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Synthesis method and purification method of 5-iodo-2-methylbenzimidazole

A technology of methylbenzimidazole and synthesis method, applied in the direction of organic chemistry, can solve the problems of unstable iodine monochloride, cumbersome operation, expensive price, etc., and achieve simple and efficient purification method, good atom economy, and recovery small loss effect

Inactive Publication Date: 2013-02-20
JIANGSU ZHONGDAN PHARMA RES +1
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  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

[0012] (1) Using expensive silver sulfate (1.0eq), the raw material cost is too high
[0013] (2) Iodine monochloride is an unstable and easily decomposed liquid, which is not easy to handle during use, and the market supply is limited
[0014] (3) HIO with a large proportion of raw material cost 3 / I 2 Both use 0.5eq, 0.5eq of "I" is not used, and the cost of raw materials is high
[0015] (4) KIO with a large proportion of raw material cost 4 / KI both use 1.0eq, only half of the "iodine" is used, and the cost of raw materials is high; after the reaction is completed, there are too many non-product solids, which makes post-processing difficult
[0016] (5) Potassium iodide has limited solubility in the reaction system. As the reaction proceeds, it is easy to be "enclosed" by the precipitated product and cannot fully participate in the reaction. The amplification effect of "enclosed" is more obvious; the by-product potassium salt increases the salt content of waste quantity
[0017] (6) The addition of solid oxidant ammonium persulfate needs to be carried out in batches, which is more cumbersome than the dropwise addition of liquid oxidant; the by-product ammonium bisulfate increases the salt content of wastewater

Method used

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  • Synthesis method and purification method of 5-iodo-2-methylbenzimidazole
  • Synthesis method and purification method of 5-iodo-2-methylbenzimidazole
  • Synthesis method and purification method of 5-iodo-2-methylbenzimidazole

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Experimental program
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Effect test

Embodiment 1

[0066] Iodination reaction: In a 3L four-necked reaction flask, add 720g methanol and 180g water, dropwise add 163g concentrated sulfuric acid, add 150g o-nitroaniline, stir to dissolve, then add 138g iodine, stir to dissolve, and control the temperature at 35°C Add 615g of 30% hydrogen peroxide dropwise, continue to stir at 35°C for 5 hours after the dropwise completion, add 633g of water after the reaction, cool to 5°C, filter with suction, wash the solid with 75g of 5% sodium thiosulfate aqueous solution, and dry in vacuo at 60°C. Obtain 275.3 grams of 4-iodo-2-nitroaniline shown in formula B, such as figure 1 As shown, reddish-brown crystals, yield 96.0%, HPLC purity 99.4%. 1 H-NMR (such as Figure 4 , CDCl 3 ,500MHz,δ5.4(s,br,2H),6.6(d,J=8.5Hz,1H),7.6(dd,J=8.5Hz,2.0Hz,1H),8.4(d,J=2.0Hz, 1H)).

[0067] Reduction reaction: In a 500mL pressure vessel, add 150g methanol, 30g 4-iodo-2-nitroaniline and 0.6g Raney nickel, remove the air, replace with hydrogen until the press...

Embodiment 2

[0070] Iodination reaction: In a 3L four-necked reaction flask, add 900g methanol and 600g water, dropwise add 326g concentrated sulfuric acid, add 150g o-nitroaniline, stir to dissolve, then add 165g iodine, stir to dissolve, and control the temperature at 0°C Add 25g of 30% hydrogen peroxide dropwise, and continue to stir at 0°C for 12 hours after the dropwise completion. After the reaction, add 633g of water, filter with suction, wash the solid with 750g of 5% sodium sulfite aqueous solution, and dry it in vacuum at 60°C to obtain 271.0g as shown in formula B. 4-iodo-2-nitroaniline, reddish-brown crystals, yield 94.5%, HPLC purity 99.2%.

[0071] Reduction reaction: In a 500mL pressure vessel, add 300g methanol, 30g 4-iodo-2-nitroaniline and 4.5g Raney nickel, remove the air, replace with hydrogen until the pressure reaches 0.01MPa, control the reaction temperature at 35°C, Keep the reaction for 8 hours. After the reaction, cool down to 10° C., replace with nitrogen, and fi...

Embodiment 3

[0074] Iodination reaction: In a 2L four-necked reaction flask, add 321g ethanol and 54g water, add 11g concentrated sulfuric acid dropwise, add 150g o-nitroaniline after dropping, stir to dissolve, then add 152g iodine, stir to dissolve, and control the temperature at 60°C Add 250g of 30% hydrogen peroxide dropwise, and continue to stir at 60°C for 3 hours after the dropwise completion. After the reaction, add 633g of water, cool to 5°C, filter with suction, wash the solid with 375g of 5% aqueous sodium sulfite, and dry it in vacuum at 60°C to obtain 272.4g of 4-iodo-2-nitroaniline represented by formula B, reddish-brown crystal, yield 95.0%, HPLC purity 99.2%.

[0075] Reduction reaction: In a 500mL pressure vessel, add 240g ethanol, 30g 4-iodo-2-nitroaniline and 9g Raney nickel, remove air, replace with hydrogen until the pressure reaches 0.3MPa, control the reaction temperature at 0°C, and keep warm The reaction was carried out for 12 hours. After the reaction was complete...

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Abstract

The invention discloses a synthesis method and purification method of 5-iodo-2-methylbenzimidazole, relating to the field of organic synthesis. The method comprises the following steps: by using o-nitroaniline as a main raw material, simple substance iodine as an iodine source and oxydol as an oxidizer, carrying out iodination reaction in a polar solvent in the presence of sulfuric acid to obtain 4-iodo-2-nitroaniline; and in the polar solvent, carrying out hydrogenation reduction by using Raney nickel as a catalyst to obtain 4-iodo-1,2-phenylenediamine, and carrying out cyclization reaction by using slight acetic acid as a catalyst and ortho-triacetate as a cyclization reagent to obtain 5-iodo-2-methylbenzimidazole, and finally, carrying out decolorization and purification in an acetate generation mode. The synthesis method disclosed by the invention belongs to green synthesis, has the advantages of high atomic economical efficiency and less waste, and is simple to operate; the catalyst has the advantages of low price, small recovery loss and less waste, and is simple to operate; and the product decolorization and purification mode is simple and efficient, the product appears a creamy white powder solid, and the purity is higher than 99.5%.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and specifically relates to a synthesis method of 5-iodo-2-methylbenzimidazole and a purification method thereof. Background technique [0002] 5-iodo-2-methylbenzimidazole, CAS registration number 2818-70-4, it is an important pharmaceutical intermediate, its chemical structure is as follows: [0003] [0004] There are three kinds of synthetic methods of 5-iodo-2-methylbenzimidazole existing reports: [0005] Popov, I.I. (Soviet Patent SU 1616911; Chemistry of Heterocyclic Compounds, 1997, 33(8), 949-953) reported that 2-methylbenzimidazole was used as raw material, first reacted with liquid bromine (1.0eq) in chloroform solvent Generate 2-methylbenzimidazole perbromide (yield 95%). After filtering and drying, the perbromide reacts with potassium iodide (1.0eq) in water at 60-80°C. After the reaction, add 10% sodium carbonate solution , add diethyl ether, separate into three layers, discar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/08
Inventor 施波姜方胜王朋朋孙溶薛建建
Owner JIANGSU ZHONGDAN PHARMA RES
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