RU2001106606A - METHOD FOR PRODUCING 1,3-OXATHIOLANE NUCLEOSIDES - Google Patents

METHOD FOR PRODUCING 1,3-OXATHIOLANE NUCLEOSIDES

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Publication number
RU2001106606A
RU2001106606A RU2001106606/04A RU2001106606A RU2001106606A RU 2001106606 A RU2001106606 A RU 2001106606A RU 2001106606/04 A RU2001106606/04 A RU 2001106606/04A RU 2001106606 A RU2001106606 A RU 2001106606A RU 2001106606 A RU2001106606 A RU 2001106606A
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RU
Russia
Prior art keywords
oxathiolane
chr
protected
hydroxymethyl
chromatography
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RU2001106606/04A
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Russian (ru)
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RU2244712C2 (en
Inventor
Джордж Р. ПЭЙНТЕР
Деннис К. Лиотта
Меррик ЭЛМОНД
Дэррил КЛИРИ
Хосе СОРИЯ
Маркос Луис ШНАЙДМАН
Original Assignee
Трайэнгл Фармасьютикалз, Инк.
Эмори Юниверсити
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Publication of RU2001106606A publication Critical patent/RU2001106606A/en
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Claims (18)

1. Способ получения 2-[R1C(О)OCH2] -1,3-оксатиоланил-5-она непосредственным взаимодействием ацеталя формулы (R1O)2CHR, где R обозначает -(СН2-O-С(О)R1) и R1 обозначает алкил, арил, гетероарил, гетероциклический радикал, алкарил, алкилгетероарил или алкилгетероциклический радикал, или аралкил, с меркаптоуксусной кислотой в органическом растворителе в присутствии кислоты Льюиса или протонной кислоты.1. The method of obtaining 2- [R 1 C (O) OCH 2 ] -1,3-oxathiolanyl-5-one by direct interaction of the acetal of the formula (R 1 O) 2 CHR, where R is - (CH 2 -O-C ( O) R 1 ) and R 1 are alkyl, aryl, heteroaryl, heterocyclic radical, alkaryl, alkyl heteroaryl or alkyl heterocyclic radical, or aralkyl, with mercaptoacetic acid in an organic solvent in the presence of a Lewis acid or protonic acid. 2. Способ по п. 1, отличающийся тем, что реакцию проводят в органическом растворителе с минимальным количеством воды. 2. The method according to p. 1, characterized in that the reaction is carried out in an organic solvent with a minimum amount of water. 3. Способ по п. 1, отличающийся тем, что вместо (R1O)2CHR используют (OH)2CHR или (R1O)(OH)CHR.3. The method according to p. 1, characterized in that instead of (R 1 O) 2 CHR use (OH) 2 CHR or (R 1 O) (OH) CHR. 4. Способ по п. 1, отличающийся тем, что вместо (R1O)2CHR используют (R1O)(ОН)CHR.4. The method according to p. 1, characterized in that instead of (R 1 O) 2 CHR use (R 1 O) (OH) CHR. 5. Способ по п. 1, отличающийся тем, что ацеталь используют в виде смеси полуацеталя, мономера ацеталя или его продуктов с более высокой степенью конденсации. 5. The method according to p. 1, characterized in that the acetal is used as a mixture of semi-acetal, acetal monomer or its products with a higher degree of condensation. 6. Способ по п. 1, включающий также получение (R1O)2CHR путем взаимодействия соединения формулы ОН-СН2-С= С-СН2-ОН с RC(O)C1 с образованием RC(О)ОСН2С(Н)= С(Н)ОС(О)R, который озонируют или каким-либо другим способом расщепляют с получением желательного соединения.6. The method according to p. 1, which also includes obtaining (R 1 O) 2 CHR by reacting a compound of the formula OH-CH 2 -C = C-CH 2 -OH with RC (O) C1 to form RC (O) OCH 2 C (H) = C (H) OC (O) R, which is ozonated or otherwise broken down to give the desired compound. 7. Способ по п. 1, включающий также получение (R1O)2CHR восстановлением (R1O)2CHC(О)Н с образованием (R1O)2CHCH2OH, который далее вступает в реакцию с C1C(O)R с образованием целевого соединения.7. The method of claim 1, further comprising preparing (R 1 O) 2 CHR by reducing (R 1 O) 2 CHC (O) H to form (R 1 O) 2 CHCH 2 OH, which then reacts with C1C ( O) R to form the target compound. 