Ioversol impurity and preparation method thereof

Abstract

The invention discloses an ioversol impurity and a preparation method thereof, the chemical structural formula of an ioversol impurity compound is # imgabs0 #, and the preparation method of the ioversol impurity compound comprises the following three steps: (1) preparation of an intermediate 1, (2) preparation of an intermediate 2 and (3) preparation of the ioversol impurity. Wherein the step (3) comprises the following steps: adding aminoglycerol and triethylamine into a three-necked flask, vacuumizing and filling nitrogen for three times, adding 80mL of DMAC at 0 DEG C under the protection of nitrogen, stirring until the solution is clarified, adding the intermediate 2, slowly heating to 25 DEG C, keeping the temperature, stirring and reacting for 2-4 hours, obtaining an ioversol impurity reaction solution after the reaction is finished, and performing post-treatment to obtain an ioversol impurity finished product. According to the invention, preparation and structure confirmation of the target ioversol impurity compound are completed, a new structure of the ioversol impurity and an efficient impurity synthesis route are developed, the synthesis method which is simple and easy to operate realizes purification of the product, and a large number of impurity reference substances can be obtained.

Description

Technical Field

[0001] The invention relates to the technical field of ioversol production, and in particular to an ioversol impurity and a preparation method thereof. Background Art

[0002] Ioversol (chemical formula: Figure 1 ) is a new generation of non-ionic X-ray contrast agent developed by Wanlin Pharmaceutical Co., Ltd. in the United States. Its chemical name is N1, N3-bis (2, 3-dihydroxypropyl) -5- [N- (2-hydroxyethyl) glycolylamino] -2, 4, 6-triiodo-1, 3-benzenedicarbamide. It was approved by the Ministry of Health for clinical use in my country in 1995. It has chemical structural characteristics that are significantly superior to other non-ionic contrast agents, such as good water solubility, low osmotic pressure, relatively stable chemical properties, ability to withstand high temperature sterilization, small side effects, large dosage and good contrast effect. Therefore, it is considered to be the most hydrophilic non-ionic X-ray contrast agent currently and is widely used in clinical practice.

[0003] Domestic and foreign literature has disclosed a number of synthetic routes of iodine alcohol. For example, US4396598A reported a method for preparing iodine alcohol by using 5-amino-N,N,-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxylic acid amide as raw material and acetoxyacetyl chloride as acylating agent, first acylation and then hydrolysis, and then reacting with chloroethanol. Its synthetic route S1 is as follows Figure 2 shown.

[0004] In the patent CN113717074A, the hydroxyl group of the hydrolyzate of iodine alcohol is first protected with acetone fork, then condensed with chloroethanol, and finally deprotected to obtain iodine alcohol. The synthetic route S2 is as follows: Figure 3 shown.

[0005] Patent CN1477093A discloses a method for preparing iodine alcohol using compound 6 and chloroethanol as raw materials. The synthetic route S3 is as follows: Figure 4 This route is prone to intramolecular coupling reaction (patent CN117800986A), and inevitably produces coupling product impurities. The specific reaction process S4 is as follows Figure 5 shown.

[0006] In the above-mentioned common iodine alcohol synthesis process at home and abroad, alkylation reaction is basically involved. The common method of alkylation is to use halogenated reagents such as chloroethanol to alkylate with amide bonds under alkaline conditions to obtain iodine alcohol. Due to the low reaction activity of chloroethanol in N-alkylation reaction, the reaction is incomplete and there are more by-products, which eventually lead to problems such as more reaction impurities and reduced yield. Although the generation of side reactions or related impurities can be reduced by controlling the influencing factors such as temperature, time and pH value, the alkylation reaction mechanism and the particularity of the reaction conditions still inevitably produce impurities on the hydroxyl group and -NHR group in practical applications (patent CN118026876A), which increases the production cost in the process of separating and purifying the product, reduces the production capacity and produces a large amount of three wastes. Patent US4396598 reports a method for preparing iodine alcohol, which uses 5-amino-2,4,6-triiodoisophthalic acid as the starting material, and obtains iodine alcohol after chlorination, condensation 1, acetylation, condensation 2, hydrolysis refining and alkylation. The advantage is that solids can be precipitated in each step, which is convenient for purification. The disadvantage is that thionyl chloride needs to be used, which is highly acidic and volatile, has high requirements for equipment, is not environmentally friendly, and the raw material acetoxyacetyl chloride used has poor stability, the quality needs to be strictly controlled, and the cost is difficult to control. Its synthetic route S5 is as follows Figure 6 shown.

