Process for preparing kifunensine intermediate and kifunensine therefrom

1. A process for preparing a compound of formula (I), or a salt thereof:

where R 1 and R 2 are each independently protecting groups which, together with the oxygen atoms to which they are attached, form part of a dioxane or dioxolane ring; and R 3 is hydrogen or a protecting group;

including the steps of:

(a) protecting the hydroxyl group at the C-6 position of N—acetyl-D-mannosamine, to give a 6—O—protected—N—acetyl-D-mannosamine, wherein the hydroxyl protecting group at the C-6 position is selected from the group consisting of a silyl group, a benzyl group, or an ester group;

(b) reducing the C-1 anomeric carbon atom of the 6—O—protected—N—acetyl-D-mannosamine using a reducing agent selected from the group consisting of a metal hydride reducing agent or hydrogen gas/metal catalyst to give a 6—O—protected —N—acetyl-D-mannitol;

(c) protecting the four hydroxyl groups of the 6—O—protected—N—acetyl-D-mannitol with protecting groups R 1 and R 2 as defined above;

(d) removing the N—acetyl protecting group using basic conditions and optionally removing the C-6 oxygen atom protecting group using basic conditions to give the compound of formula (I).

2. A process according to claim 1 where 2,2-dimethoxypropane in the presence of acetone is used to protect the four hydroxyl groups of the 6—O—protected—N—acetyl-D-mannitol in step (c), to give a 1:3, 4:5-di—O—isopropylidene-D-mannitol.

3. A process according to claim 1 where both the N—acetyl protecting group and the C-6 oxygen atom protecting group are removed in step (d).

4. A process according to claim 1 further comprising:

(e) oxamoylation of the compound of formula (I) to give a 2-oxamoylamino-D-manmtol;

(f) removal of the R 3 protecting group using basic conditions, where R 3 is not H;

(g) oxidation of the C-6 carbon atom to give a 2-oxamoylamino-D-mannose;

(h) double cyclisation of the 2-oxamoylamino-D-mannose using a methanolic ammonia solution to give kifunensine with four protected hydroxyl groups; and

(i) removal of the four hydroxyl protecting groups using acidic conditions to give kifunensine.

5. A process according to claim 3 where oxamic acid and 1,1 '-carbonyldiimidazole are used for the oxamoylation of the compound of formula (I) in step (e).

6. A process according to claim 3 where the oxamoylation step (e) is a direct coupling of the compound of formula (I) with ethyl oxamate, oxalic acid mono-n-butyl ester or di-n-butyl oxalate.

7. A process according to claim 3 where pyridinium dichromate in the presence of activated molecular sieves and pyridinium trifluoroacetate is used for the oxidation of the C-6 carbon atom in step (g).

8. A process for preparing kifunensine including the steps of:

(a) silylation of N—acetyl-D-mannosamine using tert-butyldiphenylsilyl chloride as silylating agent, to give 6—O—tert-butyldiphenylsilyl-2-deoxy-2-acetylamino-D-mannose;

(b) reduction of 6—O—tert-butyldiphenylsilyl-2-deoxy-2-acetylamino-D-mannose using sodium borohydride as reducing agent, to give 6—O—tert-butyldiphenylsilyl -2-deoxy-2-acetylamino-D-marmitol;

(c) protection of the four hydroxy groups of 6—O—tert-butyldiphenylsilyl-2-deoxy-2-acetylamino -D-mannitol using 2,2-dimethoxypropane in the presence of acetone, to give 6—O—tert-butyldiphenylsilyl-2-deoxy- 1,3:4,5 -di—O—isopropylidene -2-acetylamino-D-mannitol;

(d) double deprotection of the 6—O— and N—protecting groups of 6—O—tert-butyldiphenylsilyl -2-deoxy- 1,3 :4,5-di—O—isopropylidene-2-acetylamino-D-mannitol using aqueous barium hydroxide, to give 2-amino-2-deoxy-1,3:4,5-di —O—isopropylidene-D-mannitol;

(e) oxamoylation of 2-amino-2-deoxy- 1,3 :4,5-di—O—isopropylidene-D-mannitol using oxamic acid and 1,1 ′-carbonyidjimidazole, to give 2-deoxy- 1,3 :4,5-di—O—isopropylidene -2-oxamoylamino-D-mannitol;

(f) oxidation of 2-deoxy- 1,3 :4,5-di—O—isopropylidene-2-oxamoylamino-D-mannitol using pyridinium dichromate in the presence of activated molecular sieves and pyridinium trifluoroacetate, to give 5-deoxy-2,3:4,6-di—O—isopropylidene -5-oxamoylamino-D-mannose;

(g) double cyclisation of 5-deoxy-2,3:4,6-di—O—isopropylidene-5-oxamoylamino-D-mannose using a methanolic ammonia solution, to give 2,3:4,6-di—O—isopropylidene -kifunensine; and

(h) deprotection of 2,3:4,6-di—O—isopropylidene-kifunensine, using methanolic hydrochloric acid, to give kifunensme.

9. A process according to claim 1 where the hydroxyl protecting group at the C-6 position of N—acetyl-D-mannosamine in step (a) is a silyl protecting group.

10. A process according to 9 where the silyl protecting group is tert-butyldiphenylsilyl.

11. A process according to claim 1 where the basic conditions in step (d) are selected from aqueous barium hydroxide or sodium n-butoxide in n-butanol.

12. A process according to claim 4 where the basic conditions in step (f) are selected from aqueous barium hydroxide or sodium n-butoxide in n-butanol.

13. A process according to claim 4 where the acidic conditions in step (i) are selected from methanolic hydrochloric acid or trifluoroacetic acid.

14. A process according to claim 1 further comprising:

(e) removal of the R 3 protecting group using basic conditions, where R 3 is not H;

(f) oxamoylation of the compound of formula (I) to give a 2-oxamoylamino-D-mannitol;

(g) oxidation of the C-6 carbon atom to give a 2-oxamoylamino-D-mannose;

(h) double cyclisation of the 2-oxamoylamino-D-mannose using a methanolic ammonia solution to give kifunensine with four protected hydroxyl groups; and

(i) removal of the four hydroxyl protecting groups using acidic conditions to give kifunensine.

15. A process according to claim 4 , wherein R 3 is a silyl group or an ester group.

16. A process according to claim 14 , wherein R 3 is a silyl group or an ester group.