Methods for the preparation of (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol

1. A method for the synthesis of (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol having the structure of formula (6),

which method comprises the step of reducing the intermediate of formula α-(4):

2. A method according to claim 1 which method further comprises crystallizing intermediate of formula α-(4) with a solvent prior to the reduction thereof.

3. A method according to claim 1 which method further comprises

a) epimerizing with acid intermediate of formula β-(4) into the intermediate of formula α-(4); and

b) crystallizing intermediate of formula α-(4) with a solvent prior to the reduction thereof.

4. A method according to claim 3 which method further comprises after crystallizing intermediate of formula α-(4),

a) epimerizing with acid intermediate of formula β-(4) in the mother liquor of said crystallization into the intermediate of formula α-(4); and

b) crystallizing intermediate of formula α-(4) with a solvent; prior to the reduction thereof.

5. A method according to claim 3 wherein the epimerization of compound of formula β-(4) to compound of formula α-(4) and crystallization of compound of formula α-(4) occur simultaneously.

6. A method according to claim 5 , wherein the simultaneous epimerization of compound of formula β-(4) to compound of formula α-(4) and the crystallization of compound of formula α-(4) is performed in methanol in the presence of an acid by evaporation or partial evaporation of the methanol.

7. A method according to claim 1 which method comprises the steps of:

a) treating compound of formula (3) with a base and subsequently with an acid in the presence of a non-methanolic solvent; and subsequently reacting with methanol under acidic conditions;

wherein

P 1 and P 2 are each independently a hydrogen, a hydroxy-protecting group or may together form a vicinal-diol protecting group,

R 1 is alkyl, aryl or aralkyl;

resulting in intermediates of formula (4); and

b) reducing intermediate of formula (4) with a reducing agent and applying an intramolecular cyclization reaction to obtain compound of formula (6)

8. A method according to claim 7 wherein compounds of formula (3) are obtained by reacting compounds of formula (2) with nitromethane and a base

9. A method according to claim 8 wherein compounds of formula (2) are obtained by condensing an intermediate of formula (1) or its hydrate, hemihydrate or a mixture thereof with phosphonates of the formula (R 6 O) 2 P(═O)—CH 2 —C(═O)OR 1 , wherein

P 1 and P 2 are as defined in claim 1 ,

R 1 is as defined in claim 1 ,

R 6 is alkyl, aryl or aralkyl,

10. A method according to claim 7 wherein P 1 and P 2 together form a dialkyl methylene radical.

11. A method according to claim 8 wherein the base employed for the conversion of compounds of formula (2) into compounds of formula (3) is DBU or TMG or derivatives thereof.

12. A method according to claim 9 wherein the phosphonate of the formula (R 6 O) 2 P(═O)—CH 2 —C(═O)OR 1 is triethyl phosphonoacetate (TEPA).

13. A method according to claim 7 wherein the conversion of compounds of formula (3) into compounds of formula (4) is performed with a base selected from the group of sodium methoxide, lithium methoxide, DBU or TMG or mixtures thereof.

14. A method according to claim 8 , wherein the conversion of compounds of formula (2) into compounds of formula (4) is performed by using DBU or TMG as the base in the conversion of compounds of formula (2) to compounds of formula (3), not isolating compounds of formula (3) and using sodium or lithium methoxide as additional base in the conversion of compounds of formula (3) to compounds of formula (4).

15. A method according to claim 7 wherein the acid employed in the conversion of compounds of formula (3) into compounds of formula (4) is concentrated sulphuric acid in an amount of 2.5 to 5 equivalents based on compound of formula (2) as a 20 to 80 wt % solution in methanol.

16. A method according to claim 2 wherein crystallization of compound of formula α-(4) is performed in an alcohol.

17. A method according to claim 16 wherein the alcohol is isopropanol, t-amyl alcohol or t-butanol.

18. A method for the conversion of compound of formula β-(4) into the compound of formula α-(4) which comprises an epimerization with acid

19. A method according to claim 3 wherein epimerization of compound of formula β-(4) into compound of formula α-(4) is performed with 0.05 to 1.5 equivalents of MeSO 3 H in methanol.

20. A method according to claim 3 wherein the epimerization is performed at a temperature between 40° C. and reflux temperature.