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 the preparation of darunavir of formula (A) or the ethanolate solvate thereof:

which comprises:

(i) reacting a compound of formula (1):

wherein PG represents an amino protecting group, with N-benzyl-isobutylamine, namely a compound of formula (2):

to obtain a compound of formula (3):

(ii) treating the compound of formula (3) to remove the PG protecting group to obtain a compound of formula (4):

(iii) coupling the compound of formula (4) with 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]-carbonyl]oxy)-2,5-pyrrolidinedione of formula:

to obtain compound of formula (5):

(iv) removing the N-benzyl group from the compound of formula (5) to obtain a compound of formula (6):

(v) introducing a p-nitrophenylsulfonyl group into the compound of formula (6) to obtain a compound of formula (7):

(vi) reducing the nitro group of the compound of formula (7) to form darunavir

(vii) and thereafter recrystallizing from ethanol if the ethanolate solvate is desired.

2. A process according to claim 1 in which a compound of formula (1′) is reacted with N-benzyl-isobutylamine of formula (2) to yield a compound of formula (3′):

3. A process according to claim 1 in which the compound of formula (3) is treated by acid hydrolysis to remove the protecting group.

4. A process according to claim 1 for the preparation of a compound of formula (5) which comprises coupling the compound of formula (4) with 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione of formula:

to obtain a compound of formula (5):

5. A process according to claim 1 in which removal of the N-benzyl group is effected by catalytic reduction of the compound of formula (5).

6. A compound of formula (3′):

7. A compound of formula (4):

8. A compound of formula (5):

9. A process according to claim 2 in which the compound of formula (3′) is treated by acid hydrolysis to remove the protecting group.