Methods for preparing 2-alkynyladenosine derivatives

1 . A method for preparing a compound of formula A:

or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate or isomorphic crystalline form thereof, the method comprising the step of:

contacting 2-iodoadenosine-5′-N-ethyluronamide with a compound of formula B:

wherein Z is —C(═O)OR or —CH 2 OC(═O)R, where R is a C 1 to C 5 alkyl.

2 . A method according to claim 1 , wherein Z is —C(═O)OCH 3 or —CH 2 OC(═O)CH 3 .

3 . A method according to claim 1 , wherein said 2-iodoadenosine-5′-N-ethyluronamide is prepared from 2-iodoadenosine.

4 . A method according to claim 3 , further comprising the step of converting said 2-iodoadenosine to the acetonide-protected form of said 2-iodoadenosine of the formula:

5 . A method according to claim 4 , further comprising the step of oxidizing said acetonide-protected form of said 2-iodoadenosine to a compound of the formula:

6 . A method according to claim 5 , wherein said oxidizing step is a radical oxidation.

7 . A method according to claim 5 , wherein said oxidizing step comprises the use of a mixture comprising bis-acetoxyiodobenzene and 2,2,6,6-tetramethyl piperidinyloxy free radical (TEMPO).

8 . A method according to claim 5 , further comprising the step of converting said compound of the formula:

to a compound of the formula:

9 . A method according to claim 8 , wherein said converting step proceeds as a one pot reaction.

10 . A method according to claim 8 , wherein said converting step comprises the use of a succinimide derivative and an excess of ethylamine.

11 . A method according to claim 8 , wherein said converting step comprises the use of a composition comprising 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, ethanol and ethylamine.

12 . A method according to claim 8 , further comprising the step of deprotecting said compound of the formula:

to form said 2-iodoadenosine-5′-N-ethyluronamide.

13 . A method according to claim 1 , wherein said compound of formula B is prepared from 1,4-methanol cyclohexane.

14 . A method according to claim 13 , wherein said 1,4-methanol cyclohexane is prepared from a reaction mixture comprising trans-1,4-dimethyl-cyclohexanedicarboxylate.

15 . A method according to claim 14 , wherein said reaction mixture comprises less than about 0.2% by weight, based on the total weight of the 1,4-dimethyl-cyclohexanedicarboxylate, of cis-1,4-dimethyl-cyclohexanedicarboxylate.

16 . A method according to claim 13 , wherein said 1,4-methanol cyclohexane is prepared by a process comprising the step of reducing 1,4-dimethyl-cyclohexanedicarboxylate.

17 . A method according to claim 13 , further comprising the step of preparing the mono-tosyl derivative of said 1,4-methanol cyclohexane.

18 . A method according to claim 17 , further comprising the step of acetylide substitution of said tosyl derivative of the formula:

to form an acetylide-substituted compound of the formula:

19 . A method according to claim 18 , further comprising the step of converting said acetylide-substituted compound to a compound of formula B, where Z is —CH 2 OC(═O)R.

20 . A method according to claim 18 , further comprising the steps of oxidizing said acetylide-substituted compound and esterifying said product of said oxidation to a compound of formula B, where Z is —C(═O)OR.

21 . A method for preparing 2-iodoadenosine-5′-N-ethyluronamide, comprising the steps of:

providing 2-iodoadenosine;

protecting the hydroxyl groups of said 2-iodoadenosine with an acetonide group;

oxidizing the primary alcohol of said acetonide-protected 2-iodoadenosine to an acid derivative of said acetonide-protected 2-iodoadenosine;

converting said acid derivative to an N-ethylamide derivative of said acetonide-protected 2-iodoadenosine; and

deprotecting said N-ethylamide of said acetonide-protected 2-iodoadenosine to form said 2-iodoadenosine-5′-N-ethyluronamide.

22 . A method for preparing a compound of formula B:

wherein Z is —CH 2 OC(═O)R, where R is a C 1 to C 5 alkyl, comprising the steps of.

providing 1,4-methanol cyclohexane; and

preparing a mono-tosyl derivative of said 1,4-methanol cyclohexane;

preparing an acetylide-substituted compound of the formula:

from said mono-tosyl derivative of said 1,4-methanol cyclohexane; and

converting said acetylide-substituted compound to a compound of formula B:

23 . A method for preparing a compound of formula B:

wherein Z is —C(═O)OR, where R is a C 1 to C 5 alkyl, comprising the steps of.

providing 1,4-methanol cyclohexane;

preparing a mono-tosyl derivative of said 1,4-methanol cyclohexane;

preparing an acetylide-substituted compound of the formula:

from said mono-tosyl derivative of said 1,4-methanol cyclohexane;

oxidizing said acetylide-substituted compound using radical oxidation; and

esterifying said product of said oxidation to a compound of formula B:

24 . A method according to claim 23 , wherein said oxidizing step comprises the use of a mixture comprising bis-acetoxyiodobenzene and 2,2,6,6-tetramethyl piperidinyloxy free radical (TEMPO).

25 . A method according to claim 22 or claim 23 , wherein said 1,4-methanol cyclohexane is prepared from a reaction mixture comprising trans-1,4-dimethyl-cyclohexanedicarboxylate.

26 . A method according to claim 25 , wherein said reaction mixture comprises less than about 0.2% by weight, based on the total weight of the 1,4-dimethyl-cyclohexanedicarboxylate, of cis-1,4-dimethyl-cyclohexanedicarboxylate.

27 . A method according to claim 22 or claim 23 , wherein said 1,4-methanol cyclohexane is prepared by a process comprising the step of reducing 1,4-dimethyl-cyclohexanedicarboxylate.