Granted Patent B2

US 8,703,923 · App. 13/618,786 · Granted Apr 22, 2014

Abstract

Claims (111)

1. A process for preparing Fondaparinux sodium comprising:

(i) deprotecting and then THP protecting a levulinate pentamer of the formula:

where R 2 is Ac or Bz to obtain a THP pentamer of the formula:

(ii) hydrolyzing a THP pentamer of the formula:

where R 2 is Ac or Bz to obtain a hydrolyzed pentamer of the formula:

(iii) sulfating a hydrolyzed pentamer of the formula:

to obtain an O-sulfated pentamer of the formula:

(iv) hydrogenating an O-sulfated pentamer of the formula:

to obtain a hydrogenated pentamer of the formula:

(v) N-sulfating a hydrogenated pentamer of the formula:

to obtain Fondaparinux-THP of the formula:

(vi) deprotecting the Fondaparinux-THP to obtain Fondaparinux sodium.

2. A process for making a compound of Formula I

wherein R 1 is H, R 2 is —OSO 3 Na, R 3 is H, R 4 is NHSO 3 Na, R 5 is methyl, and R 6 and R 7 are —CO 2 Na, comprising:

(a) deprotecting a compound of Formula I wherein R 1 is levulinyl (Lev), R 2 is —OAcetyl or -Obenzoyl, R 3 is benzyl, R 4 is N 3 (azide), R 5 is methyl, R 6 is —CO 2 CH 2 C 6 H 5 and R 7 is —CO 2 Me, to provide a compound of Formula I wherein R 1 is H, R 2 is —OAcetyl or —OBenzoyl, R 3 is benzyl, R 4 is N 3 (azide), R 5 is methyl, R 6 is —CO 2 CH 2 C 6 H 5 and R 7 is —CO 2 Me;

(b) protecting the product of step (a) to provide a compound of Formula I wherein R 1 is tetrahydropyran (THP), R 2 is —OAcetyl or —OBenzoyl, R 3 is benzyl, R 4 is N 3 (azide), R 5 is methyl, R 6 is —CO 2 CH 2 C 6 H 5 and R 7 is —CO 2 Me;

(c) hydrolyzing the product of step (b) to provide a compound of Formula I wherein R 1 is tetrahydropyran (THP), R 2 is —O − or a salt thereof, R 3 is benzyl, R 4 is N 3 (azide), R 5 is methyl, and R 6 and R 7 are —CO 2 − or a salt thereof;

(d) sulfating the product of step (c) to provide a compound of Formula I wherein R 1 is tetrahydropyran (THP), R 2 is −OSO 3 − or a salt thereof, R 3 is benzyl, R 4 is N 3 (azide), R 5 is methyl, and R 6 and R 7 are —CO 2 − or a salt thereof;

(e) hydrogenating the product of step (d) to provide a compound of Formula I wherein R 1 is tetrahydropyran (THP), R 2 is —OSO 3 − or a salt thereof, R 3 is H, R 4 is NH 2 , R 5 is methyl, and R 6 and R 7 are —CO 2 − or a salt thereof;

(f) sulfating the product of step (e) to provide a compound of Formula I wherein R 1 is tetrahydropyran (THP), R 2 is —OSO 3 Na, R 3 is H, R 4 is NHSO 3 Na, R 5 is methyl, and R 6 and R 7 are —CO 2 Na; and

(g) deprotecting the product of step (f) to provide a compound of Formula I wherein R 1 is H, R 2 is —OSO 3 Na, R 3 is H, R 4 is NHSO 3 Na, R 5 is methyl, and R 6 and R 7 are —CO 2 Na.

3. The process of claim 2 , wherein deprotecting step (a) comprises treatment with a reagent selected from hydrazine, hydrazine hydrate, hydrazine acetate and R 8 NH—NH 2 where R 8 is aryl, heteroaryl or alkyl.

4. The process of claim 2 , wherein protecting step (b) comprises treatment with dihyropyran or a dihydropyran derivative and an acid selected from camphor sulfonic acid (CSA), hydrochloric acid (HCl), p-toluenesulfonic acid (pTsOH) and Lewis acids.

5. A process for preparing a THP pentamer of the formula:

comprising deprotecting and then THP protecting a compound of the formula:

wherein R 2 is Ac or Bz.

