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Publication numberWO2013011460 A1
Publication typeApplication
Application numberPCT/IB2012/053651
Publication dateJan 24, 2013
Filing dateJul 17, 2012
Priority dateJul 18, 2011
Publication numberPCT/2012/53651, PCT/IB/12/053651, PCT/IB/12/53651, PCT/IB/2012/053651, PCT/IB/2012/53651, PCT/IB12/053651, PCT/IB12/53651, PCT/IB12053651, PCT/IB1253651, PCT/IB2012/053651, PCT/IB2012/53651, PCT/IB2012053651, PCT/IB201253651, WO 2013/011460 A1, WO 2013011460 A1, WO 2013011460A1, WO-A1-2013011460, WO2013/011460A1, WO2013011460 A1, WO2013011460A1
InventorsP. Nagaraju, Mandeep THAKUR, Bhargav Pandya
ApplicantRanbaxy Laboratories Limited
Export CitationBiBTeX, EndNote, RefMan
External Links: Patentscope, Espacenet
Process for the preparation and purification of an intermediate for fondaparinux sodium
WO 2013011460 A1
Abstract
The present invention relates to process for the preparation and purification of 4-O-β-D-glucopyranosyl-1,6-anhydro-β-D-glucopyranose represented by Formula (II). The process of the invention can be used in the production of fondaparinux sodium, a heparin and blood clotting factor Xa inhibitor.
Claims  (OCR text may contain errors)
CLAIMS:
1. A process for purification of crude 4-0- -D-glucopyranosyl- 1 ,6-anhydro- -D- glucopyranose represented by Formula II;
FORMULA II
comprising the steps of:
a) treating the crude compound of Formula II with a first organic solvent;
b) treating the resultant solid of step a) with a second organic solvent; and c) obtaining pure compound of Formula II from the resultant solution of step b).
2. A process for preparation of 4-0- -D-glucopyranosyl-l,6-anhydro- -D- glucopyranose represented by Formula II;
FORMULA II
comprising the steps of:
a) reacting the compound of Formula I with a
FORMULA I
b) treating the resultant product of step a) with a first organic solvent;
c) treating the resultant solid of step b) with a second organic solvent; and d) isolating pure compound of Formula II from the resultant solution of step c).
3. The process of claim 1 or 2, wherein the first organic solvent is selected from the group consisting of isopropyl alcohol, dichloromethane, n-butanol, tert-butanol, and mixtures thereof.
4. The process of claim 1 or 2, wherein the second organic solvent is methanol.
5. The process of claim 1 or 2, wherein the process further comprises adjusting the pH of the suspension obtained by treating the crude solid with the second organic solvent.
6. The process of claim 5, wherein the pH is adjusted to between about 1 and about 4.
7. The process of claim 2, wherein the base is potassium hydroxide.
8. A process for purification of crude 4-0- -D-glucopyranosyl- 1 ,6-anhydro- -D- glucopyranose represented by Formula II;
FORMULA II
comprising the steps of:
a) treating the crude compound of Formula II with a second organic solvent; b) recovering solvent from the resultant solution of step a); and
c) treating the solid material of step b) with a first organic solvent to obtain pure compound of Formula II.
9. A process for preparation of 4-0- -D-glucopyranosyl-l,6-anhydro- -D- glucopyranose represented by Formula II;
FORMULA II comprising the steps of:
a) reacting the compound of Formula I with a
FORMULA I
b) treating the crude product of step a) with a second organic solvent;
c) recovering solvent from the resultant solution of step b); and
d) treating the solid material of step c) with a first organic solvent to obtain pure compound of Formula II.
10. The process of claim 9 or 10, wherein the second organic solvent is methanol.
1 1. The process of claim 9 or 10, wherein the first organic solvent is selected from the group consisting isopropyl alcohol, dichloromethane, n-butanol, tert-butanol, and mixtures thereof.
12. The process of claim 10, wherein the base selected is potassium hydroxide.
13. A process for the purification of crude 4-0- -D-glucopyranosyl-l,6-anhydro- -D- glucopyranose represented by Formula II comprising use of a first organic solvent, a second organic solvent and adjustment of the pH of the solution/suspension formed therein without involving the protection or deprotection of the hydroxyl group(s) present in the crude compound of Formula II.
14. The process of claim 15, wherein the first organic solvent is selected from the group consisting of isopropyl alcohol, dichloromethane, n-butanol, tert-butanol, and mixtures thereof.
15. The process of claim 15, wherein the second organic solvent is methanol.
16. The process of claim 15, which comprises the further step of adjusting the pH of the solution/suspension formed to between about 1 and about 4.
Description  (OCR text may contain errors)

