Patent EA-005126-B1 (EA)
Title: Preparation and isolation of indolocarbazole glycosides
Inventor: WEISSMAN STEVEN
IPC: C07H19/22
Filed: 2002-03-25
Abstract: 1. A process for preparing crystals of compound I: in high purity, which comprises the steps of: (a) adjusting the pH of an acidic mixture consisting essentially of an acid, alcohol, water and compound I, by adding a base to produce a solution with a pH in the range of about 1.5 to about 6.5; (b) keeping the temperature of the solution from step (a) in the range of about 50 degree C to about 100 degree C; and (c) isolating the crystals of compound I. 2. The process according to Claim 1, which comprises the steps of: (a) adjusting the pH of an acidic mixture consisting essentially of an acid, alcohol, water and compound I, by adding a base to produce a solution with a pH in the range of about 1.5 to about 6.5; (b) adjusting the solution from step (a) with an alcohol so that the solution is about 10% w/v to about 30% w/v water in an alcohol and the concentration of compound I is about 10mL/g to 20mL/g; (c) adjusting the temperature of the solution from step (b) to a temperature in the range of about 50 degree C to about 100 degree C; (d) adding an alcohol to the solution from (c) such that the solution is diluted to about 3:2 (solution: alcohol); (e) aging the solution from (d) at a temperature in the range of about 50 degree C to about 100 degree C until crystals of compound I are formed to produce a slurry; and (f) isolating the crystals of compound I. 3. The process according to Claim 2, which further comprises deprotecting intermediate II: (wherein R is independently a hydrogen or a substituted or unsubstituted benzyl protecting group, with the proviso that at least one R is a substituted or unsubstituted benzyl protecting group), via hydrogenation in the presence of a catalyst to produce a reaction mixture, followed by filtering the reaction mixture to afford the mixture of step (a). 4. The process according to Claim 3, wherein R is benzyl. 5. A process for the preparation of compound III in high purity which comprises the steps of: (a) adjusting the pH of an acidic mixture consisting essentially of an acid, alcohol, water and compound III, by adding a base to produce a solution with a pH in the range of about 1.5 to about 6.5; (b) adjusting the solution from step (a) with an alcohol so that the solution is about 10% w/v to about 30% w/v water in an alcohol and the concentration of compound III is about 10mL/g to 20mL/g; (c) adjusting the temperature of the solution from step (b) to a temperature in the range of about 50 degree C to about 100 degree C; (d) seeding the solution; (e) adding an alcohol to the solution such that the solution is diluted to about 3: 2 (solution: alcohol); (f) aging the solution from (e) at a temperature in the range of about 50 degree C to about 100 degree C until crystals of compound III are formed to produce a slurry; and (g) isolating the crystals of compound III. 6. The process according to Claim 5, which further comprises deprotecting intermediate II: (wherein R is independently a hydrogen or a substituted or unsubstituted benzyl protecting group, with the proviso that at least one R is a substituted or unsubstituted benzyl protecting group), via hydrogenation in the presence of a catalyst to produce a reaction mixture, followed by filtering the reaction mixture to afford the mixture of step (a). 7. The process according to Claim 5 or 6, wherein the pH in step (a) is adjusted to a pH in the range of about 1.5 to about 3.5; the solution in (b) is adjusted so that the solution is about 15% w/v to about 25% w/v water in an alcohol and the concentration of compound III is about 12mL/g to about 18 mL/g; and the temperature in step (c) is adjusted to about 70 degree C. 8. The process according to Claim 7, wherein the pH in step (a) is adjusted to a pH of about 2.5; the solution in (b) is adjusted so that the solution is about 20%w/v water in an alcohol and the concentration of compound III is about 15mL/g; and the temperature in step(c) is adjusted to about 70 degree C. 9. The process according to Claim 8, further comprising the step of adjusting the slurry after step (f) such that the water content is lowered to a range of about 1% w/v to about 10% w/v before isolating the crystals of compound III in step (g). 10. The process according to Claim 5, which comprises the steps of: (a) adjusting the pH of an acidic mixture consisting essentially of an acid, alcohol, water and compound III, by adding a lower alkyl amine base to produce a solution with a pH of about 2.5; (b) adjusting the solution from step (a) with isopropyl alcohol so that the solution is about 20% w/v water in isopropyl alcohol and the concentration of compound I is about 15mL/g; (c) adjusting the temperature of the solution from step (b) to a temperature of about 70 degree C; (d) seeding the solution; (e) adding isopropyl alcohol to the solution such that the solution is diluted to about 3: 2 (solution: isopropyl alcohol); (f) aging the solution from (e) at a temperature of about 70 degree C until the crystals of compound I are formed to produce a slurry; (g) adjusting the slurry so that the water content is about 3% w/v; (h) aging the slurry at about 70 degree C before cooling down to about 22 degree C; and (i) isolating the crystals of compound III. 11. The process according to Claim 10, which further comprises deprotecting intermediate II: (wherein R is independently a hydrogen or a substituted or unsubstituted benzyl protecting group, with the proviso that at least one R is a substituted or unsubstituted benzyl protecting group), via hydrogenation in the presence of a catalyst to produce a reaction mixture, followed by filtering the reaction mixture to afford the mixture of step (a). 12. The process according to Claim 11, wherein the lower alkyl amine in step (a) is triethylamine.