# US 10,870,671 B2 · Method of preparation of alpha galactosyl ceramides compounds

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- Number: US 10,870,671 B2
- Document ID: US10870671B2
- Status: Granted
- Kind: B2
- Application number: 14/439,642
- Filed: 2013-10-30
- Published: 2015-10-15
- Granted: 2020-12-22
- Earliest claimed: 2012-10-30
- Assignees: Abivax
- Applicants: Abivax
- Inventors: Vincent Serra
- Web page: https://patentgrep.com/patent/US10870671B2

## CPC

- C07H 15/26: Acyclic or carbocyclic radicals, substituted by hetero rings
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- C07D 317/28: Radicals substituted by nitrogen atoms (nitro radicals C07D317/16)
- C07H 15/04: attached to an oxygen atom of the saccharide radical
- C07H 15/06: being a hydroxyalkyl group esterified by a fatty acid
- C07H 15/18: Acyclic radicals, substituted by carbocyclic rings
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## 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):

## Claims

### Claim 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:
R1 represents a linear or branched, saturated or unsaturated C1-C20 alkyl group;
R2 represents a linear or branched, saturated or unsaturated C1-C30 alkyl group;
R3 represents C1-C6 alkyl, a C3-C6 cycloalkyl, a C1-C6 acyl or a benzoyl group; and R4 represents H or C1-C6 alkyl group; or
R3 and R4 form together with the nitrogen atom to which they are attached a C2-C6 heterocycloalkyl group or a C1-C5 heteroaryl group;
PG1 represents a hydroxyl function protecting group;
PG2 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;
PG3 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 PG1 and PG2 of the compound of formula (IV), said step b) providing a compound of formula (V):
wherein R1, R3, R4, PG3 and PG′3 are as defined above, and
c) coupling the compound of formula (V) with a compound of formula R2COCl (VII), wherein R2 represents a linear or branched, saturated or unsaturated C1-C30 alkyl group, in the presence of a base; and
d) deprotecting protecting groups PG3 and PG′3 of the product obtained in step c);
said steps providing a compound of formula (I);
or
b′) deprotecting protecting groups PG1, PG2, PG3 and PG′3 of compound of formula (IV), said step b′) providing a compound of formula (VI):
wherein R1, R3 and R4 are as defined above; and
c′) coupling the compound of formula (VI) with a compound of formula R2COCl (VII), wherein R2 represents a linear or branched, saturated or unsaturated C1-C30 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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The method according to claim 1, wherein R1 is a linear saturated C1-C20 alkyl group.

### Claim 4 (depends on 1)

The method according to claim 1, wherein R2 is a linear saturated C1-C20 alkyl group.

### Claim 5 (depends on 1)

The method according to claim 1, wherein:
R3 is an acyl group; and
R4 is H.

### Claim 6 (depends on 1)

The method according to claim 1, wherein protecting group PG1 is a benzyl group.

### Claim 7 (depends on 1)

The method according to claim 1, wherein protecting group PG2 is a carboxybenzyl group.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the protecting groups PG3 and PG′3 form together with the two oxygen atoms to which they are connected, an isopropylidene acetal group.

### Claim 9 (depends on 5)

The method according to claim 5, wherein R3 is an acyl group of formula —C(O)CH3.

### Claim 10 (depends on 1)

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).

### Claim 11 (depends on 10)

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 C23H47COCl (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).

### Claim 12 (depends on 10)

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 C23H47COCl (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).