8. Способ получения 1,3-оксатиоланового нуклеозида, включающий: (i) получение 5-галоген-2-защищенного-оксиметил-1,3-оксатиолана; и (ii) реакцию 5-галоген-2-защищенного-оксиметил-1,3-оксатиолана с защищенным пуриновым или пиримидиновым основанием при температуре ниже 25oC в отсутствие кислоты Льюиса.8. A method for producing a 1,3-oxathiolane nucleoside, comprising: (i) preparing 5-halogen-2-protected-hydroxymethyl-1,3-oxathiolane; and (ii) reacting 5-halogen-2-protected-hydroxymethyl-1,3-oxathiolane with a protected purine or pyrimidine base at a temperature below 25 ° C. in the absence of a Lewis acid. 9. Способ по п. 8, отличающийся тем, что указанную реакцию проводят при температуре ниже 10oC.9. The method according to p. 8, characterized in that the reaction is carried out at a temperature below 10 o C. 10. Способ по п. 8, отличающийся тем, что указанный 5-галогеновый заместитель представляет собой 5-хлор. 10. The method according to p. 8, characterized in that said 5-halogen substituent is 5-chloro. 11. Способ по п. 8, отличающийся тем, что указанная реакция приводит к образованию смеси α- и β-аномеров. 11. The method according to p. 8, characterized in that said reaction leads to the formation of a mixture of α- and β-anomers. 12. Способ по п. 11, отличающийся тем, что указанную смесь α- и β-аномеров или их производных разделяют кристаллизацией. 12. The method according to p. 11, characterized in that said mixture of α- and β-anomers or their derivatives is separated by crystallization. 13. Способ по п. 11, отличающийся тем, что указанную смесь α- и β-аномеров или их производных разделяют хроматографированием. 13. The method according to p. 11, characterized in that said mixture of α- and β-anomers or their derivatives is separated by chromatography. 14. Способ по п. 13, отличающийся тем, что указанная хроматография представляет собой ахиральную хроматографию. 14. The method according to p. 13, characterized in that said chromatography is an achiral chromatography. 15. Способ по п. 13, отличающийся тем, что указанная хроматография представляет собой хиральную хроматографию. 15. The method according to p. 13, characterized in that the chromatography is a chiral chromatography. 16. Способ по п. 8, отличающийся тем, что указанный 5-галоген-2-защищенный-оксиметил-1,3-оксатиолан получают галогенированием хирального 5-ацилированного-2-защищенного-оксиметил-1,3-оксатиолана. 16. The method according to p. 8, wherein said 5-halogen-2-protected-hydroxymethyl-1,3-oxathiolane is obtained by halogenation of a chiral 5-acylated-2-protected-hydroxymethyl-1,3-oxathiolane. 17. Способ по п. 8, отличающийся тем, что указанный 5-галоген-2-защищенный-оксиметил-1,3-оксатиолан получают галогенированием ахирального 5-ацилированного-2-защищенного-оксиметил-1,3-оксатиолана. 17. The method of claim 8, wherein said 5-halogen-2-protected-hydroxymethyl-1,3-oxathiolane is obtained by halogenation of an achiral 5-acylated-2-protected-hydroxymethyl-1,3-oxathiolane. 18. Способ по п. 16 или 17, отличающийся тем, что указанный 5-ацилированный-2-защищенный-оксиметил-1,3-оксатиолан содержит 5-ацильный фрагмент, выбранный из группы, состоящей из ацетата, пропионата, бутирата, бензоата, п-метоксибензоата и п-(т-бутил)-бензоата. 18. The method according to p. 16 or 17, characterized in that the specified 5-acylated-2-protected-hydroxymethyl-1,3-oxathiolane contains a 5-acyl moiety selected from the group consisting of acetate, propionate, butyrate, benzoate, p-methoxybenzoate and p- (t-butyl) benzoate.
RU2001106606/04A 1998-08-12 1999-08-12 Method for preparing 1,3-oxathiolan nucleoside, method for preparing derivative of 1,3-oxathiolanyl-5-one RU2244712C2 (en)

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US9621498P 1998-08-12 1998-08-12
US60/096,214 1998-08-12
US60/096214 1998-08-12
US12284199P 1999-03-04 1999-03-04
US60/122,841 1999-03-04
US60/122841 1999-03-04

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JP (4) JP4249393B2 (en)
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CN (1) CN1141305C (en)
AT (2) ATE282034T1 (en)
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HK (2) HK1038921A1 (en)
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