Process for preparing mannose derivatives

1. A process to prepare a compound of the following formula (I):

in which

P represents a protective group of a hydroxyl function which is a —COR 1 group with R 1 representing

an aryl or a (C 1 -C 6 )alkyl,

R represents a hydrogen atom or a protective group of a terminal alkyne,

from mannose, comprising the following steps:

(a) protecting the 5 hydroxyl groups of the mannose by a protective group P;

(b) coupling the protected mannose obtained at step (a) with a compound of the following formula (II)

2. The process according to claim 1 , wherein the protective group P is a —COR 1 group with R 1 representing an aryl group.

3. The process according to claim 1 , wherein R is a —SiR 2 R 3 R 4 group with R 2 , R 3 and R 4 representing independently from each other a (C 1 -C 6 )alkyl group or a biphenyl group.

4. The process according to claim 1 , wherein step b) is performed in the presence of a base, an alkylaluminum halide and optionally a Lewis acid.

5. The process according to claim 1 , wherein step (b) is divided into three sub-steps:

(b1) deprotonation of the compound of formula (II) with a base,

(b2) addition of an alkylaluminium halide,

(b3) coupling the product obtained at step (a) with the product of step (b2) in the presence of a Lewis acid.

6. A process to prepare a compound of formula (III):

in which

Y represents a group or a group

with A and B representing independently of each other a hydrogen, a hydroxyl, an amine or a radical selected from a (C 1 -C 6 )alkyl and an aryl, said radical being substituted or not by a (C 1 -C 6 )alkyl, a 3-8 membered ring cycloalkyl, —OR 5 , —OC(O)R 5 or —COOR 5 , R 5 representing a hydrogen or a (C 1 -C 6 )alkyl,

or A and B form together with the carbon atom to which they are bound a 3-7 membered saturated monocyclic ring having 0, 1 or 2 heteroatoms selected from O, N and S, one or several carbon or nitrogen of the ring being optionally substituted by an oxo, a (C 1 -C 6 )alkyl, —OR 6 , —NR 6 R 7 , —SO 2 R 6 —C(O)R 6 or —C(O)OR 6 , with R 6 and R 7 representing independently a hydrogen or a radical selected from a (C 1 -C 6 )alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C 1 -C 6 ) alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl or a 3-8 membered ring heterocycloalkyl, a halogen, —NR 8 R 9 , —CN, —C(O)OR 8 , —C(O)NR 8 R 9 or —OR 8 , with R 8 and R 9 being independently a hydrogen atom or a (C 1 -C 6 ) alkyl, or R 8 and R 9 form together with the nitrogen to which they are bound a 3-8 membered ring heterocycloalkyl,

with R′ representing a hydrogen atom or a radical selected from a (C 1 -C 6 ) alkyl, an aryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C 1 -C 6 ) alkyl, a 3-8 membered ring cycloalkyl, a 3-8 membered ring heterocycloalkyl, —C(O)OR a , —C(O)NR a R b or —OR a , with R a and R b being independently a hydrogen atom or a (C 1 -C 6 ) alkyl optionally substituted by a 3-8 membered ring heterocycloalkyl, or R a and R b form together with the nitrogen a 3-8 membered ring heterocycloalkyl,

R″ represents a hydrogen atom or a protective group of a hydroxyl function which is a —COR 1 group with R 1 representing an aryl or a (C 1 -C 6 )alkyl,

from mannose, comprising the following steps:

(a) protecting the 5 hydroxyl groups of the mannose by a protective group P;

(b) coupling the protected mannose obtained at step (a) with a compound of the following formula (II)

R represents a hydrogen atom or a protective group of a terminal alkyne;

(c) optionally deprotecting the terminal alkyne of the compound obtained after steps (a)(b) to obtain compound of formula (I) in which R=H;

(d) Sonogashira coupling of the compound obtained at steps (a)(b) or when applicable at step (c) with a compound of the following formula (IV):

in which X is a halogen atom;

(e) optionally deprotecting the hydroxyl groups protected by a group P to obtain compound of formula (III) in which R″=H;

(f) recovering the compound of formula (III) obtained at step (d) or when applicable at step (e).

7. The process according to claim 6 , wherein the compound of formula (III) is a compound of formula (IIIa)

with R 10 representing a hydrogen, a (C 1 -C 6 )alkyl, —SO 2 R 6 , —C(O)R 6 or —C(O)OR 6 ,

R 6 representing a hydrogen or a radical selected from a (C 1 -C 6 )alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C 1 -C 6 ) alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl or a 3-8 membered ring heterocycloalkyl, a halogen, —NR 8 R 9 , —CN, —C(O)OR 8 , —C(O)NR 8 R 9 or — 0 R 8 , with R 8 and R 9 being independently a hydrogen atom or a (C 1 -C 6 ) alkyl, or R 8 and R 9 form together with the nitrogen to which they are bound a 3-8 membered ring heterocycloalkyl,

R′ representing a hydrogen atom or a radical selected from a (C 1 -C 6 ) alkyl, an aryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C 1 -C 6 ) alkyl, a 3-8 membered ring cycloalkyl, a 3-8 membered ring heterocycloalkyl, C(O)OR a , —C(O)NR a R b or —OR a , with R a and R b being independently a hydrogen atom or a (C 1 -C 6 ) alkyl optionally substituted by a 3-8 membered ring heterocycloalkyl, or R a and R b form together with the nitrogen a 3-8 membered ring heterocycloalkyl, and

R″ represents a hydrogen atom or a protective group of a hydroxyl function which is a —COR 1 group with R 1 representing an aryl or a (C 1 -C 6 )alkyl.

