Intermediates for producing oligonucleotide analogs or salts thereof and methods for producing the same

Abstract

This invention relates to intermediates for producing oligonucleotide analogs or salts thereof, and to methods for producing the same. Specifically, it relates to compounds of formula VIII and methods for producing the same, with the definitions of each substituent being as defined in the specification. JPEG2026520829000135.jpg30170

Claims

1. A method for producing a compound of formula VIII or a salt thereof, 【Chemistry 1】 The above method is a) A step of converting the compound of formula II into the compound of formula III, b) A step of converting the compound of formula III to the compound of formula IV, c) A step of converting the compound of formula IV into the compound of formula V, d) A step of converting the compound of formula V into the compound of formula VI, e) A step of reacting a compound of formula VI with 4,4'-dimethoxytriphenylmethyl halide to form a compound of formula VII, f) The step of converting the compound of formula VII to the compound of formula VIII, 【Chemistry 2】 Here, R ａ , R ｂ , R ｃ These are the same or different, and each independently consists of hydrogen, halogen, hydroxyl group, amino group, and C. １－６ Alkyl alkyl group, C １－６ The alkyl group is selected from an alkoxy group, a 3-10 membered cycloalkyl group, a 3-10 membered heterocyclyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group can be optionally a halogen, a hydroxyl group, an amino group, or C １－６ Alkyl alkyl group or C １－６ Substituted with one or more substituents selected from alkoxy groups, R ｄ is selected from a benzyl group, a phenyl group, a biphenyl group, a C １－６ alkyl group, and the benzyl group, phenyl group, biphenyl group, C １－６ alkyl group is optionally substituted with one or more substituents selected from halogen, a hydroxy group, an amino group, a C １－６ alkyl group or a C １－６ alkoxy group, B is a base, R Ｂ is -C(O)-C １－６ Alkyl alkyl group, -C(O)-C １－６ Haloalkyl group, -C(O)-C １－６ Hydroxysubstituted alkyl group, -C(O)-C １－６ Selected from amino-substituted alkyl groups, R ２ , R ４ These are the same or different, and each is independently a hydroxyl protecting group. R ３ The method is selected from a trityl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a (trimethylsilyl)ethyl group, and a 2-tetrahydropyran group.

2. R ａ , R ｂ , R ｃ The method according to claim 1, wherein all of them are hydrogen.

3. R ｄ The method according to claim 1 or 2, wherein is a benzyl group.

4. R ２ The method according to any one of claims 1 to 3, wherein is selected from a benzyl group, a trityl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a (trimethylsilyl)ethyl group, and a 2-tetrahydropyran, preferably a benzyl group.

5. The compound of formula VIII is the compound of formula VIII-1. 【Transformation 3】 The method comprises the steps of converting the compound of formula II-1 to the compound of III-1, and reacting the compound of formula III-1 with the compound of formula D to form the compound of formula IV-1. 【Chemistry 4】 Here, R ｅ , R ｇ These are the same or different, and each independently consists of hydrogen, halogen, hydroxyl group, amino group, and C. １－６ Haloalkyl group, C １－６ Hydroxysubstituted alkyl group, C １－６ Selected from amino-substituted alkyl groups, R ｆ , R ｈ , R ｉ These are the same or different, and each independently consists of hydrogen, halogen, hydroxyl group, amino group, and C. １－６ Haloalkyl group, C １－６ Hydroxysubstituted alkyl group, C １－６ Selected from amino-substituted alkyl groups, Or, R ｈ , R ｉ It forms an oxo group and a thio group with the linked carbon atoms. R ３ , R ４ , R Ｂ The method according to any one of claims 1 to 4, wherein the method is as defined in claim 1.

6. Compound of formula IV-1 and acyl halide compound X １ -R Ｂ The method further includes the steps of reacting with to form a V-1 compound, and converting the V-1 compound to a VI-1 compound, 【Transformation 5】 Here, X in the acyl halide compound １ R Ｂ Linked to the carbonyl group in X １ represents a halogen, selected from fluorine, chlorine, bromine, and iodine, preferably chlorine. R ４ , R Ｂ This is as defined in claim 1, and R ｅ , R ｆ , R ｇ The method according to claim 5, wherein the method is as defined in claim 5.

7. Compound of formula VI-1 and DMTr-X ２ The method further comprises the steps of reacting with to form compound VII-1, and converting compound VII-1 to compound VIII-1, 【Transformation 6】 Here, X ２ represents a halogen, selected from fluorine, chlorine, bromine, and iodine, preferably chlorine. R ４ , R Ｂ This is as defined in claim 1, and R ｅ , R ｆ , R ｇ The method according to claim 5 or 6, wherein the method is as defined in claim 5.

