Process for the production of DATH and intermediates thereof
The present technology is directed to methods of producing 6,6′-diamino-6,6′-dideoxy-trehalose (“DATH”) or a salt thereof. The methods include optionally protecting one or more hydroxyl groups of D-trehalose and converting the primary hydroxyl groups of D-trehalose to produce DATH or a salt thereof through use of a halogen, azide, and/or protected amine. The present technology is also directed to intermediate products of the methods.
1. A method of producing 6,6′-diamino-6,6′-dideoxy-trehalose or a salt thereof, the method comprising:
(1) optionally providing a D-trehalose derivative, comprising protecting and/or replacing one or more primary and/or secondary hydroxyl groups of D-trehalose to provide the D-trehalose derivative;
(2) protecting one or more primary hydroxyl groups and one or more secondary hydroxyl groups of the D-trehalose or the D-trehalose derivative to provide intermediate IA or replacing the primary hydroxyl groups of the D-trehalose or the D-trehalose derivative with iodides to provide an intermediate IB;
(3) replacing the primary hydroxyl protected groups of intermediate IA with protected amines to provide intermediate 2 or with azides to provide intermediate 2B; or (a) protecting secondary hydroxyl groups at carbons 2, 3, and/or 4 of the intermediate IB to provide intermediate IB-1, and (b) replacing the iodides of intermediate IB-1 with protected amines to provide intermediate 2 or with azides to provide intermediate 2B;
(4) converting the azides, if present, of intermediate 2B into protected amines to provide intermediate 2; and
(5) converting the intermediate 2 to 6,6′-diamino-6,6′-dideoxy-trehalose or a salt thereof;
wherein the method excludes trityl, tosyl, or trityl and tosyl protecting groups.
2. The method of claim 1 , wherein the hydroxyl protected groups of the intermediate 1A comprise 4-nitrobenzenesulfonyl hydroxyl protected groups.
3. The method of claim 1 , comprising providing a D-trehalose derivative, wherein providing the D-trehalose derivative comprises protecting the primary hydroxyl groups at carbon 6 of each monosaccharide of the D-trehalose and the secondary hydroxyl groups at carbon 4 of each monosaccharide of the D-trehalose with acetal protecting groups to provide intermediate 0A-1.
4. The method of claim 3 , wherein the acetal protecting groups have a structure of formula I:
wherein R 1 is a C 1 -C 6 alkyl group.
5. The method of claim 4 , wherein R 1 is CH 3 .
6. The method of claim 3 , further comprising protecting secondary hydroxyl groups at carbons 2 and 3 of the intermediate 0A-1 to provide intermediate 0A-2.
7. The method of claim 6 , wherein the protecting secondary hydroxyl groups at carbons 2 and 3 of the intermediate 0A-1 is conducted with a benzyl protecting group.
8. The method of claim 6 , further comprising removing the acetal protecting groups to provide the D-trehalose derivative.
9. The method of claim 1 , wherein the protected amines of (3) or (4) are protected by a benzyl or a phthaloyl protecting group.
10. The method of claim 1 , wherein the protecting secondary hydroxyl groups at carbons 2, 3, and/or 4 of the intermediate 1B is conducted with an ester protecting group.
11. The method of claim 10 , wherein the ester protecting group comprises an acetyl protecting group.
12. The method of claim 1 , wherein the azides are converted into protected amines comprising acetyl protected amines.
13. The method of claim 1 , wherein (5) comprises removing all remaining protecting groups.
14. The method of claim 1 , further comprising purifying one or more times, wherein the purifying is conducted after converting, replacing, removing, and/or protecting.
15. The method of claim 14 , wherein the purifying comprises crystallization.