Method for preparing tetraethyl methylenediphosphonate

Abstract

The invention relates to the field of medicine synthesis, and discloses a method for preparing tetraethyl methylenediphosphonate, which comprises the following steps: (1) carrying out first mixing on sodium methoxide and an organic solvent to obtain a first mixed solution; (2) carrying out second mixing on the first mixed solution and diethyl phosphite to obtain a second mixed solution containing sodium diethyl phosphite; (3) carrying out distillation treatment on the second mixed solution to obtain sodium diethyl phosphite; and (4) carrying out third mixing on the sodium diethyl phosphite and dihalomethane to obtain the tetraethyl methylenediphosphonate. According to the method provided by the invention, the tetraethyl methylenediphosphonate can be prepared by adopting sodium methoxide, the use of metal sodium and sodium hydride which are high in danger is avoided, the yield is equivalent to that of the existing metal sodium or sodium ethoxide, and an economic and safe process method is provided for preparing the tetraethyl methylenediphosphonate.

Description

technical field

[0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for preparing tetraethyl methylene diphosphonate. Background technique

[0002] Vitamin A, also known as retinol, is one of the essential nutrients for the human body. It has various physiological functions such as promoting growth and reproduction, maintaining bone, epithelial tissue, vision and normal secretion of mucosal epithelium, especially for the formation of vision. , is an essential micronutrient for growth and development. Although vitamin A can be extracted from animal tissues, the resources are relatively scattered, the steps are complicated, and the cost is high. Therefore, commercial vitamin A is currently a chemically synthesized product, which is widely used in medicines, nutritional health products, cosmetics, and feed additives.

[0003] In the mainstream vitamin A chemical synthesis method, tetraethyl methylene diphosphate is an important inte...

Examples

specific Embodiment approach

[0056] According to a particularly preferred embodiment of the present invention, the method comprises:

[0057] (1) Under protective atmosphere conditions, sodium methoxide is placed in a three-necked flask, and an organic solvent is added for the first mixing to obtain the first mixed solution. The first mixed solution and the phosphorous acid in terms of contained sodium methoxide The molar ratio of diethyl ester is 9-4:1;

[0058] (2) At 15-35°C, add diethyl phosphite dropwise to the first mixed solution, and after dropping, keep warm at a temperature of 15-60°C for 6-12h for the second mixing to obtain diethyl phosphite For the second mixed solution of sodium, the molar ratio of the first mixed solution and the diethyl phosphite in terms of sodium methoxide is 1-1.2:1;

[0059] (3) Distilling the sodium diethyl phosphite solution, the conditions of the distillation treatment include: the pressure is 0-0.095MPa, and the temperature is 10-60°C to remove methanol by-product...

Embodiment 1

[0069] (1) Under the condition of nitrogen protection, weigh the sodium methoxide solid (55g) and place it in a 1000ml three-neck flask, add 260g of absolute ethanol for the first mixing to obtain the first mixed solution;

[0070] (2) Add diethyl phosphite (1 mol, purchased from Sinopharm Reagent Company, the same below) to the first mixed solution at 15°C, control the reaction temperature to 20°C, and keep warm at 20°C for 11h for the second mixing to obtain Sodium diethyl phosphite solution (the second mixed solution);

[0071] (3) The sodium diethyl phosphite solution is subjected to distillation treatment, and the conditions of the distillation treatment include: at a vacuum degree of 0.07MPa, at a temperature of 30° C., decompression distillation to remove solvent, residual diethyl phosphite and steps (2) the methyl alcohol that generates obtains 1mol sodium diethyl phosphite solid;

[0072] (4) At 30°C, add dichloromethane (4mol) dropwise to the three-necked flask cont...

Embodiment 1A

[0074] Adopt the method similar to Example 1, difference is: in step (1), the consumption of the dehydrated alcohol solvent used is different, specifically: the consumption of dehydrated alcohol solvent is 100g;

[0075] The rest were the same as in Example 1 to obtain 173.2 g of tetraethyl methylene diphosphonate.

technical field

[0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for preparing tetraethyl methylene diphosphonate. Background technique

[0002] Vitamin A, also known as retinol, is one of the essential nutrients for the human body. It has various physiological functions such as promoting growth and reproduction, maintaining bone, epithelial tissue, vision and normal secretion of mucosal epithelium, especially for the formation of vision. , is an essential micronutrient for growth and development. Although vitamin A can be extracted from animal tissues, the resources are relatively scattered, the steps are complicated, and the cost is high. Therefore, commercial vitamin A is currently a chemically synthesized product, which is widely used in medicines, nutritional health products, cosmetics, and feed additives.

[0003] In the mainstream vitamin A chemical synthesis method, tetraethyl methylene diphosphate is an important inte...

Examples

specific Embodiment approach

[0056] According to a particularly preferred embodiment of the present invention, the method comprises:

[0057] (1) Under protective atmosphere conditions, sodium methoxide is placed in a three-necked flask, and an organic solvent is added for the first mixing to obtain the first mixed solution. The first mixed solution and the phosphorous acid in terms of contained sodium methoxide The molar ratio of diethyl ester is 9-4:1;

[0058] (2) At 15-35°C, add diethyl phosphite dropwise to the first mixed solution, and after dropping, keep warm at a temperature of 15-60°C for 6-12h for the second mixing to obtain diethyl phosphite For the second mixed solution of sodium, the molar ratio of the first mixed solution and the diethyl phosphite in terms of sodium methoxide is 1-1.2:1;

[0059] (3) Distilling the sodium diethyl phosphite solution, the conditions of the distillation treatment include: the pressure is 0-0.095MPa, and the temperature is 10-60°C to remove methanol by-product...

Embodiment 1

[0069] (1) Under the condition of nitrogen protection, weigh the sodium methoxide solid (55g) and place it in a 1000ml three-neck flask, add 260g of absolute ethanol for the first mixing to obtain the first mixed solution;

[0070] (2) Add diethyl phosphite (1 mol, purchased from Sinopharm Reagent Company, the same below) to the first mixed solution at 15°C, control the reaction temperature to 20°C, and keep warm at 20°C for 11h for the second mixing to obtain Sodium diethyl phosphite solution (the second mixed solution);

[0071] (3) The sodium diethyl phosphite solution is subjected to distillation treatment, and the conditions of the distillation treatment include: at a vacuum degree of 0.07MPa, at a temperature of 30° C., decompression distillation to remove solvent, residual diethyl phosphite and steps (2) the methyl alcohol that generates obtains 1mol sodium diethyl phosphite solid;

[0072] (4) At 30°C, add dichloromethane (4mol) dropwise to the three-necked flask cont...

Embodiment 1A

[0074] Adopt the method similar to Example 1, difference is: in step (1), the consumption of the dehydrated alcohol solvent used is different, specifically: the consumption of dehydrated alcohol solvent is 100g;

[0075] The rest were the same as in Example 1 to obtain 173.2 g of tetraethyl methylene diphosphonate.

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