8. a) A step of converting the compound of formula II-1 to the compound of formula III-1, b) A step of reacting the compound of formula III-1 with the compound of formula D to form the compound of formula IV-1, c) Compound of formula IV-1 and acyl halide compound X １ -R Ｂ The steps include reacting with to form compound V-1, d) A step of converting the compound of formula V-1 to the compound of formula VI-1, e) Compound of formula VI-1 and DMTr-X ２ The steps include reacting with to form compound VII-1, f) The step of converting the compound of formula VII-1 to the compound of formula VIII-1, 【Transformation 7】 Here, R ３ , R ４ , R Ｂ This is as defined in claim 1, and R ｅ , R ｆ , R ｇ , R ｈ , R ｉ This is as defined in claim 5, and X １ This is as defined in claim 6, and X ２ The method according to any one of claims 5 to 7, wherein the method is as defined in claim 7.

9. The method according to any one of claims 1 to 8, wherein B is selected from substituted or unsubstituted purines, adenine, guanine, isoguanine, hypoxanthine, xanthine, C2-modified purine, N8-modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2-thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole, preferably substituted or unsubstituted adenine, guanine, cytosine, uracil, or thymine, and most preferably substituted or unsubstituted guanine.

10. R ３ The method according to any one of claims 1 to 9, wherein the group is selected from a trimethylsilyl group and a trityl group.

11. R ４ The method according to any one of claims 1 to 10, wherein is selected from a trityl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a (trimethylsilyl)ethyl group, and a 2-tetrahydropyran, and preferably a tert-butyldimethylsilyl group and a tert-butyldiphenylsilyl group.

12. R Ｂ is C(O)-C １－６ Selected from alkyl groups, preferably -C(O)-CH ３ ,-C(O)-CH ２ CH ３ , -C(O)-CH(CH ３ ) ２ And most preferably, -C(O)-CH(CH ３ ) ２ The method according to any one of claims 1 to 11.

13. R ｈ is hydrogen, and R ｉ The method according to any one of claims 5 to 12, wherein is a halogen, and the halogen is selected from fluorine, chlorine, bromine, and iodine, and preferably chlorine.

14. R ｅ , R ｆ , R ｇ The method according to any one of claims 5 to 13, wherein all of them are hydrogen.

15. A compound shown in formula II or a pharmaceutically acceptable salt thereof, 【Transformation 8】 Preferably, the compound shown in formula II-1 or a pharmaceutically acceptable salt thereof. 【Chemistry 9】 And, Here, R ａ 、 R ｂ 、 R ｃ are the same or different and each independently is hydrogen, halogen, hydroxy group, amino group, C １－６ alkyl group, C １－６ alkoxy group, 3- to 10-membered cycloalkyl group, 3- to 10-membered heterocyclyl group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, and the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group are optionally substituted with one or more substituents selected from halogen, hydroxy group, amino group, C １－６ alkyl group or C １－６ alkoxy group, R ｄ is selected from a benzyl group, a phenyl group, a biphenyl group, a C １－６ alkyl group, and the benzyl group, phenyl group, biphenyl group, C １－６ alkyl group is optionally substituted with one or more substituents selected from halogen, a hydroxy group, an amino group, a C １－６ alkyl group or a C １－６ alkoxy group, R ２ The hydroxyl group protecting group is preferably a benzyl group, a trityl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a (trimethylsilyl)ethyl group, or a 2-tetrahydropyran, and most preferably a benzyl group. R ３ The compound shown in formula II or a pharmaceutically acceptable salt thereof, wherein is selected from a trityl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a (trimethylsilyl)ethyl group, and a 2-tetrahydropyran, and preferably a trimethylsilyl group or a trityl group.

16. A compound shown in Formula III or a pharmaceutically acceptable salt thereof, 【Chemistry 10】 Preferably, the compound shown in formula III-1 or a pharmaceutically acceptable salt thereof. 【Chemistry 11】 And, Here, R ２ This is a hydroxyl group protecting group, preferably a benzyl group, a trityl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a (trimethylsilyl)ethyl group, or a 2-tetrahydropyran, preferably a benzyl group. R ３ The compound shown in formula III or a pharmaceutically acceptable salt thereof, wherein is selected from a trityl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a (trimethylsilyl)ethyl group, and a 2-tetrahydropyran, and preferably a trimethylsilyl group or a trityl group.

17. A compound shown in formula IV or a pharmaceutically acceptable salt thereof, 【Chemistry 12】 Preferably, the compound shown in formula IV-1 or a pharmaceutically acceptable salt thereof. 【Chemistry 13】 And, Here, R ２ This is a hydroxyl group protecting group, preferably a benzyl group, a trityl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a (trimethylsilyl)ethyl group, or a 2-tetrahydropyran, preferably a benzyl group. B is a base, R ｅ , R ｆ , R ｇ These are the same or different, and each independently consists of hydrogen, halogen, hydroxyl group, amino group, and C. １－６ Haloalkyl group, C １－６ Hydroxysubstituted alkyl group, C １－６ A compound represented by formula IV, selected from amino-substituted alkyl groups, or a pharmaceutically acceptable salt thereof.