8. The process according to claim 7 , wherein R 10 is a —C(O)R 6 group with R 6 representing an aryl or a (C 1 -C 6 )alkyl.

9. The process according to claim 6 , wherein steps (c) and (d) occur in a one-pot process.

10. The process according to claim 7 , wherein compound of formula (IVa)

wherein R 10 is a —COMe group is obtained from compound of formula (IVa) with R 10 being a protective group of an amine function different from —COMe by deprotection and acetylation in a one-pot process.

11. A process to prepare a compound of formula (V):

in which

R 11 represents:

a —CONR 12 R 13 group with R 12 and R 13 representing independently a hydrogen, a (C 1 -C 6 )alkyl or R 12 and R 13 form together with the nitrogen a 3-8 membered ring heterocycloalkyl or cycloalkyl

a radical selected from a cycloalkenyl, an aryl and a heteroaryl, said radical being substituted or not by a (C 1 -C 6 ) alkyl, an aryl, a heteroaryl, a halogen, —C(O)OR a , —C(O)NR a R b , —SO 2 R a , —SO 2 NR a R b , —NR a R b , —OR a , —CN or —NO 2 , with R a and R b being independently a hydrogen atom or a (C 1 -C 6 ) alkyl,

R″ represents a hydrogen atom or a protective group of a hydroxyl function which is a —COR 1 group with R 1 representing an aryl or a (C 1 -C 6 )alkyl,

from mannose, comprising the following steps:

(a) protecting the 5 hydroxyl groups of the mannose by a protective group P;

(b) coupling the protected mannose obtained at step (a) with a compound of the following formula (II)

R represents a hydrogen atom or a protective group of a terminal alkyne;

(c) optionally deprotecting the terminal alkyne of the compound obtained after steps (a)(b) to obtain compound of formula (I) in which R=H;

(d) Sonogashira coupling of the compound obtained at steps (a)(b) or when applicable at step (c) with a compound of the following formula (VI):

in which X is a halogen atom and X′ is a halogen or a radical R 11 ;

(e) optionally deprotecting the hydroxyl groups protected by a group P to obtain compound of formula (V) in which R″=H;

(f) recovering the compound of formula (V) obtained at step (d) or when applicable at step (e).

12. The process according to claim 11 , wherein R 11 is a pyridinone substituted or not by a (C 1 -C 6 ) alkyl.

13. The process according to claim 11 , wherein the compound of formula (V) is a compound of formula (Va)

14. The process according to claim 11 , wherein steps (c) and (d) occur in a one-pot process.

15. The process according to claim 2 , wherein R 1 is a phenyl group.

16. The process according to claim 3 , wherein R 2 , R 3 and R 4 represent a methyl group.

17. The process according to claim 4 , wherein step b) is performed in the presence of n-butyl lithium, diethyl aluminium chloride and aluminium chloride.

18. The process according to claim 7 , wherein the compound of formula

(IIIa) is obtained from compound (IVa) with R 10 representing a hydrogen, a (C 1 -C 6 )alkyl, —SO 2 R 6 , —C(O)R 6 or —C(O)OR 6 , R 6 representing a hydrogen or a radical selected from a (C 1 -C 6 )alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C 1 -C 6 ) alkyl, an aryl, a heteroaryl, a 3-8 membered ring cycloalkyl or a 3-8 membered ring heterocycloalkyl, a halogen, —NR 8 R 9 , —CN, —C(O)OR 8 , —C(O)NR 8 R 9 or —OR 8 , with R 8 and R 9 being independently a hydrogen atom or a (C 1 -C 6 ) alkyl, or R 8 and R 9 form together with the nitrogen to which they are bound a 3-8 membered ring heterocycloalkyl,

R′ representing a hydrogen atom or a radical selected from a (C 1 -C 6 ) alkyl, an aryl, a 3-8 membered ring cycloalkyl and a 3-8 membered ring heterocycloalkyl, said radical being optionally substituted by a (C 1 -C 6 ) alkyl, a 3-8 membered ring cycloalkyl, a 3-8 membered ring heterocycloalkyl,— C(O)OR a , —C(O)NR a R b or — 0 R a , with R a and R b being independently a hydrogen atom or a (C 1 -C 6 ) alkyl optionally substituted by a 3-8 membered ring heterocycloalkyl, or R a and R b form together with the nitrogen a 3-8 membered ring heterocycloalkyl,

R″ represents a hydrogen atom or a protective group of a hydroxyl function which is a —COR 1 group with R 1 representing an aryl or a (C l -C 6 )alkyl, and

X representing a halogen atom.

19. The process according to claim 8 , wherein R 6 is a methyl group.