PROCESS FOR THE PREPARATION AND PURIFICATION OF AN INTERMEDIATE FOR FONDAPARINUX SODIUM

Field of the Invention

The present invention relates to a process for the preparation and purification of 4- Ο-β-D-glucopyranosyl- 1 ,6-anhydro- -D-glucopyranose represented by Formula II. The process of the invention can be used in the production of fondaparinux sodium, a heparin and blood clotting factor Xa inhibitor.

FORMULA II

Background of the Invention

Fondaparinux sodium is indicated for the prophylaxis of deep vein thrombosis and chemically represented as methyl 0-2-deoxy-6-0-sulfo-2-(sulfoamino)-a-D- glucopyranosyl-(l→4)-0- -D-glucopyranuronosyl-(l→4)-0-2-deoxy-3,6-di-(9-sulfo-2- (sulfoamino)-a-D-glucopyranosyl-(l→4)-0-2-0-sulfo-a-L-idopyranuronosyl-(l→4)-2- deoxy-6-0-sulfo-2-(sulfoamino)-a-D-glucopyranoside decasodium salt of following Formula III.

FORMULA III

Carbohydrate Research, 101, p. 148-151 (1982), provides alkaline degradation of pentachlorophenyl 2,3,6,2',3',4',6'-hepta-(9-acetyl- -D-ceilobioside represented by Formula I;

FORMULA I

in which the corresponding 1,6-anhydro disaccharide was isolated as O-acetylated derivative (i.e., 2,3,2',3',4',6'-hexa-(9-acetyl-l ,6-anhydro- -D-cellobiose).

The present inventors have observed that the product obtained by following the process exemplified in the aforementioned reference contains a significant quantity of inorganic salts which makes the product unusable and which needs two additional purification steps involving acetylation and deacetylation.

Therefore, an object of the present invention is to provide an improved process for the preparation of 4-0- -D-glucopyranosyl-l,6-anhydro- -D-glucopyranose represented by Formula II that is simple, safe, easy to scale-up and cost effective.

Detailed Description of the Invention

The following terminology is used to understand the process of the present invention. This terminology is not intended in any way to limit the scope of the present invention. Several variants of this terminology would be evident to persons ordinarily skilled in the art.

The term "about", as used herein, when used along values assigned to certain measurements and parameters means a variation of 10% from such values, or in case of a range of values, means a 10% variation from both the lower and upper limits of such ranges.

The term "first organic solvent", as used herein, is the solvent or solvent mixture in which the compound of Formula II is insoluble. For example, the first organic solvent can be selected from the group consisting of isopropyl alcohol, dichloromethane, n-butanol, tert.-butanol, or mixtures thereof. The term "second organic solvent", as used herein, is the solvent or solvent mixture in which the compound of Formula II is soluble. For example, the second organic solvent can be methanol.

The term "ambient temperature", as used herein, refers to the temperature in the range of OC to 35C.

The present invention can be explained by way of the following aspects.