18. A compound shown in formula V or a pharmaceutically acceptable salt thereof, 【Chemistry 14】 Preferably, the compound shown in formula V-1 or a pharmaceutically acceptable salt thereof. 【Chemistry 15】 And here, R ２ The hydroxyl group protecting group is preferably a benzyl group, a trityl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a (trimethylsilyl)ethyl group, or a 2-tetrahydropyran, and most preferably a benzyl group. R ４ This is a hydroxyl group protecting group, preferably a trityl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a (trimethylsilyl)ethyl group, or a 2-tetrahydropyran, most preferably a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group. B is a base, R Ｂ is -C(O)-C １－６ Alkyl alkyl group, -C(O)-C １－６ Haloalkyl group, -C(O)-C １－６ Hydroxysubstituted alkyl group, -C(O)-C １－６ Selected from amino-substituted alkyl groups, preferably -C(O)-CH ３ ,-C(O)-CH ２ CH ３ , -C(O)-CH(CH ３ ) ２ And most preferably, -C(O)-CH(CH ３ ) ２ And, R ｅ , R ｇ These are the same or different, and each independently consists of hydrogen, halogen, hydroxyl group, amino group, and C. １－６ Haloalkyl group, C １－６ Hydroxysubstituted alkyl group, C １－６ A compound represented by formula V, selected from amino-substituted alkyl groups, or a pharmaceutically acceptable salt thereof.

19. A compound shown in formula VI or a pharmaceutically acceptable salt thereof, 【Chemistry 16】 Preferably, the compound shown in formula VI-1 or a pharmaceutically acceptable salt thereof. 【Chemistry 17】 And here, R ４ This is a hydroxyl group protecting group, preferably a trityl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a (trimethylsilyl)ethyl group, or a 2-tetrahydropyran, most preferably a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group. B is a base, R Ｂ is -C(O)-C １－６ Alkyl alkyl group, -C(O)-C １－６ Haloalkyl group, -C(O)-C １－６ Hydroxysubstituted alkyl group, -C(O)-C １－６ Selected from amino-substituted alkyl groups, preferably -C(O)-CH ３ ,-C(O)-CH ２ CH ３ , -C(O)-CH(CH ３ ) ２ And most preferably, -C(O)-CH(CH ３ ) ２ And, R ｅ , R ｇ These are the same or different, and each independently consists of hydrogen, halogen, hydroxyl group, amino group, and C. １－６ Haloalkyl group, C １－６ Hydroxysubstituted alkyl group, C １－６ A compound represented by formula VI, selected from amino-substituted alkyl groups, or a pharmaceutically acceptable salt thereof.

20. A compound shown in formula VII or a pharmaceutically acceptable salt thereof, [Chemistry 18] Preferably, the compound shown in formula VII-1 or a pharmaceutically acceptable salt thereof. 【Chemistry 19】 And here, R ４ This is a hydroxyl group protecting group, preferably a trityl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a (trimethylsilyl)ethyl group, or a 2-tetrahydropyran, most preferably a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group. B is a base, R Ｂ is -C(O)-C １－６ Alkyl alkyl group, -C(O)-C １－６ Haloalkyl group, -C(O)-C １－６ Hydroxysubstituted alkyl group, -C(O)-C １－６ Selected from amino-substituted alkyl groups, preferably -C(O)-CH ３ ,-C(O)-CH ２ CH ３ , -C(O)-CH(CH ３ ) ２ And most preferably, -C(O)-CH(CH ３ ) ２ And, R ｅ , R ｇ These are the same or different, and each independently consists of hydrogen, halogen, hydroxyl group, amino group, and C. １－６ Haloalkyl group, C １－６ Hydroxysubstituted alkyl group, C １－６ A compound represented by formula VII, selected from amino-substituted alkyl groups, or a pharmaceutically acceptable salt thereof.

21. Use of the method according to any one of claims 1 to 14, the compound shown in formula II or formula II-1 as described in claim 15, the compound shown in formula III or formula III-1 as described in claim 16, the compound shown in formula IV or formula IV-1 as described in claim 17, the compound shown in formula V or formula V-1 as described in claim 18, the compound shown in formula VI or formula VI-1 as described in claim 19, and the compound shown in formula VII or formula VII-1 as described in claim 20, in the production of oligonucleotide analogs, for example, in the production of siRNA.

22. A method for producing a compound of formula 1, comprising the steps of the method according to any one of claims 1 to 14. 【Chemistry 20】 ,method.

Images