Ivashchenko Aleksandr Vasilevich,Иващенко Александр Васильевич,Mitkin Oleg Dmitrievich,Митькин Олег Дмитриевич
申请号：
RU2017106609
公开号：
RU0002644156C1
申请日:
2017.02.28
申请国别(地区):
RU
年份:
2018
代理人:
摘要：
FIELD: medicine pharmaceuticals.SUBSTANCE: present invention relates to a novel prodrug which is cyclobutyl (S)-2-{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-ylmethoxy]phenoxy-phosphorylamino}-propanoate of general formula 1, its stereoisomer, or polycrystalline form. Stereoisomers of this compound are cyclobutyl (S)-2-{(S)-[(2R,3R,4R,5R)-5-(3,4-dihydro-2,4-dioxo-2H-pyrimidin-1-yl)-3-hydroxy-4-methyl-4-fluoro-tetrahydrofuran-2-ylmethoxy]-phenoxy-phosphorylamino}-propanoate of formula 1.1 or cyclobutyl (S)-2-{(R)-[(2R,3R,4R,5R)-5-(3,4-dihydro-2,4-dioxo-2H-pyrimidin-1-yl)-3-hydroxy-4-methyl-4-fluoro-tetrahydrofuran-2-ylmethoxy]-phenoxy-phosphorylamino}-propanoate of formula 1.2. Polycrystalline form of these compounds is a mixture of rhombic and monoclinic forms. Crystalline form is a rhombic form. Method for preparation of the prodrug of formulas 1, 1.1 and 1.2 is the reaction of cyclobutyl (S)-2-(pentafluorophenyloxy-phenoxy-phosphorylamino)-propionate of formula 2 or cyclobutyl (S)-2-((S)-pentafluorophenyloxy-phenoxy-phosphorylamino)-propionate of formula 2.1 or cyclobutyl (S)-2-((R)-pentafluorophenyloxy-phenoxy-phosphorylamino)-propionate of formula 2.2 with tert-butyl(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)-2-(hydroxymethyl)-4-methyl-4-fluoro-tetrahydrofuran-3-yl carbonate of formula 7 in the presence of an alkyl magnesium halide, followed by deprotection.EFFECT: prodrug has the properties of a polymerase NS5B HCV inhibitor and can be used in treatment of hepatitis C.10 cl, 10 ex, 3 tblНастоящее изобретение относится к новому пролекарству, представляющему собой циклобутил (S)-2-{[(2R,3R,4R,5R)-5-(2,4-диоксо-3,4-дигидро-2Н-пиримидин-1-ил)-4-фтор-3-гидрокси-4-метил-тетрагидрофуран-2-илметокси]-фенокси-фосфориламино}-пропаноат общей формулы 1, его стереоизомер, кристаллическую или поликристаллическую форму. Пролекарство обладает свойствами ингибитора NS5B HCV полимеразы и может быть исп