A first aspect of the present invention provides a process for the purification of crude 4-0- -D-glucopyranosyl-l,6-anhydro- -D-glucopyranose represented by Formula Π;

FORMULA II

comprising the steps of:

a) treating the crude compound of Formula II with a first organic solvent;

b) treating the resultant solid of step a) with a second organic solvent; and c) obtaining a pure compound of Formula II from the resultant solution of step b).

The crude compound of Formula II can be prepared by following the procedure exemplified in Carbohydrate Research, 101, p. 148-151 (1982), without involving the protection or deprotection of hydroxyl group(s). Preferably, the crude compound of Formula II is prepared by treating the compound of Formula I with a base.

In an embodiment of this aspect, step a) can involve stirring, filtering and/or washing the crude compound of Formula II with a first organic solvent, which facilitates in removing some of the impurities which are soluble in the first organic solvent, such as, for example, alkali metal salts of pentachlorophenoxide like potassium

pentachlorophenoxide, etc., by filtration.

In another embodiment of this aspect, step b) comprises treating the resultant solid with a second organic solvent to obtain a suspension followed by adjusting the pH of the suspension to dissolve the compound of Formula II and to leave the undissolved impurities, for example, inorganic salt impurities such as potassium chloride. The undissolved impurities can be easily removed by filtration.

In another embodiment of this aspect, the pH of the suspension can be adjusted to about 1 to about 4. Preferably, the pH can be adjusted to about 2 to about 3.

In another embodiment of this aspect, pH adjustment can be performed using an alcoholic acid. Preferably, methanolic hydrogen chloride can be used.

In another embodiment of this aspect, the pure compound of Formula II can be obtained using a process comprising separating the undissolved impurities from the resultant solution of step b), followed by the removal of the solvent to dryness.

Accordingly, the compound of Formula II in a first organic solvent is heated to about 40C to about 60C under stirring for about 30 minutes and filtered. The solid is again stirred, then filtered and/or washed with the first organic solvent.

The resultant solid material is then added to a second organic solvent to obtain a suspension. This is followed by the adjustment of the pH of the suspension to between about 1 and about 4 to dissolve the compound of Formula II. Any undissolved impurities are removed by filtration and the pure compound of Formula II is obtained from the filtrate after recovering the solvent.

Preferably, isopropyl alcohol is used as the first organic solvent, methanol is used as the second organic solvent and methanolic hydrogen chloride is used for adjusting the pH.

In another embodiment of this aspect, the compound of Formula II is obtained in pure form without involving the protection or deprotection of hydroxyl group(s).

In another embodiment of this aspect, the purification process can be used for the preparation of fondaparinux or sodium salt thereof.

Fondaparinux and sodium salt thereof can be prepared from pure compound of Formula II by following the teachings from Bioorganic and Medicinal Chemistry Letters, 1(2), p. 95-98 (1991). A second aspect of the present invention provides a process for the preparation of 4-0- -D-glucopyranosyl-l,6-anhydro- -D-glucopyranose, represented by Formula II;

FORMULA II

comprising:

a) reacting the compound of Formula I with a base;

FORMULA I

b) treating the resultant product of step a) with a first organic solvent;

c) treating the resultant solid of step b) with a second organic solvent; and d) isolating the pure compound of Formula II from the resultant solution of step c).

The compound of Formula I can be prepared by following the procedure exemplified in Carbohydrate Research, 101, p. 148-151 (1982).

In an embodiment of this aspect, the compound of Formula I is reacted with a base in the presence of a first organic solvent to obtain the crude product of Formula II.

In another embodiment of this aspect, the base can be selected from the group comprising alkali or alkaline earth metal hydroxides. Preferably, the base selected is potassium hydroxide. The base can optionally be pulverized before use.

Other embodiments of this aspect of the present invention are as described with respect to the first aspect described hereinbefore. A third aspect of the present invention provides a process for the purification of crude 4-0- -D-glucopyranosyl-l,6-anhydro- -D-glucopyranose represented by Formula II:

FORMULA II

comprising the following steps:

a) treating the crude compound of Formula II with a second organic solvent; b) recovering the solvent from the resultant solution of step a); and

c) treating the solid material of step b) with a first organic solvent to obtain the pure compound of Formula II.