[0007] Existing technologies such as Figure 7 As shown, compound 12 (5-amino-N,N,-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarbamide) undergoes acetylation reaction with acetic anhydride, and the hydroxyl and amino groups are completely protected to generate impurity compound 13. The amino group on the acetyl group of impurity compound 13 undergoes aminoacylation reaction with acetoxyacetyl chloride to generate impurity compound 14. Impurity compound 14 is not completely hydrolyzed during acid hydrolysis and alkaline hydrolysis, and only the acetyl group on the hydroxyl group is hydrolyzed to generate impurity compound 11. Impurity compound 11 is further hydrolyzed to generate impurity compound 15. Impurity compound 11 is an intermediate generated during the acid hydrolysis reaction of the preparation of iodine hydrolyzate, and will eventually be converted into impurity compound 15.

[0008] For drug researchers, the main work is not only how to obtain high-quality raw materials and develop efficient synthesis processes, but more importantly, to study the types and sources of impurities in raw materials and how to control the generation of process impurities. Generally, researchers first target the impurities produced in the synthesis process, and then develop efficient impurity synthesis routes to obtain a large number of impurity reference substances to ensure the development of quality testing of each batch of raw materials. In view of the above technical problems, the present invention develops a new ioversol impurity structure compound and a preparation method thereof. Summary of the invention

[0009] The invention aims to provide an ioversol impurity and a preparation method thereof.

[0010] The above technical objectives of the present invention are achieved through the following technical solutions:

[0011] An iodine alcohol impurity, the chemical structure of which is:

[0012]

[0013] A method for preparing ioversol impurities comprises the following steps:

[0014] (1) Preparation of Intermediate 1: 2.4-2.6 mmol of the compound 5-amino-2,4,6-triiodoisophthaloyl chloride was added to a three-necked flask, and under nitrogen protection, 4.0 ml of DMAC and 5.6-6.0 mmol of acetyl chloride were added, and the temperature was controlled to 25° C., and the mixture was stirred and reacted for 12 h. The reaction process was monitored by TLC. After the reaction was completed, the reaction solution was slowly poured into an appropriate amount of ice water, and then extracted with an appropriate amount of ethyl acetate. The organic layer was washed with ice water for several times, and then stirred and dried with an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation at 40° C. to obtain a white solid. The solid was dissolved with ethyl acetate at room temperature, and stirring was started. 90-110 mL of n-hexane was added to the system, stirred and crystallized for 10 min, and filtered. The filter cake was rinsed with an appropriate amount of n-hexane and dried at 40° C. under normal pressure to obtain Intermediate 1.

[0015] (2) Preparation of intermediate 2: 0.75-0.80 mmol of intermediate 1 was added to a dry three-necked flask, and under nitrogen protection, 8.0 mL of anhydrous tetrahydrofuran, 1.15-1.20 mmol of triethylamine and 0.90-1.00 mmol of acetoxyacetyl chloride were added; the temperature was controlled to 25°C, and the reaction was stirred for 12 hours; the reaction process was monitored by TLC, and after the reaction was completed, the layers were extracted with DCM and water, and the organic layer was washed with ice water several times and then dried with an appropriate amount of anhydrous sodium sulfate; an appropriate amount of silica gel was added to the filtrate, and the filtrate was concentrated to dryness by rotary evaporation at 40°C, and the sample was loaded by dry method, and the intermediate 2 was separated and purified by column chromatography.

