Method for synthesizing (R)-9(2-(diethyl phosphonyl methoxyl) propyl)-adenine

A technology of diethylphosphonomethoxy and phosphonomethoxy, which is applied in the field of synthesizing 9-[2-propyl]-adenine, can solve the difficulties in production operation, high production cost of PMPA diethyl ester, The purity of PMPA diethyl ester is only 40-45%, which achieves the effect of easy control of process operation and safe reagent

Active Publication Date: 2011-08-10
YANCHENG DESANO PHARMA CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above synthetic route, the condensation reaction of the second step EP206459, US5733788 reported that the basic catalyst used is lithium hydride or sodium hydride, and these two reagents are combustible and explosive when they meet water and wet air, and the production operation is relatively difficult, and Reaction molar yield has only 20~30%, and the purity of the PMPA diethyl ester that obtains has only 40~45%
And US5935946 report uses lithium tert-butoxide, although the molar yield has been improved to 40~45%, product purity has also been improved to 60~65%, but reagent lithium tert-butoxide is expensive commercially, so the present PMPA diethyl ester The production cost is relatively high, and at the same time, there are problems in industrial production

Method used

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  • Method for synthesizing (R)-9(2-(diethyl phosphonyl methoxyl) propyl)-adenine

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Embodiment 1

[0020] (R)-Hydroxypropyladenine

[0021] Under nitrogen protection, put 10.0 g of adenine, 0.12 g of sodium hydroxide, 8.3 g of (R)-propylene carbonate, and 70 ml of DMF into the reaction flask, and heat the mixture in stages: 90°C, 110°C and 125°C, At an interval of 1 hour, the reaction was incubated at an internal temperature of 125°C for 28 hours. After TLC showed the end of the reaction, (R)-hydroxypropyl adenine was obtained and stored at a lower temperature. The purity by area normalized HPLC analysis was 83%.

Embodiment 2

[0023] (R)-9-[2-(Diethylphosphonomethoxy)propyl]-adenine (PMPA diethyl ester)

[0024] Under the protection of nitrogen, in all the solutions obtained in Example 1, 12.0 g of di-n-butyl magnesium was added, and then 38.0 g of p-toluenesulfonyloxymethyl diethyl phosphate was added dropwise (adding in three times, each interval 1 hours), after the first addition, the temperature of the system was raised to 65°C, and it was controlled at 65°C during the second and third additions;

[0025] After the addition, the reaction was incubated for 3 hours, followed by TLC (TLC conditions: chloroform:methanol=6:1, volume). After the reaction is complete, cool down to 20°C, add 20ml of glacial acetic acid, control the internal temperature to not exceed 25°C, and pH=5. The solvent was evaporated under reduced pressure. 30 ml of water was added to the residue, followed by extraction with 300 ml of dichloromethane. The dichloromethane layer was washed 3 times with 30 ml of water each time....

Embodiment 3

[0027] (R)-9-[2-(Diethylphosphonomethoxy)propyl]-adenine (PMPA diethyl ester)

[0028] Under nitrogen protection, in all the solutions obtained according to the method of Example 1, 20.0 g of di-n-butyl magnesium was added, and then 40.0 g of diethyl p-toluenesulfonyloxymethyl phosphate was added dropwise (adding in three times, each time interval of 1 hour), the temperature of the system was raised to 35°C after the first addition, and was controlled at 35°C during the second and third additions; after the addition, the temperature was kept for 6 hours, and the reaction was tracked by TLC. After the same post-treatment as above, 21.2 g of orange oil was obtained, the purity of which was analyzed by area-normalized HPLC was 81%, and the yield was 67.7%.

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Abstract

The invention provides a method for synthesizing (R)-9(2-(diethyl phosphonyl methoxyl) propyl)-adenine. The method includes the following steps of: implementing condensation reaction of (R)-hydroxypropyl adenine and tosyloxy methyl diethyl phosphate in solvent under the catalysis of catalytic amount of dialkyl magnesium, and then collecting generated PMPA diethyl ester from the reaction product. By using the method to produce the PMPA diethyl ester, the yield rate and the purity can be improved to over 80 percent, the used agent is safe, and the process operation is easy to control.

Description

technical field [0001] The present invention relates to a method for synthesizing (R)-9-[2-(diethylphosphonomethoxy)propyl]-adenine. Background technique [0002] Tenofovir (PMPA) is the first nucleotide analogue approved by the US FDA for the treatment of HIV-1 infection, and the approved indication is to be used in combination with other antiretroviral drugs for the treatment of HIV-1 infection. Its chemical name is (R)-9-[2-(phosphonomethoxy)propyl]-adenine, and its structural formula is as follows: [0003] [0004] (R)-9-[2-(diethylphosphonomethoxy) propyl]-adenine (abbreviated as PMPA diethyl ester, the same below) is a key intermediate for the synthesis of PMPA, and the current synthesis of PMPA diethyl ester The main method is: using adenine as a raw material, condensing with (R)-propylene carbonate to generate (R)-hydroxypropyl adenine, and then reacting with p-toluene under the catalysis of lithium hydride (sodium) or lithium tert-butoxide Diethyl sulfonyloxym...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561A61P31/18
Inventor 李金亮赵楠
Owner YANCHENG DESANO PHARMA CO LTD
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