The method of selective derivatization taxan

 

The invention relates to a new method of acylation of the hydroxyl group taxane, including processing taxane allermuir agent selected from the group consisting of anhydrides, dicarbonate, thiodicarb and isocyanate in the reaction mixture containing less than one equivalent of base for each equivalent taxane, preferably 1:1-1:100, with the formation of the C(10) acylated taxane. The invention also relates to a method for solirovanie C(10) hydroxyl group taxane and ways of transformation of C(7) hydroxyl group of 10-acyloxy-7-hydroxyhexane in acetal or ketal. Technical result: a new method of selective derivatization taxan with which C(10) hydroxyl group is protected or derivatised before C(7) hydroxyl group. 4 C. and 28 C.p. f-crystals, 2 tab.

Description text in facsimile form (see graphic part)/

Claims

1. The method of acylation With(10) hydroxyl group taxane, including processing taxane allermuir agent selected from the group consisting of anhydrides, dicarbonate, thiodicarb and isocyanates in the reaction mixture containing less than one equivalent of base is own by p. 1, in which taxon has With(7) and C(10) hydroxyl group and allerease agent selectively interacts with the C(10) hydroxyl group.

3. The method according to p. 1, in which Texan interacting with allermuir agent is 10-deacetylbaccatin III.

4. The method according to p. 1, in which taxon has the structure

where R1is hydrogen, hydroxy, protected hydroxy or together with R14or R2forms a carbonate;

R2is keto-FROM2acyloxy or together with R1forms a carbonate;

R4is-FROM4or acyloxy;

R7is hydrogen, halogen, -FROM7, -OCOZ7or OCOOZ7;

R9is hydrogen, keto, -FROM9, -OCOZ9or OCOOZ9;

R10is hydroxy;

R13is hydroxy, protected hydroxy, keto or

R14is hydrogen, -FROM14acyloxy or together with R1forms a carbonate;

T2T4T7T9and T14are independently hydrogen or hydroxyamino group.

X1is-OH6, -SX7or-NX8X9;

X2is hydrogen, guide, hydrocarbon, substituted hydrocarbon or heteroaryl;

X5is-X10, -OH10, -SX10, -NX8X10or-SO2X11;

X6is hydrocarbon, substituted hydrocarbon, heteroaryl, hydroxyamino group;

X7is hydrocarbon, substituted hydrocarbon, heteroaryl or sulphidizing group;

X8is hydrogen, hydrocarbon or substituted hydrocarbon;

X9is aminosidine group;

X10is hydrocarbon, substituted hydrocarbon or heteroaryl;

X11is hydrocarbon, substituted hydrocarbon, heteroaryl, -OH10or-NX8X14;

X14is hydrogen, hydrocarbon, substituted hydrocarbon or heteroaryl;

Z7and Z9are independently hydrocarbon, substituted hydrocarbon or heteroaryl.

5. The method according to p. 4, in which

R1is hydroxy or, together with R14or R2forms a carbonate;

R2is OCOZ2, -OCOOZ2or together with R1forms a carbonate;

R4is OCOZ4;

R9is hydrogen or keto;

R13is hydroaxe, protected hydroxy or together with R1forms a carbonate;

X1is-OH6or-NX8X9;

X2is hydrogen, hydrocarbon or substituted hydrocarbon;

X3and X4are independently hydrogen, hydrocarbon, substituted hydrocarbon or heteroaryl;

X5is-X10, -OH10or-NX8X10;

X6is hydroxyamino group;

X8is hydrogen, hydrocarbon or substituted hydrocarbon;

X9is aminosidine group;

X10is hydrocarbon, substituted hydrocarbon or heteroaryl;

Z2and Z4are independently hydrocarbon, substituted hydrocarbon or heteroaryl.

6. The method according to p. 1, in which the reaction mixture contains a Lewis acid.

7. The method according to p. 6, in which Texan interacting with allermuir agent is 10-deacetylbaccatin III.

8. The method according to p. 6, in which taxon has the structure

where R1is hydrogen, hydroxy, protected hydroxy or together with R14or R2forms a carbonate;

R2is keto-FROM2acyloxy or together with R17, -OCOZ7or OCOOZ7;

R9is hydrogen, keto, -FROM9, -OCOZ9or OCOOZ9;

R10is hydroxy;

R13is hydroxy, protected hydroxy, keto or

R14is hydrogen, -FROM14acyloxy or together with R1forms a carbonate;

T2T4T7T9and T14are independently hydrogen or hydroxyamino group.

X1is-OH6, -SX7or-NX8X9;

X2is hydrogen, hydrocarbon, substituted hydrocarbon or heteroaryl;

X3and X4are independently hydrogen, hydrocarbon, substituted hydrocarbon or heteroaryl;

X5is-X10, -OH10, -SX10, -NX8X10or-SO2X11;

X6is hydrocarbon, substituted hydrocarbon, heteroaryl, hydroxyamino group;

X7is hydrocarbon, substituted hydrocarbon, heteroaryl or sulphidizing group;

X8is hydrogen, hydrocarbon or substituted hydrocarbon;

X9is aminosidine group;

X10one the major hydrocarbon, heteroaryl, -OH10or-NX8X14;

X14is hydrogen, hydrocarbon, substituted hydrocarbon or heteroaryl;

Z7and Z9are independently hydrocarbon, substituted hydrocarbon or heteroaryl.

9. The method according to p. 8, in which

R1is hydroxy or, together with R14or R2forms a carbonate;

R2is OCOZ2, -OCOOZ2or together with R1forms a carbonate;

R4is OCOZ4;

R9is hydrogen or keto;

R13is hydroxy, protected hydroxy or a group of

R14is hydrogen, hydroxy, protected hydroxy or together with R1forms a carbonate;

X1is-OX6or-NX8X9;

X2is hydrogen, hydrocarbon or substituted hydrocarbon;

X3and X4are independently hydrogen, hydrocarbon, substituted hydrocarbon or heteroaryl;

X5is-X10, -OH10or-NX8X10;

X6is hydroxyamino group;

X8is hydrogen, hydrocarbon or substituted hydrocarbon;

X9is Amin>and Z4are independently hydrocarbon, substituted hydrocarbon or heteroaryl.

10. The method according to p. 9, in which the Lewis acid is chosen from the group consisting of halides or triflates of elements from groups IB, IIB, IIIB, IVB, VB, VIIB, VIII, IIIA, IVA and the lanthanides and actinides.

11. The method according to p. 10, in which the Lewis acid is chosen from the group consisting of zinc chloride, tin chloride, trichloride cerium, copper chloride, trichloride lanthanum, trichloride dysprosium and trichloride ytterbium.

12. The method according to p. 1, where C(10) acylated taxon includes C(7) hydroxyl group, and the method further includes processing C(10) acylated taxane silylium agent for sililirovanie C(7) hydroxyl group.

13. The method according to p. 12, in which C(10) acylated Texan is bakatina III.

14. The method according to p. 1, where C(10) acylated taxon includes C(7) hydroxyl group, and the method further includes processing C(10) acylated taxane allermuir agent for acylation With(7) hydroxyl group.

15. The method according to p. 14, in which C(10) acylated Texan is bakatina III.

16. The method according to p. 1, where C(10) acylated taxon includes(13) hydroxy, metal oxide or ammoniagenes same C(10) acylated taxane precursor of the side chain, selected from the group consisting of-lactams, oxazolines, oxazolidin-carboxylic acids, anhydrides of oxazolidin-carboxylic acids and derivatives azaserine.

17. How sililirovanie C(10) hydroxyl group taxane, including processing taxane silylamine or miscellanea, which correspond to the structures of 6 or 7, respectively:

where RD, RE, RF, RGand RHare independently hydrocarbon, substituted hydrocarbon or heteroatom with education(10) similarvideo taxane.

18. The method according to p. 17, in which taxon treated with silylamines or miscellanea in the presence of catalyst of alkali metal base.

19. The method according to p. 17, in which taxon treated with silylamines or miscellanea in the presence of a catalyst selected from the group consisting of lijiaming catalysts.

20. The method according to p. 17, in which silylated or bisyllabic selected from the group consisting of three(hydrocarbon)selectrebateslocation and bis-three(hydrocarbon)selectrebateslocation, and gidrolabilna group represents a substituted or unsubstituted alkyl or omnitele includes processing(10) similarvideo taxane allermuir agent for acylation With(7) hydroxyl group.

22. The method according to p. 17, in which taxon treated silylamine or miscellanea, is a 10-deacetylbaccatin III, and the method further includes processing(10) similarvideo taxane allermuir agent for acylation With(7) hydroxyl group.

23. The method according to p. 17, in which taxon has the structure

where R1is hydrogen, hydroxy, protected hydroxy or together with R14or R2forms a carbonate;

R2is keto-FROM2acyloxy or together with R1forms a carbonate;

R4is-FROM4or acyloxy;

R7is hydrogen, halogen, -FROM7or acyloxy;

R9is hydrogen, keto, -FROM9or acyloxy;

R10is hydroxy;

R13is hydroxy, protected hydroxy, keto or

R14is hydrogen, -FROM14acyloxy or together with R1forms a carbonate;

T2T4T7T9and T14are independently hydrogen or hydroxyamino group;

X1is-OH6, -SX7or-NX8X9;

X2is hydrogen, hydrocarbon, Sames is substituted hydrocarbon or heteroaryl;

X5is-X10, -OH10, -SX10, -NX8X10or-SO2X11;

X6is hydrocarbon, substituted hydrocarbon, heteroaryl, hydroxyamino group;

X7is hydrocarbon, substituted hydrocarbon, heteroaryl or sulphidizing group;

X8is hydrogen, hydrocarbon or substituted hydrocarbon;

X9is aminosidine group;

X10is hydrocarbon, substituted hydrocarbon or heteroaryl;

X11is hydrocarbon, substituted hydrocarbon, heteroaryl, -OH10or-NX8X14;

X14is hydrogen, hydrocarbon, substituted hydrocarbon or heteroaryl.

24. The method according to p. 23, in which

R1is hydroxy or, together with R14or R2forms a carbonate;

R2is OCOZ2, -OCOOZ2or together with R1forms a carbonate;

R4is OCOZ4;

R9is hydrogen or keto;

R13is hydroxy, protected hydroxy or a group of

R14is hydrogen, hydroxy, protected hydroxy or together with R1the image is karbila or substituted hydrocarbon;

X3and X4are independently hydrogen, hydrocarbon, substituted hydrocarbon or heteroaryl;

X5is-X10, -OH10or-NX8X10;

X6is hydroxyamino group;

X8is hydrogen, hydrocarbon or substituted hydrocarbon;

X9is aminosidine group;

X10is hydrocarbon, substituted hydrocarbon or heteroaryl;

Z2and Z4are independently hydrocarbon, substituted hydrocarbon or heteroaryl.

25. The way of transformation of C(7) hydroxyl group of 10-acyloxy-9-oxo-7-hydroxyhexane in acetal or ketal, including processing 10-acyloxy-9-oxo-7-hydroxyhexane kataliziruemom agent in the presence of an acid catalyst with the formation of the C(10) katalizirovannogo taxane.

26. The method according to p. 25, in which(10) Deputy 10-acyloxy-9-oxo-7-hydroxyhexane is acetoxy.

27. The way of transformation of C(7) hydroxyl group taxane in acetal or ketal, including processing taxane catalyzing agent in the presence of an acid catalyst with the formation of the C(7) katalizirovannogo taxane, and Texan has the structure

R2is keto-FROM2acyloxy or together with R1forms a carbonate;

R4is-FROM4or acyloxy;

R7is hydroxy;

R9is hydrogen, keto, -FROM9or acyloxy;

R10is acyloxy;

R13is hydroxy, protected hydroxy, keto or

R14is hydrogen, -FROM14acyloxy or together with R1forms a carbonate;

T2T4and T14are independently hydrogen or hydroxyamino group;

T9is hydroxyamino group;

X1is-OH6, -SX7or-NX8X9;

X2is hydrogen, hydrocarbon, substituted hydrocarbon or heteroaryl;

X3and X4are independently hydrogen, hydrocarbon, substituted hydrocarbon or heteroaryl;

X5is-X10, -OH10, -SX10, -NX8X10or-SO2X11;

X6is hydrocarbon, substituted hydrocarbon, heteroaryl, hydroxyamino group;

X7is hydrocarbon, substituted hydrocarbon, heteroaryl or sulphidizing proposesto group;

X10is hydrocarbon, substituted hydrocarbon or heteroaryl;

X11is hydrocarbon, substituted hydrocarbon, heteroaryl, -OH10or-NX8X14;

X14is hydrogen, hydrocarbon, substituted hydrocarbon or heteroaryl.

28. The method according to p. 27, in which

R1is hydroxy or, together with R14or R2forms a carbonate;

R2is OCOZ2, -OCOOZ2or together with R1forms a carbonate;

R4is OCOZ4;

R9is hydrogen or keto;

R13is hydroxy, protected hydroxy or a group of

R14is hydrogen, hydroxy, protected hydroxy or together with R1forms a carbonate;

X1is-OH6or-NX8X9;

X2is hydrogen, hydrocarbon or substituted hydrocarbon;

X3and X4are independently hydrogen, hydrocarbon, substituted hydrocarbon or heteroaryl;

X5is-X10, -OH10or-NX8X10;

X6is hydroxyamino group;

X8is hydrogen, hydrocarbon or replaced by the military hydrocarbon or heteroaryl;

Z2and Z4are independently hydrocarbon, substituted hydrocarbon or heteroaryl.

29. The method according to p. 25, in which the acid catalyst is an inorganic acid.

30. The method according to p. 25, in which kataliziruemyj agent has the formula

where X31X32X33and X34are independently hydrocarbon, substituted hydrocarbon or heteroaryl.

31. The method according to p. 25, in which kataliziruemyj agent has the formula

where X31X32and X33are independently hydrocarbon, substituted hydrocarbon or heteroaryl.

32. The method according to p. 25, in which kataliziruemom agent is a vinyl ether.

Priority points and attributes:

18.08.1997 on PP.1-32;

09.04.1998 on PP.1-32 (clarification of signs);

20.04.1998 on PP.1-32 (clarification of signs).

 

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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