[0016] (3) Preparation of iodine alcohol impurity: 16.0-18.0 mmol of aminoglycerol and 16.0-18.0 mmol of triethylamine were added to a three-necked flask. Under nitrogen protection, an appropriate amount of DMAC and 6.70-6.90 mmol of intermediate 2 were added. The temperature was controlled to 25° C. and the mixture was stirred and reacted for 2-4 h. After the reaction was completed, an iodine alcohol impurity reaction liquid was obtained. After post-treatment, an iodine alcohol impurity finished product was obtained.

[0017] Furthermore, the developing solvent used for TLC monitoring in the above step (1) is: PE:EA=8:1; the developing solvent used for TLC monitoring in step (2) is: PE:EA=2:1.

[0018] Furthermore, in the above steps (1), (2) and (3), the three-necked flask is evacuated and filled with nitrogen at least three times to form nitrogen protection.

[0019] Furthermore, in the above step (1), 4.0 ml of DMAC was added at 0°C, stirred until clear, and then 5.8 mmol of acetyl chloride was slowly added dropwise at a temperature of 0-10°C, and then the temperature was raised to 25°C.

[0020] Furthermore, in the above step (2), 8.0 mL of anhydrous tetrahydrofuran was added at 0°C, stirred until dissolved, and then 1.17 mmol of triethylamine was added, stirring was continued for about 10 min, 0.94 mmol of acetoxyacetyl chloride was slowly added dropwise, and then the temperature was raised to 25°C.

[0021] Furthermore, in the above step (3), 80 mL of DMAC was added at 0°C, stirred until dissolved, and then 6.79 mmol of intermediate 2 was added, and the temperature was slowly raised to 25°C.

[0022] Furthermore, the organic layers in the above steps (1) and (2) are washed three times with ice water.

[0023] Furthermore, 2 g of 200-300 mesh silica gel is added to the filtrate after drying and filtering with anhydrous sodium sulfate in the above step (2).

[0024] Furthermore, in the above step (2), column chromatography used 200-300 mesh silica gel: 20 g; eluent: PE:EA=4:1.

[0025] In summary, the present invention has the following beneficial effects: the present invention completes the preparation and structural confirmation of the target ioversol impurity compound, and develops a new structure of ioversol impurities and an efficient impurity synthesis route. The raw materials involved in the preparation process can all be purchased on the market. The simple and easy-to-operate synthesis method realizes the purification of the product, and a large amount of impurity reference substances can be obtained, which greatly improves the quality of the raw material drug ioversol products, provides a higher quality raw material drug for the contrast agent market, and improves the benefits of the enterprise to a certain extent. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the chemical structural formula of ioversenol;

[0027] Figure 2 This is the first synthetic route of ioversetol in the prior art;

[0028] Figure 3 This is the second synthesis route of ioversetol in the prior art;

[0029] Figure 4 This is the third synthesis route of ioversel in the prior art;

[0030] Figure 5It is the chemical formula of the coupling product impurity produced by synthetic route three;

[0031] Figure 6 This is the fourth synthesis route of ioversetol in the prior art;

[0032] Figure 7 It is a reaction process in which the ioversol hydrolyzate is prepared by acid hydrolysis to generate ioversol impurities;

[0033] Figure 8 is the chemical structural formula of the ioversenol impurity;

[0034] Fig. 9 is the chemical formula for the preparation of intermediate 1;

[0035] Fig.10 is the chemical formula for the preparation of intermediate 2;

[0036] Fig.11 is the chemical formula for the synthesis of the impurities of ioversol of the present invention;

[0037] Fig.12 is a hydrogen nuclear magnetic resonance spectrum of the ioversol impurity of the present invention;

[0038] Fig.13 is the carbon nuclear magnetic resonance spectrum of the ioversol impurity of the present invention;

[0039] Fig.14 is a mass spectrum of the ioversol impurity of the present invention;

[0040] Fig.15 is an infrared absorption spectrum of the ioversol impurity of the present invention;

[0041] Fig.16 It is the ultraviolet absorption spectrum of the impurities of ioversenol of the present invention. DETAILED DESCRIPTION

[0042] The present invention is further described in detail below in conjunction with the accompanying drawings, and the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0043] Example 1

