Process for the preparation of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1S,2R)-3[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate

1. A process for preparing compound of formula (6),

or an addition salt, thereof; comprising:

(i) introducing an isobutylamino group in compound of formula (1)

wherein

PG represents an amino-protecting group;

R 1 is hydrogen or C 1-6 alkyl;

(ii) introducing a p-nitrophenylsulfonyl group in the resultant compound of step (i);

(iii) reducing the nitro moiety of the resultant compound of step (ii);

(iv) deprotecting the resultant compound of step (iii); and

(v) coupling the resultant compound of step (iv) with a (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl derivative.

2. A process according to claim 1 for preparing compound of formula (6), comprising the steps of:

(i) introducing an isobutylamino group in compound of formula (1′);

to obtain compound of formula (2′);

(ii) introducing a p-nitrophenylsulfonyl group into compound of formula (2′) to obtain compound of formula (3′);

(iii) reducing the nitro moiety of compound of formula (3′) to obtain compound of formula (4′);

(iv) deprotecting compound of formula (4′) to obtain compound of formula (5)

coupling compound of formula (5) with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl derivative to obtain compound of formula (6).

3. A process according to claim 1 wherein step (i) is carried out in toluene.

4. A process according to claim 1 wherein step (ii) is carried out in toluene, ethylacetate, methylene chloride, dichloromethane, or tetrahydrofuran.

5. A process according to claim 1 wherein step (iii) is carried out in the presence of up to 10 mol % primary or secondary amine, with palladium on charcoal under a hydrogen atmosphere.

6. A process according to claim 1 wherein step (iv) is carried out in acidic or basic conditions.

7. A process according to claim 2 wherein compound of formula (5) is crystallized by dissolving in a solvent system, adjusting the pH to a value higher than 9 and keeping the concentration of compound of formula (5) in solution in a value between 4% and 15% (w/w).

8. A process according to claim 2 wherein compound of formula (5) is crystallized at a temperature between 0° C. and 10° C.

9. A process according to claim 7 wherein seed crystals of compound of formula (5) are added during crystallization.

10. A process according to claim 7 wherein the solvent system comprises one or more water-miscible solvents and water.

11. A process according to claim 7 wherein the solvent system comprises one or more water-immiscible solvents and water.

12. A process according to claim 10 wherein the solvent system is methanol, isopropanol, and water in a ratio 1:6.5:8 respectively.

13. A process according to claim 2 wherein (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is reacted with bis-(4-nitrophenyl)carbonate before coupling to compound of formula (5).

14. A process according to claim 2 wherein (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is reacted with disuccinimidyl carbonate before coupling to compound of formula (5).

15. A process according to claim 13 wherein the reaction of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol and the carbonic acid derivative is activated by an (amine-) base.

16. A process according to claim 2 wherein step (i) is carried out in toluene.

17. The process according to claim 5 wherein the amine is ethanolamine.

18. The process according to claim 15 wherein the (amine-) base is triethylamine or pyridine.