Method for preparing calcium dibutyryladenosine cyclophosphate

A technology of dibutyryl cyclic adenosine monophosphate calcium and dibutyryl cyclic adenosine monophosphate, which is applied in the field of drug synthesis, can solve the problems of low product purity, low production efficiency, and low yield, and achieve simplified preparation process, short production cycle, and improved purity Effect

Active Publication Date: 2016-05-11
SHANGHAI ZIYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] At present, chemical synthesis methods are mostly used to prepare calcium dibutyrylcyclic adenosine monophosphate, but there are following disadvantages: (1) the acylation reaction time is very long, the yield is low (about 60%), and the production efficiency is low (8~10 days); (2) The extraction process is rough, resulting in low product purity (liquid phase purity 85%), which affects the efficacy of the product

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  • Method for preparing calcium dibutyryladenosine cyclophosphate
  • Method for preparing calcium dibutyryladenosine cyclophosphate
  • Method for preparing calcium dibutyryladenosine cyclophosphate

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Embodiment 1 2

[0044] The synthesis of embodiment 1 dibutyryl cyclic adenosine monophosphate calcium

[0045] Dissolve 10 g of cyclic adenosine monophosphate in an aqueous solution of 80 g of purified water and 4 g of triethylamine, stir evenly, and concentrate completely at 50° C., add 86 g of pyridine as a solvent to the residual solid, and after complete dissolution, concentrate under reduced pressure to obtain a cyclic adenosine monophosphate Glycoside triethylamine salt, 13g.

[0046]Take 13g of cyclic adenosine monophosphate triethylamine salt into a 1000ml three-neck flask, add 600ml of tetrahydrofuran and stir to dissolve, then add 50ml of n-butyric anhydride, react in the dark at 30°C for 36 hours, cool down to room temperature, add water for 1 hour, 25°C Concentrate under reduced pressure to remove tetrahydrofuran, add water to 500ml, wash the water phase twice with methyl tert-butyl ether, 100ml each time, distill the water phase under reduced pressure at 60°C, and extract the rem...

Embodiment 2 2

[0057] The synthesis of embodiment 2 dibutyryl cyclic adenosine monophosphate calcium

[0058] Dissolve 10 g of cyclic adenosine monophosphate in an aqueous solution of 80 g of purified water and 4 g of triethylamine, stir evenly, and concentrate completely at 50° C., add 86 g of pyridine as a solvent to the residual solid, and after complete dissolution, concentrate under reduced pressure to obtain a cyclic adenosine monophosphate Glycoside triethylamine salt, 12.5g.

[0059] Take 12.5g of cyclic adenosine monophosphate into a 1000ml three-neck flask, add 600ml of tetrahydrofuran and stir to dissolve, then add 50ml of n-butyric anhydride, 5ml of triethylamine, react in the dark at 65°C for 20 hours, cool down to room temperature, add water and hydrolyze for 3 hours , concentrated under reduced pressure at 35°C to remove tetrahydrofuran, added water to 350ml, washed the aqueous phase twice with methyl tert-butyl ether, distilled the aqueous phase at 60°C under reduced pressure...

Embodiment 3 2

[0062] The synthesis of embodiment 3 dibutyryl cyclic adenosine monophosphate calcium

[0063] Dissolve 10 g of cyclic adenosine monophosphate in an aqueous solution of 80 g of purified water and 4 g of triethylamine, stir evenly, and concentrate completely at 50° C., add 86 g of pyridine as a solvent to the residual solid, and after complete dissolution, concentrate under reduced pressure to obtain a cyclic adenosine monophosphate Glycoside triethylamine salt, 13.2g.

[0064] Take 10g of cyclic adenosine monophosphate and place it in a 1000ml three-necked flask, add 600ml of pyridine under nitrogen protection and stir to dissolve, then add 50ml of n-butyric anhydride, 5ml of triethylamine, react in the dark at 80°C for 25 hours, cool down to room temperature, add water for hydrolysis Concentrate under reduced pressure at 45°C for 1 hour to remove pyridine, add water to 400ml, wash the aqueous phase twice with methyl tert-butyl ether, 100ml each time, distill the aqueous phase...

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Abstract

The invention relates to the technical field of drug synthesis, in particular to a method for preparing calcium dibutyryladenosine cyclophosphate. The preparation method comprises the following steps: taking adenosine cyclophosphate as a raw material, and preparing adenosine cyclophosphate triethylamine salt with triethylamine under an aprotic solvent; taking butyric anhydride as an acylating agent, and synthesizing the calcium dibutyryladenosine cyclophosphate in an organic aprotic solvent. Compared with the traditional process, the method has the advantages that the production period is shortened from the original 9-10 days to 3-4 days, the yield of crude products is increased to 78-82 percent, the purification yield is increased to 90-94 percent, and the total reaction yield is increased to 70-75 percent. The method disclosed by the invention adopts a continuous washing method and performs reversed phase extraction, and the liquid chromatogram purity of the obtained dibutyryladenosine cyclophosphate is 98-98.5 percent.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of dibutyryl cyclic adenosine monophosphate calcium. Background technique [0002] Calcium dibutyryl cyclic adenosine monophosphate is a derivative of cyclic adenosine monophosphate (cAMP). Because cAMP is not easy to pass through the cell membrane, and the cAMP that enters the cell is quickly hydrolyzed by the phosphodiesterase in the cell, it is made into a derivative of cyclic adenosine monophosphate. Cyclic adenosine monophosphate dibutyryl is more permeable to cells than cAMP, and can resist the destructive effect of phosphodiesterase in the body, so its action time and speed are longer and faster than cAMP, and it has better drug concentration in the body A new generation of products with distribution and kinetic properties. Calcium dibutyryl cyclic adenosine monophosphate can participate in cell energy metabolism and protein synthesis in the b...

Claims

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Application Information

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IPC IPC(8): C07H19/213C07H1/00
Inventor 刘伟张志刚
Owner SHANGHAI ZIYUAN PHARMA
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