[0044] Preparation of intermediate 1: Add compound 5-amino-2,4,6-triiodoisophthaloyl chloride (2.4-2.6mmol) to a three-necked flask, evacuate and fill with nitrogen three times, add DMAC (4.0ml) at 0℃ under nitrogen protection, stir until clear, control the temperature at 0-10℃ and slowly add acetyl chloride (5.6-6.0mmol). Raise the temperature to 25℃, keep warm and stir to react for 12h. Monitor by TLC (developing solvent: PE:EA=8:1), after the reaction is complete, slowly pour the reaction solution into ice water (100mL), and then extract with ethyl acetate (100mL). Wash the organic layer with ice water (100mL×3 times), stir and dry with an appropriate amount of anhydrous sodium sulfate (about 10min), and filter. The filtrate is concentrated by rotary evaporation at 40℃ to obtain a white solid. The solid was dissolved in ethyl acetate (10 mL) at room temperature, stirred, and n-hexane (90-110 mL) was added to the system. Stirring crystallization for 10 min, and filtered. The filter cake was rinsed with n-hexane (20 mL) and dried at 40 ° C under normal pressure to obtain 1.45 g of intermediate 1 as a white solid. The yield was 90%. The reaction equation for the preparation process of intermediate 1 is specifically referred to Fig. 9 shown.

[0045] Preparation of intermediate 2: Add intermediate 1 (0.75-0.80 mmol) to a dry three-necked flask, evacuate and fill with nitrogen three times, add anhydrous tetrahydrofuran (8.0 mL) at 0°C under nitrogen protection, stir until dissolved, then add triethylamine (1.15-1.20 mmol). Continue stirring for about 10 minutes, slowly add acetoxyacetyl chloride (0.90-1.00 mmol). Warm to 25°C, keep warm and stir to react for 12 hours. TLC monitoring (developing solvent: PE:EA=2:1), the reaction is completed, extract with DCM (100 mL) and water (100 mL), wash the organic layer with ice water (100 mL×3), dry with an appropriate amount of anhydrous sodium sulfate (about 10 minutes), and filter. Add silica gel (200-300 mesh, 2 g) to the filtrate, and concentrate to dryness at 40°C by rotary evaporation. Dry loading, column chromatography (200-300 mesh silica gel: 20 g; eluent: PE: EA = 4: 1) was used to separate and purify 0.40 g of intermediate 2 as a white solid. The yield was 65%. The reaction equation for the preparation process of intermediate 2 is shown in the following table. Fig.10 shown.

[0046] Preparation of iodine alcohol impurity: Add aminoglycerol (16.0-18.0mmol) and triethylamine (16.0-18.0mmol) to a three-necked flask, evacuate and fill with nitrogen three times, add DMAC (80mL) at 0°C under nitrogen protection, stir until dissolved, and then add intermediate 2 (6.70-6.90mmol). Slowly heat to 25°C, keep warm and stir to react for 2-4h. After the reaction is completed, the iodine alcohol impurity compound reaction solution is obtained, and the iodine alcohol impurity (target impurity compound 11) product is obtained after post-treatment. Its chemical formula is referenced Figure 8 The reaction equation for the preparation process of the iodine alcohol impurity compound is shown in Fig.11 shown.

[0047] The finished product of the iodine alcohol impurity compound obtained in Example 1 was subjected to hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, mass spectrum, infrared absorption spectrum, and ultraviolet absorption spectrum analysis, and the test results were as follows: Fig.12 , Fig.13 , Fig.14 , Fig.15 , Fig.16 As shown, according to the above test results, the target iodine alcohol impurity compound structure (reference Figure 8 ) confirmation.

[0048] This specific embodiment is only an explanation of the present invention, and it is not a limitation of the present invention. After reading this specification, those skilled in the art can make non-creative modifications to this embodiment as needed, but they are protected by patent law as long as they are within the scope of the claims of the present invention.

