US 2019/0119313 A1Published application

Improved preparation of vaccines against streptococcus pneumoniae type 3

AssigneesMax-Planck-Gesellschaft zur Forderung der Wissenschaften e.V., Vaxxilon AG

InventorsPeter H. Seeberger, Claney Lebev Pereira, Sharavathi Guddehalli Parameswarappa, Adam Daniel James Calow, Petra Menova, Ju Yuel Baek

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Abstract

The present invention relates to the preparation of a synthetic tetrasaccharide, hexasaccharide and octasaccharide representing part of the repeating unit of the Streptococcus pneumoniae type 3 capsular polysaccharide as well as conjugates thereof. Said conjugates are particularly useful for prevention and/or treatment of diseases associated with Streptococcus pneumoniae, and more specifically of diseases associated with Streptococcus pneumoniae type 3. The disclosed synthetic method has the huge advantages over the state of the art synthetic methods that intermediate products are crystalline, coupling reaction yields are higher, less reaction steps are required and purification of intermediate products is easier.

Claims13

Dependent claims

A synthetic method comprising the following steps:

a) providing a disaccharide of formula 2
wherein
Nap represents 2-naphthylmethyl group,
R1 represents an orthogonal oxidation-stable and acid-stable protecting group,
R2 represents an orthogonal oxidation-stable and acid-stable protecting group,
R3 is an aryl or alkyl group, and
X represents —OAc or —SR5, with R5 being selected from -Me, -Et, -Pr, -Bu, -Ph and -Tol;
and a saccharide of formula 3
wherein
R1 represents an orthogonal oxidation-stable and acid-stable protecting group,
R2 represents an orthogonal oxidation-stable and acid-stable protecting group,
R3 is an aryl or alkyl group,
W represents -L-P or -Bn,
P is —NR′R″ or —N3,
R′ and R″ represent independently of each other -Bn, -Cbz, -Allyl or
R′ and R″ form together phthaloyl,
L represents —(CH2)n— or —C2H4—O—C2H4—,
n is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10,
r is 1, 2 or 3;
b) coupling of the disaccharide of formula 2 with the saccharide of formula 3 in presence of a catalyst to obtain a saccharide of formula 1
wherein
Nap represents 2-naphthylmethyl group,
R1 represents an orthogonal oxidation-stable and acid-stable protecting group,
R2 represents an orthogonal oxidation-stable and acid-stable protecting group,
R3 is an aryl or alkyl group,
W represents -L-P or -Bn,
P is —NR′R″ or —N3,
R′ and R″ represent independently of each other -Bn, -Cbz, -Allyl or
R′ and R″ form together phthaloyl,
L represents —(CH2)n— or —C2H4—O—C2H4—,
n is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10, and
r is 1, 2 or 3.

29 more elements

The method according to any one of claims 1-5 further comprising

a6) reacting the disaccharide of formula 2 according to claim 1 with an alcohol HO—W in presence of a catalyst to yield a disaccharide of formula 9
wherein
Nap represents 2-naphthylmethyl group,
R1 represents an orthogonal oxidation-stable and acid-stable protecting group,
R2 represents an orthogonal oxidation-stable and acid-stable protecting group,
R3 is an aryl or alkyl group,
W represents -L-P or -Bn,
P is —NR′R″ or —N3,
R′ and R″ represent independently of each other -Bn, -Cbz, -Allyl or
R′ and R″ form together phthaloyl,
L represents —(CH2)n— or —C2H4—O—C2H4—,
n is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10;
and
b6) converting the disaccharide of formula 9 according to claim 6 to the saccharide of formula 3-A according to claim 1 by treatment with an oxidizing agent

11 more elements

Dependencies are inferred from the claim text.