In one embodiment of this aspect, step a) can involve adding the crude compound of Formula II to the second organic solvent, adjusting the pH of the resultant suspension, filtering and collecting the resultant solution.

In another embodiment of this aspect, the pH of the suspension can be adjusted to between about 1 and about 4. Preferably, the pH can be adjusted to between about 2 and about 3.

In another embodiment of this aspect, pH adjustment can be performed using an alcoholic acid. Preferably, methanolic hydrogen chloride can be used.

The crude compound of Formula II is added to a second organic solvent to obtain a suspension followed by adjusting the pH of the suspension to between about 1 and about 4 to dissolve the compound of Formula II in a second organic solvent and to leave the undissolved impurities, for example, inorganic salt impurities such as potassium chloride. The undissolved impurities are removed by filtration and the resultant solution is collected for recovery of the solvent.

In another embodiment of this aspect, step b) comprises recovery of the solvent from the resultant solution of step a) to get the solid material. In another embodiment of this aspect, step c) comprises stirring, filtering and/or washing the solid material with the first organic solvent followed by removal of the solvent to dryness to obtain the pure compound of Formula II.

Accordingly, step c) comprises stirring, filtering and/or washing the solid material of step b) with a first organic solvent, followed by removal of the solvent to dryness to obtain pure compound of Formula II.

Preferably, methanol is used as the second organic solvent, dichloromethane, isopropyl alcohol or a mixture thereof is used as the first organic solvent and methanolic hydrogen chloride is used for adjusting the pH.

In another embodiment of this aspect, the compound of Formula II is obtained in pure form without involving the additional steps of protection or deprotection of the hydroxyl group(s).

In another embodiment of this aspect, the process can be used for the preparation of fondaparinux or sodium salt thereof.

A fourth aspect of the present invention provides a process for preparation of 4-0- -D-glucopyranosyl-l,6-anhydro- -D-glucopyranose represented by Formula II;

FORMULA II

comprising:

a) reacting the compound of Formula I with a base;

FORMULA I

b) treating the crude product of step a) with a second organic solvent; c) recovering the solvent from the resultant solution of step b); and

d) treating the solid material of step c) with a first organic solvent to obtain the pure compound of Formula II.

In an embodiment of this aspect, the compound of Formula I is reacted with a base in the presence of a second organic solvent to obtain the crude product of Formula II.

In another embodiment of this aspect, the base can be selected from the group comprising alkali or alkaline earth metal hydroxides. Preferably, the base selected is potassium hydroxide. The base can optionally be pulverized before use.

Other embodiments of this aspect of the present invention are as described with respect to the third aspect described hereinbefore.

A fifth aspect of the present invention provides a process for the purification of crude 4-0- -D-glucopyranosyl-l,6-anhydro- -D-glucopyranose represented by Formula II comprising use of the first organic solvent, the second organic solvent and adjusting the pH of the solution/suspension formed therein without involving the process of protection or deprotection of the hydroxyl group(s) of crude compound of Formula II.

In an embodiment of this aspect, the pH of the solution/suspension formed can be adjusted to between about 1 and about 4. Preferably, the pH can be adjusted to between about 2 and about 3.

In another embodiment of this aspect, the pH adjustment can be performed using an alcoholic acid. Preferably, methanolic hydrogen chloride can be used for this purpose.

The process for this aspect is the same as described in the previous aspects. The process, reaction and/or purification conditions and terminologies described in the previous aspects are appropriate to this aspect of invention too.

A sixth aspect of the present invention provides highly pure 4-Ο-β-ϋ- glucopyranosyl- 1 ,6-anhydro- -D-glucopyranose represented by Formula II.

