Process and intermediates for the preparation of Voxelotor

1 . A process for preparing Voxelotor

or a salt or solvate thereof, comprising:

(a) reacting a compound of formula (I)

or a salt or solvate thereof, wherein

R 3 represents hydrogen or a hydroxyl protecting group,

R 4 and R 4 ′ are independently selected from C 1-6 alkyl and C 1-6 alkoxyl;

with a compound of formula (II)

 or a salt or solvate thereof, wherein X is selected from OH, Cl, Br, I, OTf, OTs and OMs;

 to obtain a compound of formula (IV)

or a salt or solvate thereof, and

(b) converting the compound of formula (IV), or a salt or solvate thereof, into Voxelotor or a salt or solvate thereof.

2 . Process according to claim 1 , wherein step (b) comprises:

reduction of the amide group in the compound of formula (IV), or a salt or solvate thereof, to the aldehyde; and

if needed (if R 3 is a hydroxyl protecting group), cleaving the hydroxyl protecting group either before or after the step of reduction of the amide group.

3 . Process according to claim 1 , wherein the compound of formula (II), or a salt or solvate thereof, is obtained by a process comprising reacting a compound of formula (III)

or a salt or solvate thereof, wherein

X is selected from OH, Cl, Br, I, OTf, OTs and OMs, and

Y is selected from Cl, Br, I, OTf and OMs;

with a compound of formula (VIII)

or a salt or solvate thereof, wherein each R 2 is independently selected from the group consisting of OH, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxyl, or together they form a C 2-3 alkylenedioxy group optionally substituted by C 1-6 alkyl, or a benzyldioxy group optionally substituted by C 1-6 alkyl, or the —B(R 2 ) 2 group is —BF 3 K.

4 . Process according to claim 1 , comprising:

reacting a compound of formula (III′)

or a salt or solvate thereof, wherein Y is selected from Cl, Br, I, OTf and OMs;

with a compound of formula (VIII)

or a salt or solvate thereof, wherein each R 2 is independently selected from the group consisting of OH, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxyl, or together they form a C 2-3 alkylenedioxy group optionally substituted by C 1-6 alkyl, or a benzyldioxy group optionally substituted by C 1-6 alkyl, or the —B(R 2 ) 2 group is —BF 3 K;

to obtain a compound of formula (II′)

or a salt or solvate thereof,

 converting the compound of formula (II′), or a salt or solvate thereof, into a compound of formula (II″)

or a salt or solvate thereof, wherein X is selected from Cl, Br, I, OTf, OTs and OMs, preferably Cl;

reacting the compound of formula (II″), or a salt or solvate thereof, with a compound of formula (I)

or a salt or solvate thereof, wherein

R 3 represents hydrogen or a hydroxyl protecting group, and

R 4 and R 4 ′ are independently selected from C 1-6 alkyl and C 1-6 alkoxyl;

to obtain a compound of formula (IV)

or a salt or solvate thereof; and

converting the compound of formula (IV), or a salt or solvate thereof, into Voxelotor or a salt or solvate thereof.

5 . A process for preparing Voxelotor

or a salt or solvate thereof comprising:

(a) reacting a compound of formula (I)

or a salt or solvate thereof, wherein

R 3 represents hydrogen or a hydroxyl protecting group,

R 4 and R 4 ′ are independently selected from C 1-6 alkyl and C 1-6 alkoxyl;

with a compound of formula (III)

or a salt or solvate thereof, wherein

X is selected from OH, Cl, Br, I, OTf, OTs and OMs, and

Y is selected from Cl, Br, I, OTf and OMs;

to obtain a compound of formula (V)

or a salt or solvate thereof,

(b) reacting the compound of formula (V), or a salt or solvate thereof,

with a compound of formula (VIII)

or a salt or solvate thereof, wherein each R 2 is independently selected from the group consisting of OH, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxyl, or together they form a C 2-3 alkylenedioxy group optionally substituted by C 1-6 alkyl, or a benzyldioxy group optionally substituted by C 1-6 alkyl, or the —B(R 2 ) 2 group is —BF 3 K;

to provide a compound of formula (IV)

or a salt or solvate thereof, and

(c) converting the compound of formula (IV), or a salt or solvate thereof, into Voxelotor or a salt or solvate thereof.

6 . Process according to claim 5 , wherein step (c) comprises:

reduction of the amide group in the compound of formula (IV), or a salt or solvate thereof, to the aldehyde; and

if needed (if R 3 is a hydroxyl protecting group), cleaving the hydroxyl protecting group either before or after the step of reduction of the amide group.

7 . Process according to claim 3 , wherein said reacting of a compound of formula (III), or a salt or solvate thereof, with a compound of formula (VIII), or a salt or solvate thereof, is carried out in the presence of Pd(amphos)Cl 2 .

8 . Process according to claim 4 , wherein said reacting of a compound of formula (III′), or a salt or solvate thereof, with a compound of formula (VIII), or a salt or solvate thereof, is carried out in the presence of Pd(amphos)Cl 2 .

9 . Process according to claim 5 , wherein said reacting of a compound of formula (V), or a salt or solvate thereof, with a compound of formula (VIII), or a salt or solvate thereof, is carried out in the presence of Pd(amphos)Cl 2 .