Processes for the preparation of 0-(2-aminobenzo[d]oxazol-5-yl)methyl hydroxylamine for the synthesis of 6,11-bicyclic erythromycin derivative EDP-182

Abstract

The present invention relates to processes and intermediates for the preparation of 6-11 bicyclic erythromycin derivative known as EDP-182 (IX-a). In particular, the present invention relates to processes and intermediates for the preparation of O-(2-aminobenzo[d]oxazol-5-yl)methyl hydroxylamine:

Description

Claims

1. A process for preparing a compound of formula (XI):

2. The Process of claim 1 further comprising the step of hydrolyzing the compound of formula XI with a base or an acid in a protogenic organic solvent or aqueous solution, to yield a compound of formula (X):

3. A process for the synthesis of a compound of formula (XV):

4. The Process of claim 3 further comprising the step of deprotecting the compound of formula XV with a base or an acid in a protogenic organic solvent or aqueous solution, to yield a compound of formula (X):

5. The process of claim 1, wherein step 1 comprises hydrogenating 4-(hydroxymethyl)-2-nitrophenol with palladium on carbon in the presence of hydrogen gas to provide 2-amino-4-(hydroxymethyl)phenol.

6. The process of claim 1, wherein step 2 comprises treating 2-amino-4-(hydroxymethyl)phenol with cyanogenbromide in methanol to provide (2-aminobenzo[d]oxazol-5-yl)methanol.

7. The process of claim 1, wherein step 3 comprises reacting thionyl chloride with (2-aminobenzo[d]oxazol-5-yl)methanol to provide 5-(chloromethyl)benzo [d]oxazol-2-amine.

8. The process of claim 1, wherein step 4 comprises reacting N-hydroxysuccinimide with 5-(chloromethyl)benzo[d]oxazol-2-amine in the presence of diisopropylethylamine to provide 1-((2-aminobenzo[d]oxazol-5-yl)methoxy)pyrrolidine-2,5-dione.

9. The process of claim 1, wherein step 4 comprises reacting N-hydroxysuccinimide with 5-(chloromethyl)benzo[d]oxazol-2-amine in the presence of DBU to provide 1-((2-aminobenzo[d]oxazol-5-yl)methoxy)pyrrolidine-2,5-dione.

10. The process of claim 2 comprising reacting methylamine with provide 1-((2-aminobenzo[d]oxazol-5-yl)methoxy)pyrrolidine-2,5-dione in methanol to provide O-(2-aminobenzo[d]oxazol-5-yl)methyl hydroxylamine.

11. The process of claim 3, wherein step 1 comprises treating 2-amino-4-methylphenol with cyanogenbromide in ethanol to provide (2-aminobenzo[d]oxazol-5-yl)methane.

12. The process of claim 3, wherein step 2 comprises treating (2-arinobenzo[d]oxazol-5-yl)methane with succinic anhydride in the presence of HATU and N-methylmorpholine to give 1-(5-methylbenzo[d]oxazol-2-yl)pyrrolidine-2,5-dione.

13. The process of claim 3, wherein step 3 comprises brominating 1-(5-methylbenzo[d]oxazol-2-yl)pyrrolidine-2,5-dione with NBS in the presence of benzoyl peroxide to yield 1-(5-(bromomethyl)benzo[d]oxazol-2-yl)pyrrolidine-2,5-dione.

14. The process of claim 3, wherein step 4 comprises reacting N-hydroxyphthalimide with 1-(5-(bromomethyl)benzo[d]oxazol-2-yl)pyrrolidine-2,5-dione in the presence of diisopropylethylamine to provide 1-(5-(N-methoxythal omide)benzo[d]oxazol-2-yl)pyrrolidine-2,5-dione.

15. The process of claim 4 comprising reacting hydrazine with 1-(5-(N-methoxypyrrolidine-2,5-dione))(benzo[d]oxazol-2-yl)pyrrolidine-2,5-dione in methanol to provide O-(2-aminobenzo[d]oxazol-5-yl)methyl hydroxylamine.

16. The process of claim 2 further comprising the step of adding the compound of formula X to the compound of formula (VIII-a):

17. The Process of claim 16 further comprising the step of deprotecting the compound of formula (IX-b) with a protogenic organic solvent or aqueous solution, to yield a compound of formula (IX-a):