FORMULA II

In an embodiment of this aspect, 4-0- -D-glucopyranosyl-l,6-anhydro- -D- glucopyranose having purity of at least 90% as determined by HPLC, is provided.

A seventh aspect of the present invention provides the use of pure compound of Formula II prepared as described in the above aspects for the preparation of fondaparinux and sodium salt thereof by following the teachings from Bioorganic and Medicinal Chemistry Letters, 1(2), p. 95-98 (1991).

While the present invention has been described in terms of its specific aspects, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

In the following section, aspects are described by way of examples to illustrate the processes of the invention and products thereof. However, examples mentioned below are not intended in any way to limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.

Example 1 : Preparation and purification of 4-0- -D-grucopyranosyl-L6-anhvdro- -D- glucopyranose

A solution of pentachlorophenyl 2,3,6,2 ,3 ^ ^'-hepta-O-acetyl- -D-cellobioside of Formula I (400 g) in isopropyl alcohol (4 L) at ambient temperature was cooled to 2C to 5C and pulverized potassium hydroxide (355 g) was added to it. This reaction mixture was stirred and the temperature was allowed to rise to ambient temperature. At ambient temperature, the mixture was stirred until the reaction was complete (about 2 hours). The mixture was then heated to 50C to 55C and stirred for 30 minutes. The solid obtained was filtered and washed with isopropyl alcohol (400 mL). The solid was stirred with isopropyl alcohol (2.8 L) at 50C for 30 minutes followed by filtering and washing with isopropyl alcohol (400 mL). The resultant solid was suspended into methanol (800 mL to 1600 mL) followed by cooling to 2C to 5C. The pH of the suspension was adjusted to 2 to 3 using 15% methanolic hydrochloride. The solid so obtained was filtered and washed with methanol (400 mL). Solvent was recovered from the filtrate to dryness under vacuum to obtain the pure compound of Formula II as foamy solid.

Yield: 142 g

Example 2: Preparation and purification of 4-Q- -D-grucopyranosyl-l,6-anhvdro- -D- glucopyranose

A solution of pentachlorophenyl 2,3,6,2 ,3 ^ ^'-hepta-O-acetyl- -D-cellobioside of Formula I (100 g) in methanol (300 mL) at ambient temperature was cooled to 2C to 5C and pulverized potassium hydroxide (88.6 g) was added to it. This reaction mixture was stirred and the temperature was allowed to rise to ambient temperature. At ambient temperature, the mixture was stirred until the reaction was complete (about 2 hours). The mixture was cooled to 2C to 5C and 15% methanolic hydrogen chloride was added to it until the pH of the mixture reached 2 to 3. At this pH, the reaction mixture was filtered and the residual solid was washed with methanol (100 mL). The solvent was recovered from the filtrate under vacuum. The solid material so obtained was stirred with dichloromethane (500 mL) followed by removal of solvent through decantation/filtration. The resultant solid was stirred with isopropyl alcohol (500 mL), filtered and dried to obtain the pure compound of Formula II.

Yield: 29 g

Non-Patent Citations
Reference
1BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS vol. 1, no. 2, 1991, pages 95 - 98
2CARBOHYDRATE RESEARCH vol. 10, no. 1, 1982, pages 148 - 151
3 *EDNA M. MONTGOMERY ET AL: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 65, no. 10, 16 October 1943 (1943-10-16), pages 1848-1854, XP55040760, ISSN: 0002-7863, DOI: 10.1021/ja01250a018
4 *GEERT-JAN BOONS ET AL: "An Improved Procedure for the Preparation of 1,6-Anhydro Sugars", SYNLETT, vol. 1995, no. 07, 1 July 1995 (1995-07-01), pages 755-756, XP55040794, ISSN: 0936-5214, DOI: 10.1055/s-1995-5057
Classifications
International ClassificationC07H3/10, C07H1/06
Cooperative ClassificationC07H1/06, C07H3/10
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