Efficient and scalable process for the manufacture of Fondaparinux sodium
View Patent ↗The present invention relates to a process for the synthesis of the Factor Xa anticoagulent Fondaparinux and related compounds. The invention relates, in addition, to efficient and scalable processes for the synthesis of various intermediates useful in the synthesis of Fondaparinux and related compounds.
1. A process for the preparation of a protected heparinic pentasaccharide precursor to Fondaparinux sodium having the structure
comprising the step of coupling a EDC trimer having the structure
with a BA dimer having the structure
2. A process for preparing EDC trimer having the formula
wherein the EDC trimer is prepared using a Schmidt glycosylation comprising the steps:
(a) coupling an E monomer having the structure
to a DC Building Block having the structure
to obtain an EDC precursor having the structure
(b) converting the EDC precursor to the EDC trimer.
3. A process for preparing DC Building Block having the formula
where the DC Building Block is prepared from 1,6-anhydrocellobiose having the structure
comprising at least four of the following steps performed sequentially:
(a) protecting 1,6-anhydrocellobiose to form CB1 having the structure
(b) tosylating CB1 to form CB2 having the structure
(c) reacting CB2 with base to form CB3 having the structure
(d) protecting CB3 to form CB4 having the structure
(e) reacting CB4 with azide to form CB5 having the structure
(f) acetylating CB5 to form CB6 having the structure
(g) deprotecting CB6 to form CB7 having the structure
(h) oxidizing CB7 to form CB8 having the structure
(i) benzylating CB8 to form the DC dimer,
wherein, if the last step of the four sequential steps is not step (i), the method further comprises converting the product of the fourth sequential step to the DC Building Block.
4. The process of claim 3 , wherein the process includes at least six steps from steps (a)-(i) performed sequentially, wherein, if the last step of the six sequential steps is not step (i), the method further comprises converting the product of the sixth sequential step to the DC Building Block.
5. The process of claim 3 , wherein the process includes all of steps (a)-(i).
6. The process of claim 1 wherein the BA dimer is prepared using a Schmidt glycosylation comprising the step of coupling a B monomer having the structure
where Lev is levulinyl, Bn is benzyl, Bz is benzoyl and TCA is trichloracetimidate, to an A monomer having the structure
to form the BA dimer.
7. A process for preparing Building block A (AMod5) having the formula:
wherein Building block A is prepared from a compound of formula IntA1
the process comprising the steps:
(a) cyclizing a compound of formula IntA1 to form a compound of formula IntA2:
(b) epoxidizing a compound of formula IntA2 to form a compound of formula IntA2a:
(c) converting a compound of formula IntA2a to a compound of formula IntA3:
(d) converting a compound of formula IntA3 to a compound of formula IntA4:
(e) converting a compound of formula IntA4 to a compound of formula Monomer A2:
(f) converting a compound of formula Monomer A2 to a compound of formula AMod1:
(g) converting a compound of formula AMod1 to a compound of formula AMod3:
(h) converting a compound of formula AMod3 to a compound of formula AMod4:
(i) converting a compound of formula AMod4 to a compound of formula AMod5:
and
(j) recrystallizing AMod5.
8. The process of claim 7 where the AMod5 is substantially free of the β-methyl glycoside.
9. The process of claim 1 where the protected heparinic pentasaccharide that is formed contains less than about 1% of the β-methyl glycoside.
10. The process of claim 1 where the protected heparinic pentasaccharide that is formed contains less than about 0.5% of the β-methyl glycoside.
11. The process of claim 1 where the protected heparinic pentasaccharide that is formed contains less than about 0.1% of the β-methyl glycoside.
12. The process of claim 1 where the protected heparinic pentasaccharide that is formed contains less than about 0.05% of the β-methyl glycoside.
13. The process of claim 1 where the protected heparinic pentasaccharide that is formed contains less than about 0.01% of the β-methyl glycoside.
14. A method of preparing a monosaccharide of the formula AMod3
comprising deprotecting PMB, anhydro ring opening, acetylating and α-methylglycosylating a compound of the formula Monomer A2
15. A method of purifying a monosaccharide of the formula
comprising crystallizing the monosaccharide from an organic solvent selected from C 5 -C 7 hydrocarbons.
16. The method of claim 15 , wherein the solvent is heptane.
17. The method of claim 1 , further comprising converting the compound of formula
to Fondaparinux sodium.
18. The method of claim 2 , further comprising converting the compound of formula
to Fondaparinux sodium.