Introduction
contrast agent can increase the degree of contrast between visceral tissue and cavity tract in clinical examination and treatment, and present the morphological profile of the organ and cavity tract or the characteristics of the lesion tissue with clearer images. Most commonly used contrast agents are drugs containing different iodine concentrations, i.e. iodine contrast agents. Because the iodine contrast agent has the advantages of low contrast density, low toxicity and good tolerance. So at present, iodine contrast agent is the most widely used x-ray contrast agent. Among them, iodine is the most safe and is currently the first-line representative drug for non-ionic monomer iodine contrast agents. Today, developed countries have basically completely replaced ionic contrast agents with iodinehel. In 2016, the market size of iodhellol was worth as high as 2.4 billion yuan. Ranked first among x-ray contrast agents. Therefore, looking at the synthetic process of iodhellol in raw materials, it has high research and application value.
iodinehel chemical name is 5-[acetyl(2,3-dihydroxypropyl)amino]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodine-1,3-phthalene amide , white or white-like powder or crystalline powder; odorless; has moisture-induced. Very easily dissolved in water or methanol , and almost insoluble in trichloromethane or diethyl ether. The molecular formula is C19H26I3N3O9, the molecular weight is 821.13800, the density is 1.078 g/mL±0.002 g/mL at 25 °C (lit.), the melting point is 254-2560C, and the boiling point is 891.5ºC at 760 mmHg.
Currently there are three mainstream synthesis processes. The first type is iodine hellol obtained by using dimethyl 5-nitroblastate as the starting material and undergoing ester amine exchange, reduction, iodo and alkylation. The disadvantage of this method is that its operation is very complex and inefficient, and the requirements for the equipment are very high. The second method is to obtain iodine hellol through acylation, amidation, reduction, iodine, acetylation and resynthesis using 5-nitroisophthalic acid as the starting material. This method is cumbersome to operate and has high requirements for instruments and equipment, so it is not suitable for industrial production. The third method is iodohelol produced by 5- amino-2,4,6-triiodo-1,3-phthalic acid as the starting material and undergoes chlorine substitution, acetylation, amidation and alkylation reactions. The reaction steps of this method are very complicated and the yield is very low.
The quality level of raw materials is directly related to the success or failure of the injection. Whether or not you can obtain high-quality and high-standard iodine-hellol raw materials that are consistent with the international advanced level is the focus of the research. Today, we will take the first method as an example, using 5-amino-n and 3-phthalamide, which are generally cheaper in China, as starting materials, and improve the process to adapt to large-scale industrial production. This is used to obtain iodhellol raw materials drugs that meet the standards of the United States Pharmacopoeia, European Pharmacopoeia, and Chinese Pharmacopoeia. The specific synthesis route is shown in Figure 1 below.
1. Materials and methods
LC-2030A high performance liquid chromatograph, Shimadzu, Japan; AVANCE AV-400 MHz nuclear magnetic resonance instrument, Swiss Bruker Company: 6520Q-T OF mass spectrometer, American Agilent Company : YPT-3 melting point instrument, Tianjin Jingtuo Instrument Technology Co., Ltd.; 5-amino-V, N-bis(2,3-dihydroxypropyl)-2,4,6 triiodo-1,3-phthalamide, Chengdu Lijing Technology Co., Ltd. (purity 99.0%); all reagents are commercially available chemical pure reagents.
2. Synthesis of
1.2.15- acetyl amino-V,N-bis(2.3-dihydroxypropyl)-2,4,6 triiodine-1,3-phthalamide (4) To a dry three-necked bottle equipped with mechanical stirring and thermometer, 5-amino-V,N-bis(2,3-dihydroxypropyl)-2,4,6-triiodine-1,3-phthalamide (2) was added 100g (0.14mol), acetic anhydride 108.6g (1.06mol), and 90mL of acetic acid were stirred and dissolved, and then 1.21g (0.007mol) of p-toluenesulfonic acid was slowly added. After addition, the temperature was increased to 110°C for 3 hours, and the acylation reaction was carried out to obtain Compound 2. The reaction end point is when the residual amount of compound 2 is less than 2% (mass fraction). After the reaction is completed, sodium acetate is added to quench the reaction. The solvent was distilled off under reduced pressure to obtain Compound 3. The HPLC external standard method calculated the yield was 95%. The product did not require further treatment and was directly carried out in the next reaction.The product was added in the previous step, and 160mL of methanol was added and dissolved with stirring. 18.8g of NaOH (0.47mol) was added, and 47mL of water was adjusted to adjust the pH of the reaction solution to 10~11. After the solution was clear, the stirring was continued for 2h, and the hydrolysis reaction was carried out at 40°C. The reaction end point is when the residual amount of compound 3 is less than 1% (mass fraction). Slowly add concentrated HCI dropwise to adjust pH to neutral, cool down and stir overnight, and a white solid was precipitated, filtered and dried, the crude product of 5-acetamide-N,N-bis(2.3-dihydroxypropyl)-2,4,6-triiodo-1,3-phthalamide (4) was obtained, with a yield of 86.0%. The total yield of the two steps was 81.7%, and the purity was 98.0%. Melting point 274~278℃. ](d, 2H, NH), 4.52~4.77 (m, 4H, OH), 3.58 (m, 2H, CH), 3.15~3.47 (m, 8H, CH,), 2.02 (s, 3H, CH,); 8169.34 (m, C, C=0), 8151.09 (t, 2C, C-CO), 8147.50 (1, C, C-N), 8100.02 (m, 2C, C-I), 891.22 (d, C, C-I, 869.93 (1, 2C, CH), 864.14 (d, 2C, CH, CH, OH), 842.45 (m, 2C, NH-CH,), 822.82-(d, C, CH,); MS: CHI, N, O, ; M] 747.06; M+H] *748.02.
