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Method for synthesizing benfotiamine

A synthesis method and benfotiamine technology are applied in the field of organic compound preparation process improvement, can solve problems such as increasing process steps, increasing production cycle, reducing production efficiency and the like, and achieve the effects of high purity, improved production efficiency and low price

Inactive Publication Date: 2013-02-06
TONGJI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After the reaction is completed, it needs to be placed at room temperature for about 1 week, which greatly increases the production cycle and reduces the production efficiency, and the reaction product needs to be reprocessed, concentrated and recrystallized, etc., which increases the process steps and produces a large amount of acidic industrial wastewater ,polluted environment

Method used

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  • Method for synthesizing benfotiamine
  • Method for synthesizing benfotiamine
  • Method for synthesizing benfotiamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: Add 15.33g (0.1mol) of phosphorus oxychloride to 10.8mL of water, place it in an ice bath and stir for 0.5 hours, add 26.53g (0.1mol) of thiamine in batches, and then heat to 50°C and stir for 2 After hours, cool to room temperature to obtain phosphorthiamine solution. The HPLC content of phosphorthiamine is 91.36%. Use 15% NaOH solution to adjust the pH of the solution to 8-9, add 28.11g (0.2mol) benzoyl chloride, at 0- Stir at 5°C and monitor the pH of the reaction solution to stabilize the pH value of the solution. When the pH of the reaction solution no longer changes, continue to stir and react for 1 hour, adjust the pH of the solution to 3.5-4.0, and filter with suction to obtain 33.58 g of phenylphosphonium. Thiamine is a white solid. The yield was 71.9%.

[0027] MP:164-165℃; H 1 NMR(400MHz , CDCl 3 ): 2.18 (s, 3H), 2.56 (s, 3H), 2.58 (t, J =6.7, 2H), 4.33 (t, J =6.7, 2H), 4.83 (s, 2H), 7.44 (m, 2H), 7.57 (dd, J =7.3, J =1.5,1H), 7.60 (m, 2H), 7.70 (s,...

Embodiment 2

[0028] Example 2: Add 15.33g (0.1mol) of phosphorus oxychloride to 7.2mL water, place in an ice bath and stir for 0.5 hours, add 21.23g (0.08mol) of thiamine in batches, and then heat to 60°C and stir for 2 After hours, cool to room temperature to obtain phosphorthiamine solution. The HPLC content of phosphorthiamine is 92.37%. Use 15% NaOH solution to adjust the pH of the solution to 8-9, add 28.11g (0.2mol) benzoyl chloride, Stir at 5°C and monitor the change of the pH of the reaction solution to stabilize the pH of the solution. When the pH of the reaction solution no longer changes, continue to stir and react for 1 hour, adjust the pH of the solution to 3.5-4.0, and filter with suction to obtain 27.69 g of phenphos Thiamine is a white solid. The yield was 74.2%.

[0029] MP:164-165℃;H 1 NMR(400MHz , CDCl 3 ): 2.18 (s, 3H), 2.56 (s, 3H), 2.58 (t, J =6.7, 2H), 4.33 (t, J =6.7, 2H), 4.83 (s, 2H), 7.44 (m, 2H), 7.57 (dd, J =7.3, J =1.5,1H), 7.60 (m, 2H), 7.70 (s, 1H), 8.67 (s, ...

Embodiment 3

[0030] Example 3: Add 15.33g (0.1mol) of phosphorus oxychloride to 3.6mL of water, place it in an ice bath and stir for 0.5 hours, add 15.92g (0.06mol) of thiamine in batches, then heat to 70°C and stir for 2 After hours, cool to room temperature to obtain phosphorthiamine solution. The HPLC content of phosphorthiamine is 93.23%. Adjust the pH of the solution to 8-9 with 15% NaOH solution. Add 28.11g (0.2mol) of benzoyl chloride, Stir at 5°C and monitor the pH of the reaction solution to stabilize the pH value of the solution. When the pH of the reaction solution no longer changes, continue to stir and react for 1 hour, adjust the pH of the solution to 3.5-4.0, and filter with suction to obtain benfotiamine White solid 23.71g. The yield was 84.7%.

[0031] MP:164-165℃;H 1 NMR(400MHz , CDCl 3 ): 2.18 (s, 3H), 2.56 (s, 3H), 2.58 (t, J =6.7, 2H), 4.33 (t, J =6.7, 2H), 4.83 (s, 2H), 7.44 (m, 2H), 7.57 (dd, J =7.3, J =1.5,1H), 7.60 (m, 2H), 7.70 (s, 1H), 8.67 (s, 1H).

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Abstract

The invention relates to a method for synthesizing benfotiamine, in particular to a process for synthesizing benfotiamine which is an anti-diabetic medicament by the phosphorylation of thiamine which severs as the raw material, the opening of the thiazole ring and the reaction of multiple steps. Benfotiamine is subjected to phosphorylation under the control of appropriate temperature and other conditions in a short time by taking phosphorus oxychloride as a phosphorylation reagent to obtain monophosphothiamine, and finally the steps of ring opening and benzoylation are carried out to obtain benfotiamine. The process has the advantages of high conversion rate of raw materials, low-cost, high product purity and greatly reduced production cycle and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the improvement of the preparation process of organic compounds, in particular to a synthesis method of benfotiamine. Background technique [0002] Benfotiamine is a fat-soluble derivative of thiamine, a synthetic vitamin B1 derivative that is slightly soluble in water. Synthesized in Japan in the 1960s, it was gradually used in the treatment of neuropathy, sciatica and other neuropathic pains caused by alcoholism after 1962. Since the 1990s, European scholars have conducted a series of studies on thiamine, especially benfotiamine, in the treatment and prevention of diabetes and its complications, and have made significant progress in recent years. The drug has been used in Europe for more than a decade to treat various conditions, including nerve damage associated with diabetes. Benfotiamine was developed by the Japanese company Akira. The chemical name of benfotiamine is: S-[2-[[(4-amino-2-methyl-5-pyrimidinyl)methyl]formyl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6512
Inventor 匡春香龚浩
Owner TONGJI UNIV
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