Patent EA-004235-B1 (EA)
Title: Diphosphate salt of a 4''-substituted-9-deoxo-9a-aza-9a-homoerythromycin derivative
Inventor: RAFKA ROBERT JOHN
IPC: C07H17/08
Filed: 2000-06-13
Abstract: 1. Two polymorphs of (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[[2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(propylamino) methyl]-alpha-L-ribo-hexopyranosyl] oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-beta-D-xylo-hexopyranosyl] oxy]-1-oxa-6-azacyclopentadecan-15-one diphosphate having the formula wherein n is 0 to 8 and the polymorphs are selected from the group consisting of: a. a smectic crystalline meso-phase of a liquid crystal; and b. a crystalline diphosphate exhibiting the X-ray powder diffraction pattern Peak No. 1 2 3 4 5 6 7 8 9 10 Space d 16.2 12.4 10.8 9.0 6.9 6.5 6.2 5.4 5.1 4.9 2. The diphosphate liquid crystal according to Claim 1 having a lath-like habit and exhibiting longitudinal cleavage. 3. The diphosphate liquid crystal according to claim 2 gaining about 15% by weight with a subsequent loss of birefringence at about 87% relative humidity. 4. The diphosphate salt according to claim 2, wherein the liquid crystal has about 5 to 6 % water. 5. The diphosphate salt according to claim 1 wherein the salt has about 48 % C, about 9% H, about 4% N, about 6% P and about 5.5%H2O. 6. The diphosphate salt polymorph according to claim 1 having a well-ordered crystalline plate or prism habit. 7. The diphosphate salt according to claim 6 wherein the plate or prism habit is highly birefringent. 8. The crystalline diphosphate salt according to claim 1, wherein the compound gradually absorbs water to about 13% at about 87% relative humidity. 9. The diphosphate salt according to claim 8, wherein a rapid uptake of water to about 48% occurs at about 90% relative humidity. 10. The diphosphate salt according to claim 9 wherein the diphosphate salt became deliquescent at about 90% relative humidity. 11. The diphosphate salt according to claim 1 wherein thermogravametric analysis discloses that 3 waters are lost by about 75 degree C, a fourth water is lost by about 120 degree C, a fifth water is lost by about 170 degree C, and the three final waters are lost by about 200 degree C. 12. The diphosphate salt according to claim 1 wherein the maximum number of water molecules necessary for the stabilization of the crystalline lattice is eight. 13. The diphosphate salt according to claim 1 wherein drying in about 70 degree C in air or about 45 degree C in a vacuum removed the water leaving a psuedomorph. 14. The diphosphate salt according to claim 1 wherein the aqueous solubility is about 280mg/mL. 15. A method of making 2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[[2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(propylamino) methyl]-alpha-L-ribo-hexopyranosyl] oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-beta-D-xylo-hexopyranosyl] oxy]-1-oxa-6-azacyclopentadecan-15-one diphosphate having the formula wherein n is 0 to 8, comprising dissolving the free base with magnetic stirring in absolute ethanol at ambient temperature; adding a solution of phosphoric acid in absolute ethanol over about 2 to 5 minutes; dissolving the resulting solid in water; collecting the crystal crop at ambient temperature; and rinsing with several small portions of about 10/1 (v/v)ethanol-water. 16. A method of converting the diphosphate salt according to claim 15 to an impurity-free free base comprising partitioning the salt between methylene chloride and water; raising the pH to about 8 to 10, and collecting and evaporating of the organic phase.