Synthesis of 2-aralkyloxyadenosines, 2-alkoxyadenosines, and their analogs
View Patent ↗Provided is a method for the synthesis of an aralkyloxyadenosine or an alkoxyadenosine. The method includes protecting the hydroxyl sugar groups with a protecting group to produce a protected halogenated adenosine. The protected halogenated adenosine is alkoxylated, and the hydroxyl sugar groups of the protected halogenated adenosine are deprotected to provide the aralkyloxyadenosine or alkoxyadenosine.
1. A method for the preparation of a compound of the formula
wherein
R 1 and R 2 are independently selected from hydrogen, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 8 cycloalkyl, C 3 –C 8 cycloalkenyl, C 7 –C 12 aralkyl, C 6 –C 12 aryl, 5–7 membered heteroaryl, and 4–7 membered heterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1 –C 6 alkyl, C 1 –C 6 alkoxy, amino, mono-(C 1 –C 6 alkyl)amino, di-(C 1 –C 6 alkyl)amino, halogen, hydroxy, cyano, nitro, carboxylate, carboxamide, sulfonate, and sulfonamide; or
NR 1 R 2 taken in combination forms a 4–7 membered heterocycloalkyl or a 5–7 membered heteroaryl group, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1 –C 6 alkyl, C 1 –C 6 alkoxy, amino, mono-(C 1 –C 6 alkyl)amino, di-(C 1 –C 6 alkyl)amino, halogen, hydroxy, cyano, nitro, carboxylate, carboxamide, sulfonate, and sulfonamide;
R 3 is aryl, cycloalkyl or heteroaryl, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, alkoxy, and halogen; and
n is an integer of 2 or 3; which method comprises:
a) protecting the hydroxyl groups of a compound of the formula
wherein R 1 and R 2 have a meaning as described for formula (I), and X represents halogen, mesylate, tosylate or triflate, to afford a compound of the formula
wherein R 1 , R 2 and X have a meaning as described above, and Bc, Bc′ and Bc″ represent, independently from each other, the same or a different silyl group of the formula, —SiR A R B R C , in which R A , R B , and R C are, independently from each other,
C 1 –C 6 alkyl, phenyl or benzyl; or Bc represents a silyl group of the formula,
—SiR A R B R C , in which R A , R B , and R C are, independently from each other, C 1 –C 6 alkyl; and Bc′ and B″ combined are 1,1,3,3-tetraisopropyl-disiloxan-1,3-diyl;
treating a resulting compound of formula (III) in the absence of an extrinsic solvent with an alcohol of the formula
R 3 (CH 2 ) n OH (IV)
wherein R 3 and n have a meaning as described for formula (I), and a strong base, to afford a compound of the formula
wherein R 1 , R 2 , R 3 , Bc, Bc′, Bc″ and n have a meaning as described above; and
removing the silyl groups of a resulting compound of formula (V) to afford a compound of formula (I) wherein R 1 , R 2 , R 3 and n have a meaning as described above.
2. The method of claim 1 , wherein Bc, Bc′ and Bc″ are, independently from each other, a silyl group of the formula, —SiR A R B R C , in which R A , R B , and R C are, independently from each other, C 1 –C 6 alkyl.
3. The method of claim 2 , wherein R A is C 3 –C 6 alkyl and R B and R C are, independently from each other, C 1 –C 4 alkyl.
4. The method of claim 2 , wherein Bc, Bc′ and Bc″ are the same silyl group selected from the group consisting of t-butyldimethylsilyl, triethylsilyl, isopropyldiethylsilyl, triisopropylsilyl, isopropyldimethylsilyl and diisopropylethylsilyl.
5. The method of claim 4 , wherein R 3 is 4-chlorophenyl and n is 2.
6. The method of claim 5 , wherein the strong base in step (b) is sodium hydride.
7. The method of claim 4 , wherein the removal of the silyl groups in step (c) is accomplished with a fluoride salt or a base adduct of hydrogen fluoride.
8. The method of claim 7 , wherein the removal of the silyl groups in step (c) is accomplished with a fluoride salt comprising a tetra(C 1 –C 10 )alkylammonium cation.
9. The method of claim 8 , wherein the fluoride salt is selected from the group consisting of tetramethylammonium fluoride, tetraethylammonium fluoride and tetrabutylammonium fluoride.
10. The method of claim 9 , wherein the fluoride salt is tetrabutylammonium fluoride.
11. The method of claim 7 , wherein the removal of the silyl groups in step (c) is accomplished with a base adduct of hydrogen fluoride selected from the group consisting of hydrogen fluoride-pyridine, hydrogen fluoride-pyrazine, hydrogen fluoride-pyrimidine, hydrogen fluoride-trialkylamine, hydrogen fluoride-piperidine, hydrogen fluoride-pyrrole and hydrogen fluoride-pyrrolidine.
12. The method of claim 11 , wherein the base adduct of hydrogen fluoride is selected from the group consisting of triethylamine trihydrofluoride and hydrogen fluoride-pyridine.
13. The method of claim 1 , wherein Bc is a silyl group of the formula, —SiR A R B R C , in which R A , R B , and R C are, independently from each other, C 1 –C 6 alkyl, and Bc′ and B″ combined are 1,1,3,3-tetraisopropyl-disiloxan-1,3-diyl.
14. The method of claim 13 , wherein Bc is selected from the group consisting of t-butyldimethylsilyl, triethylsilyl, isopropyldiethylsilyl, triisopropylsilyl, isopropyldimethylsilyl and diisopropylethylsilyl.
15. The method of claim 14 , wherein R 3 is 4-chlorophenyl and n is 2.
16. The method of claim 15 , wherein the strong base in step (b) is sodium hydride.
17. The method of claim 14 , wherein the removal of the silyl groups in step (c) is accomplished with a fluoride salt or a base adduct of hydrogen fluoride.
18. The method of claim 17 , wherein the removal of the silyl groups in step (c) is accomplished with a fluoride salt comprising a tetra(C 1 –C 10 )alkylammonium cation.
19. The method of claim 18 , wherein the fluoride salt is selected from the group consisting of tetramethylammonium fluoride, tetraethylanunonium fluoride, and tetrabutylanimonium fluoride.
20. The method of claim 19 , wherein the fluoride salt is tetrabutylanimonium fluoride.
21. The method of claim 17 , wherein the removal of the silyl groups in step (c) is accomplished with a base adduct of hydrogen fluoride selected from the group consisting of hydrogen fluoride-pyridine, hydrogen fluoride-pyrazine, hydrogen fluoride-pyrimidine, hydrogen fluoride-trialkylamine, hydrogen fluoride-piperidine, hydrogen fluoride-pyrrole and hydrogen fluoride-pyrrolidine.
22. The method of claim 21 , wherein the base adduct of hydrogen fluoride is selected from the group consisting of triethylamine trihydrofluoride and hydrogen fluoride-pyridine.
23. The method of claim 1 , wherein R 1 and R 2 are hydrogen.
24. A method of accelerating healing of a wound in a mammal which method comprises administering topically to said wound a pharmaceutical composition comprising 2-[2-(4-chlorophenyl)ethoxy]adenosine.
25. The method of claim 24 , wherein the wound is a diabetic foot ulcer.