6. The process of claim 5 , further comprising hydrolyzing the THP pentamer to produce a hydrolyzed pentamer of the formula:

7. The method of claim 6 , further comprising sulfating the hydrolyzed pentamer to obtain an O-sulfated pentamer of the formula:

8. The method of claim 7 , further comprising hydrogenating the O-sulfated pentamer to obtain a hydrogenated pentamer of the formula:

9. The method of claim 8 , further comprising N-sulfating the hydrogenated pentamer to obtain fondaparinux-THP of the formula:

10. The method of claim 9 , further comprising converting the fondaparinux-THP to fondaparinux sodium.

11. A process for making a compound of Formula (I)

wherein R 1 is levulinyl (Lev), R 2 is —OAcetyl or —OBenzoyl, R 3 is benzyl, R 4 is N 3 (azide), R 5 is methyl, R 6 is —CO 2 CH 2 C 6 H 5 and R 7 is —CO 2 Me;

comprising linking a compound of Formula EDC

wherein R 1 is levulinyl (Lev), R 2 is —OAcetyl or —OBenzoyl, R 3 is benzyl, R 4 is N 3 (azide) and R 6 is —CO 2 CH 2 C 6 H 5 , with a compound of Formula BA

wherein R 2 is —OAcetyl or —OBenzoyl, R 3 is benzyl, R 4 is N 3 (azide), R 5 is methyl and R 7 is —CO 2 Me.

12. The process of claim 11 , further comprising

(i) deprotecting and then THP protecting the compound of Formula (I) to obtain a THP pentamer of the formula:

(ii) hydrolyzing a THP pentamer of the formula:

where R 2 is Ac or Bz to obtain a hydrolyzed pentamer of the formula:

(iii) sulfating a hydrolyzed pentamer of the formula:

to obtain an O-sulfated pentamer of the formula:

(iv) hydrogenating an O-sulfated pentamer of the formula:

to obtain a hydrogenated pentamer of the formula:

(v) N-sulfating a hydrogenated pentamer of the formula:

to obtain Fondaparinux-THP of the formula:

and

(vi) deprotecting the Fondaparinux-THP to obtain Fondaparinux sodium.

13. A process for preparing a compound of Formula I:

wherein

R 1 is H, levulinyl (Lev) or tetrahydropyran (THP);

R 2 is —O − or a salt thereof, —OH, —OAcyl, or —OSO 3 − or a salt thereof;

R 3 is H, benzyl or a protecting group removable by hydrogenation;

R 4 is N 3 (azide), NH 2 , NH-protecting group, or NHSO 3 − or a salt thereof;

R 5 is C 1 -C 6 alkyl; and

R 6 and R 7 are independently selected from —CO 2 − or a salt thereof, —CO 2 H, and —CO 2 R x , wherein R x is a C 1 -C 6 alkyl, aryl, C 1 -C 4 alkoxy(aryl), aryl(C 1 -C 6 alkyl), or C 1 -C 4 alkoxy(aryl)(C 1 -C 6 alkyl); and

wherein said compound has alpha (α) stereochemistry at the carbon bearing the —OR 5 group;

said process comprising linking a compound of Formula II:

wherein

R 1 is H, levulinyl (Lev) or tetrahydropyran (THP);

R 2 is —O − or a salt thereof, —OH, —OAcyl, —OSO 3 − or a salt thereof;

R 3 is H, benzyl or a protecting group removable by hydrogenation;

R 4 is N 3 (azide), NH 2 , NH-protecting group, or NHSO 3 − or a salt thereof;

R 6 and R 7 are independently selected from —CO 2 − or a salt thereof, —CO 2 H, and —CO 2 R x ,

wherein R x is a C 1 -C 6 alkyl, aryl, C 1 -C 4 alkoxy(aryl), aryl(C 1 -C 6 alkyl), or C 1 -C 4 alkoxy(aryl)(C 1 -C 6 alkyl); and

R 9 is R 1 or R 2 ;

with a compound of Formula III

wherein

R 2 is —O − or a salt thereof, —OH, —OAcyl, —OSO 3 − or a salt thereof;

R 3 is H, benzyl or a protecting group removable by hydrogenation;

R 4 is N 3 (azide), NH 2 , NH-protecting group, or NHSO 3 − or a salt thereof;

R 5 is C 1 -C 6 alkyl.

