Preparation of new intermediate of heparin pentasaccharide and preparation method thereof

Patent metadata

Field	Value
Publication number	US-9624315-B2
Application number	US-201314389806-A
Country	US
Kind code	B2
Filing date	Apr 2, 2013
Priority date	Apr 2, 2012
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

The present invention relates to a process of a chemically synthetic drug, and in particular, to a new intermediate of a heparin pentasaccharide and a preparation method thereof. The process has high reaction efficiency, and an easy reaction operation. The reaction intermediate is easy to be purified, and is appropriate for an industrialization production.

First claim

The invention claimed is:

1. A compound having the following formula I, which can be used as an intermediate for the preparation of heparin pentasaccharide,

wherein the configuration of monosaccharide units and the stereochemistry of the connecting bond among each of the monosaccharides is D-glucosyl-α-1,4-D-glucuronosyl-β-1,4-D-glucosyl-α-1,4-L-idoronosyl-α-1,4-D-glucose, wherein the definition of each substituent is as follows:
R represents C 1 -C 20 alkyl or substituted alkyl, wherein the alkyl can be either linear alkyl or branched or cyclic alkyl;
R 4 represents benzyl or substituted benzyl, and R 4 in the same molecular formula represents either identical group or different group;
R 5 represents hydrogen ion or alkali metal ion.

2. The compound according to claim 1 , characterized in that R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, benzyl, or cyclohexyl.

3. The compound according to claim 1 , characterized in that R is methyl; R 4 is benzyl or substituted benzyl; and R 5 is hydrogen ion or sodium ion.

4. A compound having the following formula II, which can be used as an intermediate for the preparation of heparin pentasaccharide

wherein the configuration of monosaccharide units and the stereochemistry of the connecting bond among each of the monosaccharides is D-glucosyl-α-1,4-D-glucuronosyl-β-1,4-D-glucosyl-α-1,4-L-idoronosyl-α-1,4-D-glucose, wherein the definition of each substituent is as follows:
R represents C 1 -C 20 alkyl or substituted alkyl, wherein the alkyl can be either linear alkyl or branched or cyclic alkyl;
R 4 represents benzyl or substituted benzyl, and R 4 in the same molecular formula represents either identical group or different group.

5. The compound according to claim 4 , characterized in that R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, benzyl, or cyclohexyl.

6. The compound according to claim 4 , characterized in that R is methyl; and R 4 is benzyl or substituted benzyl.

7. A process for the preparation of the compound of formula I according to claim 1 , characterized in that the process comprises the following steps:
a) firstly, treating the fully protected pentasaccharide compound of the following formula III with sodium hydroxide,

such that the compound of formula III is subjected to ester hydrolysis, in order to obtain the compound having the following formula IV wherein R 5 is sodium ion, alternatively, the compound is subjected to hydrolysis and subsequent acid neutralization, in order to obtain the compound having the following formula IV wherein R 5 is hydrogen ion,

wherein R represents C 1 -C 20 alkyl or substituted alkyl, wherein the alkyl can be either linear alkyl or branched or cyclic alkyl; R 1 represents C 1 -C 20 alkyl, substituted alkyl, hydrogen ion, sodium ion, wherein the alkyl can be either linear alkyl or branched or cyclic alkyl, R 1 in the same molecular formula represents either identical group or different group; R 2 represents linear or branched aliphatic acyl or aryl acyl, R 2 in the same molecular formula represents either identical group or different group; R 3 represents azido group; R 4 represents benzyl or substituted benzyl, R 4 in the same molecular formula represents either identical group or different group; R 5 is hydrogen ion or sodium ion;
b) secondly, treating the compound of formula IV with a reductant, i.e. the group R 3 is reduced to amino group, in order to obtain the compound of formula I.

8. The process according to claim 7 , characterized in that R 2 in the compound of formula III is selected from acetyl, 4-oxovaleryl, and benzoyl; and wherein the acid is preferably hydrochloric acid.

9. The process according to claim 7 , wherein the compound of formula IV is subjected to reduction after separation and purification.

10. A process for the preparation of the compound according to claim 1 having the following formula I:

comprising the following steps:
a) firstly, treating the fully protected pentasaccharide compound of formula III with a reductant,

reducing R 3 group into amino group, in order to obtain the compound of the following formula V,

wherein R represents C 1 -C 20 alkyl or substituted alkyl, wherein the alkyl can be either linear alkyl or branched or cyclic alkyl; R 1 represents C 1 -C 20 alkyl, substituted alkyl, hydrogen ion, sodium ion, wherein the alkyl can be either linear alkyl or branched or cyclic alkyl, R 1 in the same molecular formula represents either identical group or different group; R 2 represents linear or branched aliphatic acyl or aryl acyl, R 2 in the same molecular formula represents either identical group or different group; R 4 represents benzyl or substituted benzyl, R 4 in the same molecular formula represents either identical group or different group;
b) secondly, treating the compound of formula V with sodium hydroxide, such that the compound of formula V is subjected to ester hydrolysis, in order to obtain the compound of formula I wherein R 5 is sodium ion, alternatively, it is subjected to ester hydrolysis and subsequent acid neutralization, in order to obtain the compound of formula I wherein R 5 is hydrogen ion.

11. The process according to claim 10 , characterized in that R 2 in the compound of formula V is selected from acetyl, 4-oxovaleryl, and benzoyl; and wherein the acid is preferably hydrochloric acid.

12. The process according to claim 7 , characterized in that the reductant is selected from trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, or hydrogen sulfide.

13. A process for the preparation of the compound of formula II:

characterized in that treating the compound having the following formula I:

with a sulfating reagent, and treating the obtained crude product with sodium ion exchange resin, in order to obtain the compound of formula II; wherein the sulfating reaction can be carried out in a single step or in several steps.

14. The process according to claim 13 , characterized in that the sulfating agent is selected from sulfur trioxide-pyridine complex, sulfur trioxide-trimethylamine complex, sulfur trioxide-triethylamine complex, or gaseous sulfur trioxide.

15. A process for the preparation of heparin pentasaccharide compound of formula VI, characterized in that treating the compound according to claim 4 having the following formula II:

with a catalyst, palladium hydroxid

Assignees

• Zhejiang Hisun Pharm Co Ltd
• Zhejiang Hisum Pharmaceutical Co Ltd

Inventors

• Guo Yanghui
• Wei Hegeng
• Bai Hua
• Wu Yingqiu
• Zhang Yue
• Zhou Junhui
• Ding Yili
• Bai Lingwei
• Yang Shibao

Classifications

• C07H11/00

  Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof (halo-sugars C07H5/02; thio-, seleno-, or telluro-sugars C07H5/08) · CPC title

• C07H1/00 Primary

  Processes for the preparation of sugar derivatives · CPC title

• C07H15/18

  Acyclic radicals, substituted by carbocyclic rings · CPC title

• C07H15/04

  attached to an oxygen atom of the saccharide radical · CPC title

• C08B37/0075 Primary

  Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof · CPC title