of iodine monochloride, N-iodosuccinimide, elemental iodine and a combination of potassium iodide and potassium iodate;
in step h) the acylchlorinating agent is selected from thionyl chloride, oxalyl chloride and phosphorus trichloride.
7. Use of compound 1 and/or compound 2 according to claim 1 for quality control of a compound as shown below:
Figure FDA0002505896690000031
8. use of compound 1 and/or compound 2 according to claim 1 in quality control of non-ionic iodine contrast agents.
9. The use of claim 8, the non-ionic iodocontrast agent being selected from the group consisting of iopromide, iohexol, iopamidol, ioversol, iomeprol and iodixanol; preferably, the non-ionic iodine contrast agent is iopromide.
CN202010446491.8A 2020-05-25 2020-05-25 Diiodoisophthaloyl chloride compound, preparation method and application thereof Pending CN113717067A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010446491.8A CN113717067A (en) 2020-05-25 2020-05-25 Diiodoisophthaloyl chloride compound, preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010446491.8A CN113717067A (en) 2020-05-25 2020-05-25 Diiodoisophthaloyl chloride compound, preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN113717067A true CN113717067A (en) 2021-11-30

Family

ID=78671519

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010446491.8A Pending CN113717067A (en) 2020-05-25 2020-05-25 Diiodoisophthaloyl chloride compound, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN113717067A (en)

Similar Documents

Publication Publication Date Title
US7115778B2 (en) Process for the preparation of iopamidol
CN105705483B (en) The preparation method of Iopamidol
WO2008104853A1 (en) Processes for the preparation of pure ioversol
CN107778191A (en) A kind of preparation method of Iopromide and its intermediate
JP6248119B2 (en) Production of intermediates for X-ray contrast media
US6596904B1 (en) Process for producing ioversol
JPH0511117B2 (en)
TWI770120B (en) Organo-iodized compounds, process for the one-pot preparation of and uses of organo-iodized compounds
CN113717067A (en) Diiodoisophthaloyl chloride compound, preparation method and application thereof
AU717842B2 (en) Process for the preparation of contrast agents
CN110054571A (en) The different peptide chloride derivative of 5- amino -2,4,6- triiodo and its application in synthesis Iopamidol impurity
RU2566823C2 (en) Method of obtaining contrast agents
WO2010133180A1 (en) Poly-iodo benzene compound, preparation method and use thereof
CN112778151B (en) Preparation method of 5-amino-2, 4, 6-triiodo-1, 3-phthalic acid impurity
CA1110661A (en) 3,5-bis(acylamino)benzamides
CN105272899A (en) Novel compound and method for synthesizing iopamidol impurity D, impurity F, impurity G and impurity J by means of novel compound
CN101190888B (en) Method for preparing 5-acetamido-2,4,6-triiodo-1,3-benzenedicarboxamides
JP7128890B2 (en) Methods for hydrolyzing tert-butyl esters in gadolinium-based contrast agents
CN114773312B (en) Preparation process of alolol hydrochloride intermediate
KR20220139775A (en) Preparing method of iopamidol
JP4476365B2 (en) Production of triiodobenzene compounds
CN110003038A (en) The preparation of the midbody compound of Ioforminol
CN116854610A (en) Process for the preparation of impurities K and H of iopamidol and intermediates thereof
CN117800986A (en) Preparation method of ioversol impurity
JPS6157837B2 (en)

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination