RU2003105816A

RU2003105816A - METHOD FOR PRODUCING A DISCODERMOLIDE AND ITS ANALOGUES

Info

Publication number: RU2003105816A
Application number: RU2003105816/04A
Authority: RU
Inventors: Фредерик Рей КИНДЕР
Original assignee: Новартис Аг
Priority date: 2000-08-07
Filing date: 2001-08-06
Publication date: 2004-08-20

Claims

1. The method of obtaining the compounds of formula V

which includes in the first step a coupling reaction of a ketone compound of the formula I

with an aldehyde compound of the formula II

in the presence of a dialkyl boro halide or triflate, an amine base and a polar organic solvent to give a β-hydroxyketone of formula III

in the second step, the reduction of the ketone compound obtained in the first step by treating it with a borohydride reagent in a polar organic solvent and a proton solvent to obtain a 1,3-diol of formula IV

and in the third step, lactonization and removal of the acid labile hydroxyl protecting group of the 1,3-diol obtained in the second step by treating it with hydrogen halide dissolved in a polar solvent or mixture of solvents to obtain the desired compound of formula V, wherein R ¹ is C ₁ -C ₆ alkyl, benzyl or acid labile hydroxyl protecting group; R ₂ is C ₁ -C ₆ alkyl or benzyl; R ₃ represents a hydrogen atom, C ₁ -C ₆ alkyl, benzyl, C (O) -C ₁ -C ₁₂ alkyl, C (O) Ph, C (O) OC ₁ -C ₁₂ alkyl, C (O) OPh, C (O) NH-C ₁ -C ₁₂ alkyl, C (O) NHPh or an acid labile hydroxyl protecting group; R ₃ ″ is an acid labile hydroxyl protecting group; R ₄ is a hydrogen atom or methyl; and X is O, NH, HCH ₃ , S or CH ₂ , provided that when X is O and R ₃ is an acid labile hydroxyl protecting group of a compound of formula I , the residue —X — R _{3 of the} compound of formula V is —OH.

2. The method according to claim 1, wherein the coupling reaction step is carried out in the presence of β-chlorodiisopinocamphenylborane, triethylamine and diethyl ether at a temperature between -78 and -20 ° C.

3. The method according to claim 1, wherein the reduction step is carried out in the presence of tetramethylammonium triacetoxyborohydride, acetonitrile and acetic acid at a temperature between (-40) and (-10) ° C.

4. The method according to claim 1, in which the stage of lactonization and removal of acid labile hydroxyl protective groups is carried out in the presence of aqueous hydrogen chloride, methanol and tetrahydrofuran at a temperature in the range of -20 and 40 ° C.

5. The compound of formula I

where R ₁ represents a C ₁ -C ₆ alkyl, benzyl or acid labile hydroxyl protecting group;

R ₂ is C ₁ -C ₆ alkyl or benzyl;

R ₃ represents a hydrogen atom, C ₁ -C ₆ alkyl, benzyl, C (O) -C ₁ -C ₁₂ alkyl, C (O) Ph, C (O) O-C ₁ -C ₁₂ alkyl, C (O) OPh, C (O) NH-C ₁ -C ₁₂ alkyl, C (O) NHPh or an acid labile hydroxyl protecting group;

R ₄ represents a hydrogen atom or methyl; and

X is O, NH, NCH ₃ , S or CH ₂ .

6. The compound according to claim 5 of formula Ia

where each of R ₁ 'and R ₂ ' is C ₁ -C ₆ alkyl;

X 'is O or CH ₂ ; a

R ₃ and R ₄ have the same meanings as indicated in paragraph 5.

7. The compound according to claim 6 of formula Ib

wherein R ₃ 'represents a C ₁ -C ₆ alkyl, C (O) -C ₁ -C ₁₂ alkyl, benzyl, C (O) O-C _1- C ₁₂ alkyl or an acid labile hydroxyl protecting group; and R ₁ 'and R ₂ ' have the same meanings as specified in claim 6.

8. The compound according to claim 7 of formula IC

where R ₃ "denotes an acid labile hydroxyl protecting group.

9. The compound of claim 8, which is (2R, 3S, 4R) -3 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -N-methoxy-N, 2,4-trimethyl-5-oxohexanamide corresponding to the formula

10. The method of obtaining the compounds of formula I according to claim 5, which includes in the first stage the addition of a methyl or ethyl-containing organometallic reagent to the aldehyde of formula VI

in the presence of a polar organic solvent to give an alcohol of formula VII

and in the second stage, the oxidation of the alcohol compound obtained in the first stage, its treatment with an oxidizing agent and a base in a polar organic solvent to obtain the target compound of formula I, in which R ₁ , R ₂ , R ₃ , R ₄ and X have the same meanings as specified in clause 5.

11. The method according to claim 10, in which the stage of accession is carried out in the presence of methylmagnesium bromide and diethyl ether at a temperature in the range of -78 and 40 ° C.

12. The method according to claim 10, in which the oxidation step is carried out in the presence of a complex of sulfur trioxide with pyridine, triethylamine and dichloromethane at a temperature in the range of -78 and 40 ° C.

13. The compound of formula III

R ₂ is C ₁ -C ₆ alkyl or benzyl;

R ₃ represents a hydrogen atom, C ₁ -C ₆ alkyl, benzyl, C (O) -C ₁ -C ₁₂ alkyl, C (O) Ph,

C (O) O-C ₁ -C ₁₂ alkyl, C (O) OPh, C (O) ONH-C ₁ -C ₁₂ alkyl, C (O) NHPh or an acid labile hydroxyl protecting group;

R ₄ represents a hydrogen atom or methyl;

X is O, NH, NCH ₃ , S or CH ₂ ;

and each R ₃ ″ is an acid labile hydroxyl protecting group.

14. The compound according to item 13, which is (2R, 3S, 4R, 7S, 8Z, 10S, 11S, 12S, 13Z, 16S, 17R, 18R, 19S, 20S, 21E) -19 - [(aminocarbonyl) oxy ] -3,11,17-tris [[(1,1-dimethylethyl) dimethylsilyl] oxy] -7-hydroxy-N-methoxy-N, 2,4,10,12,14,16,18,20-nonamethyl -5-oxo-8,13,21,23-tetracosatetraenamide corresponding to the formula

15. The compound of formula IV

R ₂ is C ₁ -C ₆ alkyl or benzyl;

R ₃ represents a hydrogen atom, C ₁ -C ₆ alkyl, benzyl, C (O) -C ₁ -C ₁₂ alkyl, C (O) Ph, C (O) O-C ₁ -C ₁₂ alkyl, C (O) OPh, C (O) NH — C ₁ -C ₁₂ alkyl, C (O) NHPh or an acid labile hydroxyl protecting group;

R ₄ represents a hydrogen atom or methyl;

X is O, NH, NCH ₃ , S or CH ₂ ; and

each R ₃ ″ is an acid labile hydroxyl protecting group.

16. The compound of claim 15, which is (2R, 3S, 4S, 5S, 7S, 8Z, 10S, 11S, 12S, 13Z, 16S, 17R, 18R, 19S, 20S, 21E) -19 - [(aminocarbonyl ) hydroxy] -3,11,17-tris [[(1,1-dimethylethyl) dimethylsilyl] oxy] -5,7-dihydroxy-N-methoxy-N, 2,4,10,12,14,16,18 , 20-nonamethyl-8,13,21,23-tetracosatetraenamide corresponding to the formula