Method of preparation of alpha galactosyl ceramides compounds

Patent metadata

Field	Value
Publication number	US-10870671-B2
Application number	US-201314439642-A
Country	US
Kind code	B2
Filing date	Oct 30, 2013
Priority date	Oct 30, 2012
Publication date	Dec 22, 2020
Grant date	Dec 22, 2020

Abstract

The present invention relates to a method of preparation of α-galactosyl ceramides compounds of formula (I):

comprising a step a) of glycosylation of a compound of formula (II):

with a compound of formula (III):

First claim

The invention claimed is:

1. A method of preparation of a compound of formula (I):

said method comprising:
a) glycosylating a compound of formula (II):

with a compound of formula (III):

thereby producing a compound of formula (IV):

wherein:
R 1 represents a linear or branched, saturated or unsaturated C 1 -C 20 alkyl group;
R 2 represents a linear or branched, saturated or unsaturated C 1 -C 30 alkyl group;
R 3 represents C 1 -C 6 alkyl, a C 3 -C 6 cycloalkyl, a C 1 -C 6 acyl or a benzoyl group; and R 4 represents H or C 1 -C 6 alkyl group; or
R 3 and R 4 form together with the nitrogen atom to which they are attached a C 2 -C 6 heterocycloalkyl group or a C 1 -C 5 heteroaryl group;
PG 1 represents a hydroxyl function protecting group;
PG 2 represents a primary amine function protecting group selected from the group consisting of carboxybenzyl (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate groups, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts) and other sulfonamides (Nosyl & Nps) groups;
PG 3 represents a hydroxyl function protecting group;
PG′ 3 represents a hydroxyl function protecting group; and
LG represents a leaving group; and

said method further comprising, after step a):
b) deprotecting protecting groups PG 1 and PG 2 of the compound of formula (IV), said step b) providing a compound of formula (V):

wherein R 1 , R 3 , R 4 , PG 3 and PG′ 3 are as defined above, and
c) coupling the compound of formula (V) with a compound of formula R 2 COCl (VII), wherein R 2 represents a linear or branched, saturated or unsaturated C 1 -C 30 alkyl group, in the presence of a base; and
d) deprotecting protecting groups PG 3 and PG′ 3 of the product obtained in step c);
said steps providing a compound of formula (I);
or
b′) deprotecting protecting groups PG 1 , PG 2 , PG 3 and PG′ 3 of compound of formula (IV), said step b′) providing a compound of formula (VI):

wherein R 1 , R 3 and R 4 are as defined above; and
c′) coupling the compound of formula (VI) with a compound of formula R 2 COCl (VII), wherein R 2 represents a linear or branched, saturated or unsaturated C 1 -C 30 alkyl group, in the presence of a base, said step c′) providing a compound of formula (I); to produce the compound of formula (I),

wherein the method comprises no less than two and no more than two steps of purification by silica-gel column chromatography.

2. The method according to claim 1 , wherein LG is a trichloroacetimidate group.

3. The method according to claim 1 , wherein R 1 is a linear saturated C 1 -C 20 alkyl group.

4. The method according to claim 1 , wherein R 2 is a linear saturated C 1 -C 20 alkyl group.

5. The method according to claim 1 , wherein:
R 3 is an acyl group; and
R 4 is H.

6. The method according to claim 1 , wherein protecting group PG 1 is a benzyl group.

7. The method according to claim 1 , wherein protecting group PG 2 is a carboxybenzyl group.

8. The method according to claim 1 , wherein the protecting groups PG 3 and PG′ 3 form together with the two oxygen atoms to which they are connected, an isopropylidene acetal group.

9. The method according to claim 5 , wherein R 3 is an acyl group of formula —C(O)CH 3 .

10. The method according to claim 1 , wherein a first of the two steps of purification by silica-gel column chromatography occurs between steps (a) and (b).

11. The method according to claim 10 , wherein step (c′), after step (b′), is performed by coupling of a compound of formula (VIa):

with a compound of formula C 23 H 47 COCl (VIIa), in the presence of a base, thereby providing a compound of formula (Ia),

wherein a second of the two steps of purification occurs after step (c).

12. The method according to claim 10 , wherein step (c), after step (b), is performed by coupling of a compound of formula (Va)

with a compound of formula C 23 H 47 COCl (VIIa), in the presence of a base, thereby providing a compound of formula (Ia)

wherein a second of the two steps of purification occurs after step (d).

Assignees

• Abivax

Inventors

• Serra Vincent

Classifications

• C07H15/06

  being a hydroxyalkyl group esterified by a fatty acid · CPC title

• C07H15/18

  Acyclic radicals, substituted by carbocyclic rings · CPC title

• C07H15/04 Primary

  attached to an oxygen atom of the saccharide radical · CPC title

• C07H15/26 Primary

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title