Claims

1. An iodine alcohol impurity, characterized in that: Its chemical structure is:

2. A method for preparing an ioversol impurity, characterized in that: The preparation of the ioversol impurity according to claim 1 comprises the following steps: (1) Preparation of intermediate 1: Add 2.4-2.6 mmol of the compound 5-amino-2,4,6-triiodoisophthaloyl dicarboxylic acid chloride to a three-necked flask, add 4.0 ml of DMAC and 5.6-6.0 mmol of acetyl chloride under nitrogen protection, control the temperature to 25°C, and stir to react for 12 hours; the reaction process is monitored by TLC. After the reaction is completed, the reaction solution is slowly poured into an appropriate amount of ice water, and then extracted with an appropriate amount of ethyl acetate. The organic layer is washed with ice water several times and then stirred and dried with an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate is concentrated by rotary evaporation at 40°C to obtain a white solid; The solid was dissolved in ethyl acetate at room temperature, stirring was started, 90-110 mL of n-hexane was added to the system, and the mixture was stirred for crystallization for 10 min, and filtered; the filter cake was rinsed with an appropriate amount of n-hexane and dried at 40° C. under normal pressure to obtain intermediate 1; (2) Preparation of intermediate 2: 0.75-0.80 mmol of intermediate 1 was added to a dry three-necked flask, and under nitrogen protection, 8.0 mL of anhydrous tetrahydrofuran, 1.15-1.20 mmol of triethylamine and 0.90-1.00 mmol of acetoxyacetyl chloride were added; the temperature was controlled to 25°C, and the mixture was stirred and reacted for 12 hours; the reaction process was monitored by TLC, and after the reaction was completed, the layers were extracted with DCM and water, and the organic layer was washed with ice water several times and then dried with an appropriate amount of anhydrous sodium sulfate; an appropriate amount of silica gel was added to the filtrate, and the mixture was concentrated to dryness by rotary evaporation at 40°C, and the sample was loaded by dry method, and the intermediate 2 was separated and purified by column chromatography; (3) Preparation of iodine alcohol impurity: 16.0-18.0 mmol of aminoglycerol and 16.0-18.0 mmol of triethylamine were added to a three-necked flask. Under nitrogen protection, an appropriate amount of DMAC and 6.70-6.90 mmol of intermediate 2 were added. The temperature was controlled to 25° C. and the mixture was stirred and reacted for 2-4 h. After the reaction was completed, an iodine alcohol impurity reaction liquid was obtained. After post-treatment, an iodine alcohol impurity finished product was obtained.

3. A method for preparing an iodine alcohol impurity according to claim 2, characterized in that: The developing solvent used for TLC monitoring in step (1) is: PE:EA=8:1; the developing solvent used for TLC monitoring in step (2) is: PE:EA=2:

1.

4. A method for preparing an ioversol impurity according to claim 2, characterized in that: In step (1), step (2) and step (3), the three-necked flask is evacuated and filled with nitrogen at least three times to form a nitrogen protection.

5. A method for preparing an ioversol impurity according to claim 2, characterized in that: Step (1) Add 4.0 ml of DMAC at 0°C, stir until clear, then slowly add 5.8 mmol of acetyl chloride dropwise at a temperature of 0-10°C, and then raise the temperature to 25°C.

6. A method for preparing an ioversol impurity according to claim 2, characterized in that: Step (2) Add 8.0 mL of anhydrous tetrahydrofuran at 0°C, stir until dissolved, then add 1.17 mmol of triethylamine, continue stirring for about 10 min, slowly add 0.94 mmol of acetoxyacetyl chloride dropwise, and then raise the temperature to 25°C.

7. A method for preparing an ioversol impurity according to claim 2, characterized in that: Step (3) Add 80 mL of DMAC at 0°C, stir until dissolved, then add 6.79 mmol of intermediate 2, and slowly heat to 25°C.

8. A method for preparing an ioversol impurity according to claim 2, characterized in that: The organic layers in step (1) and step (2) are both washed three times with ice water.

9. A method for preparing an ioversol impurity according to claim 2, characterized in that: In step (2), 200-300 mesh silica gel: 2 g is added to the filtrate after drying and filtering with anhydrous sodium sulfate.

10. A method for preparing an ioversol impurity according to claim 2, characterized in that: In step (2), column chromatography was performed using 200-300 mesh silica gel: 20 g; Eluent: PE:EA=4:1.

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