3. Synthesis of iodine 1
To a dry three-necked bottle equipped with mechanical stirring and thermometer, add 50g (0.067mol) of compound 4, NaOH 5.4g (0.135mol), 100mL of water, stir and dissolve at 25°C, add 2.5g (0.04mol) of boric acid after dissolution, continue stirring for 1 h, add 6g (0.08mol) of glycidol, and react for 22h. When the remaining amount of compound 4 is less than When 3% (mass fraction), it is used as the end point of the reaction. Add HCl to quench the reaction. Remove the solvent by rotary evaporation, add 200mL of methanol, stir overnight, filter, and add 500mL of water. Use Amber lite F PCI IN a cationic resin and Amber liteFPA91CI anionic resin to remove the cations and anions in the solution. Remove the solvent under reduced pressure to obtain a crude iodine oxide product. Recrystallize with isopropanol azeotropic to obtain high-purity iodine oxide, yield 80.2%, purity 99.7% (Figure 1), melting point 171~177℃.
4. Results and Discussion
original patent route uses H, SO, catalysis. When H, SO is added in actual operation, the reaction system heats up sharply and coking will occur, making the reaction liquid darker and difficult to control. Sun Yuejun and Qin Haifang use acetyl chloride as the acylation reagent. Although the product conversion rate is high, anhydrous conditions are required, the reaction conditions are difficult to control, the price is high, and it is corrosive to stainless steel equipment. In this experiment, the Toluenesulfonic acid catalysis avoids these problems well, speeds up the reaction, greatly shortens the reaction time. Acetic anhydride acetylation is cheap, with high product conversion rate, mild reaction conditions, and environmentally friendly, and meets the current production requirements of green chemistry. Therefore, this paper adopts acetylation method catalyzed by p-toluenesulfonic acid, and the impact of ingredients ratio and reaction temperature on reaction yield is also investigated.
original patent route uses 1,2-propylene glycol with a higher boiling point as solvent. The reaction is high when distilled off the solvent under reduced pressure, which is easy to produce impurities, affecting product quality. Qin Haifang uses diethylene glycol methyl ether as the reaction solvent, and the post-treatment is complicated and the price is high. Luo Shineng uses ethylene glycol monomethyl ether as the reaction solvent and sodium methoxide as the alkali. The solvent has a high boiling point and is difficult to evaporate, the reaction time is long, and anhydrous conditions are required, and the reaction conditions are difficult to control. During the alkylation reaction, 0-alkylation by-products and other unknown impurities will be produced. Therefore, the solvents selected must be easy to obtain, environmentally friendly and low toxicity. If the solvent used in the N-alkylation step is different from the recrystallization solvent, the solvent of the kang-based system must be removed, otherwise a small amount of residual solvent will cause the crystallization process to lose control.
In this experiment, water is used as the reaction solvent, and a simple inorganic alkali is the same as the recrystallization solvent. It is cheap and easy to obtain, and the post-treatment is simple. The quality and yield of the product are improved, which meets the production requirements of green chemistry. In addition, boric acid is used to protect compound 4 by boron complexing, and boron groups are introduced into the substrate to provide protection for hydroxyl groups that may be used as nucleophilic sites to avoid the generation of 0-alkylated impurities. The experimental results show that the yield of iodine has improved to a certain extent. In addition, the effects of reaction reagents and reaction temperature on iodine oxide yield were investigated.
