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Method for synthesizing higher fatty acid zidovudine ester

A technology of higher fatty acid and zidovudine, which is applied in the direction of drug combination, sugar derivatives, organic chemistry, etc., can solve the problems of being unsuitable for industrial production, corrosive and toxic, difficult to separate and purify, etc., and achieve high yield , Improve stability, mild condition effect

Inactive Publication Date: 2008-09-10
XIAMEN UNIV
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0010] 1. From the perspective of environmental friendliness, the reagents thionyl chloride, oxalyl chloride and the solvent benzene are all low-boiling liquids, and are corrosive and toxic. Benzene can also cause cancer, thus causing serious environmental burdens
[0011] 2. From the perspective of cost and process, when preparing in large quantities, especially for carboxylic acids with complex structures, the amount of thionyl chloride and oxalyl chloride must be increased, and the amount of N,N-dimethyl-4-aminopyridine It is also relatively large, which increases the cost of synthesis and increases the pollution to the environment
In addition, for carboxylic acids with complex structures, the lower yield will make separation and purification difficult, and column chromatography must be used, which increases the process cost
Therefore, in general, the above two methods are not suitable for industrial production

Method used

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  • Method for synthesizing higher fatty acid zidovudine ester
  • Method for synthesizing higher fatty acid zidovudine ester
  • Method for synthesizing higher fatty acid zidovudine ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Step 1 Preparation of myristic acid mixed anhydride 1

[0026] Myristic acid (4.1 g, 18 mmol) and N,N-dimethyl-4-aminopyridine (440 mg, 3.6 mmol) were dissolved in dichloromethane (36 mL), triethylamine (3.7 mL, 27 mmol) was added, Ethyl chloroformate (1.8 mL, 19 mmol) was added dropwise at room temperature. The mixed solution was reacted at 40° C. for 12 h, cooled to room temperature and directly proceeded to the next reaction.

[0027] Step 2 synthesis of zidovudine myristate

[0028] Triethylamine (3.7mL, 27mmol) was added to the reaction solution obtained in step 1, and then zidovudine (4.8g, 18mmol) and N,N-dimethyl-4-aminopyridine (440mg, 3.6mmol) Dissolved in dichloromethane (9 mL) and added to the reaction solution through the dropping funnel. The mixed solution was reacted at 40° C. for 10 h and cooled to room temperature.

[0029] Step 3 Purification of zidovudine myristate

[0030] The reaction solution obtained in step 2 was filtered through diatomaceou...

Embodiment 2

[0032] Step 1 Preparation of palmitic acid mixed anhydride 1

[0033] Palmitic acid (9.2g, 36mmol) and N,N-dimethyl-4-aminopyridine (1.32g, 10.8mmol) were dissolved in tetrahydrofuran (120mL), triethylamine (7.4mL, 54mmol) was added, and Ethyl chloroformate (7.2 mL, 72 mmol) was added dropwise. The mixed solution was reacted at 68°C for 10 h, cooled to room temperature and directly proceeded to the next reaction.

[0034] Step 2 Synthesis of Zidovudine Palmitate

[0035] Triethylamine (7.4mL, 54mmol) was added to the reaction solution obtained in step 1, and then zidovudine (9.6g, 36mmol) and N,N-dimethyl-4-aminopyridine (1.32g, 10.8mmol ) was dissolved in tetrahydrofuran (18 mL) and added to the reaction solution through a dropping funnel. The mixed solution was reacted at 68°C for 7h and cooled to room temperature.

[0036] Purification of step 3 zidovudine palmitate

[0037] The reaction solution obtained in step 2 was filtered through diatomaceous earth to remove insolu...

Embodiment 3

[0039] Step 1 prepares stearic acid mixed anhydride 1

[0040] Dissolve stearic acid (5.1g, 18mmol) and N,N-dimethyl-4-aminopyridine (0.11g, 9mmol) in 1,2 dichloroethane (18mL), add pyridine (3.6mL, 45mmol ), ethyl chloroformate (8.5 mL, 90 mmol) was added dropwise at room temperature. The mixed solution was reacted at 84°C for 8h, cooled to room temperature and directly proceeded to the next reaction.

[0041] Step 2 synthesizes zidovudine stearate

[0042] Pyridine (3.6mL, 45mmol) was added to the reaction solution obtained in step 1, then zidovudine (4.8g, 18mmol) and N,N-dimethyl-4-aminopyridine (0.11g, 9mmol) were dissolved in 1,2 Dichloroethane (18 mL) was added to the reaction solution through the dropping funnel. The mixed solution was reacted at 84°C for 5h and cooled to room temperature.

[0043] The purification of step 3 zidovudine stearate

[0044] The reaction solution obtained in step 2 was filtered through diatomaceous earth to remove insoluble solids, the...

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Abstract

The invention provides a synthesis method for a higher fatty acid zidovudine ester, relating to a zidovudine ester, in particular to a synthesis method for a novel prodrug higher fatty acid zidovudine ester; the invention provides the synthesis method for the higher fatty acid zidovudine ester, which is high in yield and suitable for the industrialized production. The method is that higher fatty acid and N, N-dimethyl-4-aminopyridine are dissolved in an organic solvent, and the organic solvent is added with chloro formate and alkali for reaction, so that the mixed anhydride is obtained; zidovudine, the N, N-dimethyl-4-aminopyridine and the alkali are added to the solvent, and the mixed anhydride is added to the solvent for reaction, and the higher fatty acid zidovudine ester is obtained.

Description

technical field [0001] The invention relates to a zidovudine ester, in particular to a synthesis method of a novel prodrug higher fatty acid zidovudine ester. Background technique [0002] Zidovudine was first synthesized as an anticancer drug in 1964. It was found to have an inhibitory effect on human acquired immunodeficiency virus HIV in 1984. In 1987, it was the first to be approved by the US FDA as an anti-HIV drug. important drug for treatment. Studies at home and abroad have shown that esterifying the 5'-hydroxyl of zidovudine to make a prodrug can improve the absorption, distribution and metabolism of the drug in the body, improve the antiviral activity of the drug, and reduce the side effects of the drug. There is no factory production at home and abroad. [0003] At present, there are mainly two methods for the esterification of the 5' hydroxyl group of zidovudine that have been reported, both of which are reported by Agrawal K.C. (J.Med.Chem.1990, 33, 1505-1510)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073A61P35/00
Inventor 郑啸王秀敏朱文芳王利娟
Owner XIAMEN UNIV
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