14. The process of claim 13 , where the compound of Formula II is

and the compound of Formula III is

15. A process for preparing a compound of Formula I:

wherein

R 1 is H, levulinyl (Lev) or tetrahydropyran (THP);

R 2 is —O − or a salt thereof, —OH, —OAcyl, or —OSO 3 − or a salt thereof;

R 3 is H, benzyl or a protecting group removable by hydrogenation;

R 4 is N 3 (azide), NH 2 , NH-protecting group, or NHSO 3 − or a salt thereof;

R 5 is C 1 -C 6 alkyl; and

R 6 and R 7 are independently selected from —CO 2 − or a salt thereof, —CO 2 H, —CO 2 R x ,

wherein R x is a C 1 -C 6 alkyl, aryl, C 1 -C 4 alkoxy(aryl), aryl(C 1 -C 6 alkyl), or C 1 -C 4 alkoxy(aryl)(C 1 -C 6 alkyl),

wherein said compound has alpha (α) stereochemistry at the carbon bearing the —OR 5 group;

said process comprising linking a compound of Formula IV:

wherein

R 1 is H, levulinyl (Lev) or tetrahydropyran (THP);

R 2 is —O − or a salt thereof, —OH, —OAcyl, —OSO 3 − or a salt thereof;

R 3 is H, benzyl or a protecting group removable by hydrogenation;

R 4 is N 3 (azide), NH 2 , NH-protecting group, or NHSO 3 − or a salt thereof; and

R 6 is selected from —CO 2 − or a salt thereof, —CO 2 H, —CO 2 R x wherein R x is a C 1 -C 6 alkyl, aryl, C 1 -C 4 alkoxy(aryl), aryl(C 1 -C 6 alkyl), or C 1 -C 4 alkoxy(aryl)(C 1 -C 6 alkyl);

with a compound of Formula V:

wherein

R 1 is H, levulinyl (Lev) or tetrahydropyran (THP);

R 2 is —O − or a salt thereof, —OH, —OAcyl, —OSO 3 − or a salt thereof;

R 3 is H, benzyl or a protecting group removable by hydrogenation;

R 4 is N 3 (azide), NH 2 , NH-protecting group, or NHSO 3 or a salt thereof;

R 5 is C 1 -C 6 alkyl;

R 7 is selected from —CO 2 − or a salt thereof, —CO 2 H, —CO 2 R x wherein R x is a C 1 -C 6 alkyl, aryl, C 1 -C 4 alkoxy(aryl), aryl(C 1 -C 6 alkyl), or C 1 -C 4 alkoxy(aryl)(C 1 -C 6 alkyl); and

R 9 is R 1 or R 2 .

16. The process of claim 15 , where the compound of Formula IV is

and the compound of Formula V is

17. A process for making a compound of Formula (I)

wherein R 1 is tetrahydropyran (THP), R 2 is —OAcetyl or —OBenzoyl, R 3 is benzyl, R 4 is N 3 (azide), R 5 is methyl, R 6 is —CO 2 CH 2 C 6 H 5 and R 7 is —CO 2 Me comprising:

(a) deprotecting a compound of Formula (I) in which R 1 is levulinyl (Lev), R 2 is —OAcetyl or —OBenzoyl, R 3 is benzyl, R 4 is N 3 (azide), R 5 is methyl, R 6 is —CO 2 CH 2 C 6 H 5 and R 7 is —CO 2 Me to provide a compound of Formula I wherein R 1 is H, R 2 is —OAcetyl or —OBenzoyl, R 3 is benzyl, R 4 is N 3 (azide), R 5 is methyl, R 6 is —CO 2 CH 2 C 6 H 5 , and R 7 is —CO 2 Me; and

(b) THP protecting the compound of step (a).

18. The process of claim 17 , wherein the deprotecting step (a) comprises treatment with a reagent selected from hydrazine, hydrazine hydrate, hydrazine acetate and R 8 NH—NH 2 where R 8 is aryl, heteroaryl or alkyl.

19. The process of claim 18 , wherein the deprotecting step (a) comprises treatment with hydrazine.

20. The process of claim 17 , wherein the protecting step (b) comprises treatment with dihyropyran or a dihydropyran derivative and an acid selected from camphor sulfonic acid (CSA), hydrochloric acid (HCl), p-toluenesulfonic acid (pTsOH) and Lewis acids.

21. The process of claim 20 , wherein the protecting step (b) comprises treatment with dihyropyran and an acid selected from hydrochloric acid and p-toluenesulfonic acid.

22. A method of preparing an oligosaccharide comprising a β-glucosamine glycosidic linkage comprising reacting a 1,6-anhydro glucopyranosyl acceptor having an azide functional group at C2 and a hydroxyl group at C4 with a uronic acid glycopyranosyl donor having an activated anomeric carbon, a levulinate group at C2, and a protected acid group at C5 to form an oligosaccharide having a β-glycosidic linkage between the hydroxyl group of the glucopyranosyl acceptor and the anomeric carbon of the glycopyranosyl donor.

Assignments (8)