examines the effect of the ingredients ratio (n glycerol: n compound 4) on the yield, and the yield of iodohel has increased to a certain extent.When the feed ratio of glycidyl and compound 4 exceeds 1.2:1, the yield increase is not obvious. Taking into account the production efficiency and production cost, the optimal molar ratio of glycidyl and compound 4 is selected as 1.2:1.
examines the effect of reaction temperature on the yield of iodhellol, and it can be seen that as the temperature increases, the yield of iodhellol continues to increase; when the temperature exceeds 25℃, the 0-alkylation by-products gradually increase, and some degraded impurities will be produced, resulting in a decrease in the quality and yield of the product, which also brings great difficulties to the post-treatment of the product. After referring to the relevant research of Gal in dro, the optimal reaction temperature of the comprehensive selection is 25℃.
uses the domestic cheap and easy-to-get 5-amino-N,N'-bis(2.3-dihydroxypropyl)-2,4.6-triiodo-1,3-phthalamide and acetic anhydride as starting materials. After acylation and hydrolysis, alkylation, iodine hexol was synthesized. The reaction yields were 81.7% and 80.2% respectively, and the total yield was 65.52%. The product was confirmed by NMR and MS structure. The optimal conditions for the synthesis process of iodhellol were determined by discussing the reaction parameters by variables. The acylation reaction conditions are the molar ratio of acetic anhydride to compound 2 at 7.6:1, 110°C; the optimal reaction conditions for hydrolysis are the molar ratio of NaOH to compound 3 at 5.0:1, 40°C; the optimal reaction conditions for alkylation are: the molar ratio of glycidol to compound 4 at 1.2:1, 25°C. The process is simple and low-cost, and is suitable for industrial production.
This process uses isopropyl alcohol azeotropic belt of water to recrystallize the crude iodine oxide product to obtain high-purity iodine oxide, with a purity of more than 99.7%, meeting the standard requirements of USP, EP, and CP.
There is a saying in the medical community that says, "If you want precise medical treatment, you must first accurately diagnose." Nowadays, with the continuous improvement of technical level, people's demand for accurate diagnosis is also increasing. The emergence of contrast agents has extremely widespread and important application value in the field of disease diagnosis. Especially after entering the new century, contrast technology has developed rapidly. In 2016, the market share of x-ray contrast agents reached US$3.7 billion. The most important x-ray contrast agent is iodine-containing contrast agent. It has a wide range of uses, such as auxiliary angiography during CT ray examination, endospinal angiography, venous urography, cardioangiogram, etc.
Looking back at this aspect of the domestic market, according to the sample data collected by the Science and Technology Development Center of the Pharmaceutical Society from 22 cities, in 2005, the amount of iodine-containing contrast agent used in the hospital was only RMB 380 million, but by 2016, it directly exceeded RMB 1.75 billion. From the perspective of market structure, iodine hexol is currently the largest iodine-containing contrast agent in China. In 2016, the entire market size was about 2.4 billion, followed by iodophorol and iodoxamol. These two are also widely used iodine contrast agents, which we will introduce in detail later.
Now, with people's understanding of diseases and the requirements for diagnostic accuracy continue to improve. Accurate diagnostic equipment has further moved to small and medium-sized hospitals. According to forecasts, China's GDP will surpass the United States to reach US$28.6 trillion in 2026. Based on this level, by 2026, my country's per capita contrast agent consumption will exceed half of the level of developed countries, that is, two US dollars, and the contrast agent market size will expand to US$2.8 billion, of which iodine contrast agents will account for US$2.4 billion.
There is another very important point, that is, compared with other drugs, the price of contrast agents is generally higher, so the market capacity is very considerable. It can be said to be a large gold mine that has not been mined yet. Because judging from the current domestic situation, not many people have discovered this gold mine. One of the big reasons for this is the problem of raw materials. At present, most of the raw materials containing iodine contrast agents in China come from Sitaili, and they have a monopoly. But the optimistic point is that many companies have applied for raw materials now. For example, Jinhai Iodine Chemical has started to make arrangements since a long time ago. As the name suggests, the quality of iodine directly determines the quality level of the raw materials. Jinhai Iodine Chemical relies on the exclusive resources of Chile, the world's largest iodine mine. We continue to provide customers with the best quality iodine products, including dozens of different series such as refined iodine, seaweed iodine, potassium iodine, potassium iodine, sodium iodide, cuprous iodide and povidone iodine.
Of course, we need to solve the problem of raw materials. Not only do we need to do it, but we also need to be able to produce it. In recent years, more and more companies have been in the contrast agent field. I believe that the competition for the entire market will become more and more intense in the next few years. There is a saying that monks who come early are the temple masters, which is particularly appropriate in this field. The people who are ahead are always the wisest, and those who follow the trend can only drink the trend.
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