Carbohydrate conjugate RNA agents and process for their preparation
This disclosure relates to an improved process for the preparation of carbohydrate conjugates. The disclosure also relates to carbohydrate conjugated iRNA agents comprising these carbohydrate conjugates, which have improved purity and are advantageous for the in vivo delivery of the iRNA agents.
1. A process for preparing a compound of formula (A)
wherein
each occurrence of X is hydrogen or a hydroxy protecting group;
each occurrence of Y is an amine protecting group;
n is 0-20;
each occurrence of q, r and s is independently 1-7;
L is a linking group;
R 1 is an iRNA agent;
the compound of formula (A) contains no more than 1000 ppm of metal impurities; and
the compound of formula (A) contains no more than 0.5% by weight of each of the following two urea side products
and
each of the following saccharide compounds
the process comprising:
(a) converting a compound of formula (VI) to a compound of formula (VII):
wherein said converting step comprises:
(i) reacting the compound of formula (VI) with a base;
(ii) reducing the product of step (i); and
(iii) reacting the product of step (ii) with an acid, and
(b) converting the compound of formula (VII) to a compound of formula (A).
2. The process of claim 1 , wherein the base is a metal alkoxide.
3. The process of claim 1 , wherein
the base is sodium methoxide,
step (ii) comprises reacting the product of step (i) with sodium borohydride, and
the acid in step (iii) is hydrochloric acid.
4. The process of claim 1 , wherein Y is acetyl.