Narodowy Instytut Leków;Slaski Uniwerytet Medyczny;Uniwersystet Slaski w Katowicach
发明人:
申请号：
EP19460029.2
公开号：
EP3575310A1
申请日:
2019.05.28
申请国别(地区):
EP
年份:
2019
代理人:
摘要：
The invention relates to the phosphonate derivatives of the 3-carboxyacylbetulinic acid with antiviral activity, of formula 1A or of formula 1B, wherein:R is an alkyl group (C1-C4),R1 is an alkyl group (C1-C4),R2 is a hydroxyl or carbonyl or acetyloxy or carboxyacyloxy group,R3 is an acetyloxymethyl or hydroxymethyl or carboxyl group.The invention also relates to a method of preparing the derivatives of formula 1A, where there are following steps: (a) compound of formula 2A, wherein: R is an alkyl group (C1-C4), and R1 is an alkyl group (C1-C4), is subjected to alkaline hydrolysis in the presence of an aqueous solution of a metal hydroxide, in an organic solvent or in a mixture of organic solvents, resulting in 30-phosphonate of 3-acetylbetulin； (b) the product of step (a) is reacted with the Jones reagent taken in an amount of 1 to 4 ml per 1 mmol of the product of step (a), in at least 10 ml of an organic solvent per 1 mmol of the product of step (a), resulting in 30-phosphonate of 3-acetylbetulinic acid； (c) the product of step (b) is subjected to alkaline hydrolysis in the presence of an aqueous solution of a metal hydroxide in an organic solvent, resulting in 30-phosphonate of betulinic acid； (d) the product of step (c) is reacted with a dicarboxylic acid anhydride or with a dicarboxylic acid, at a molar ratio of between 1:1 to 1:10, for at least 30 minutes.The invention also relates to a method of preparing the derivatives of formula 1B, where there are following steps: (a) compound of formula 2B, wherein R is an alkyl group (C1-C4), and R1 is an alkyl group (C1-C4), is reacted with the Jones reagent taken in an amount of 2 to 6 ml per 1 mmol of the compound of formula 2B, resulting in 29-phosphonate of betulonic acid； (b) the product of step (a) is reduced by sodium or lithium borohydride, resulting in 29-phosphonate of betulinic acid； (c) the product of step (b) is reacted with a dicarboxylic acid anhydride or with a dicarboxylic acid
