WO2005092834A1 - Processes for the purification of voglibose and intermediates thereof - Google Patents

Processes for the purification of voglibose and intermediates thereof Download PDF

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Publication number
WO2005092834A1
WO2005092834A1 PCT/IB2005/000777 IB2005000777W WO2005092834A1 WO 2005092834 A1 WO2005092834 A1 WO 2005092834A1 IB 2005000777 W IB2005000777 W IB 2005000777W WO 2005092834 A1 WO2005092834 A1 WO 2005092834A1
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formula
voglibose
solution
compound
crude
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PCT/IB2005/000777
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French (fr)
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Jayachandra Suresh Babu
Gajanan Jijaba Chavan
Chandra Has Khanduri
Yatendra Kumar
Purna Chandra Ray
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Ranbaxy Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives

Definitions

  • voglibose is (lS)-(l(OH),2,4,5/l,3)-5-[[2-hydroxy-l-(hydroxymethyl) ethyl] amino]-l-C-(hydroxymethyl)-l, 2,3, 4-cyclohexanetetrol, which has excellent inhibitory activity against glucoside hydrolase.
  • Several processes have been reported for the preparation of voglibose involving the use of ion-exchange chromatography with water as eluent, followed by concentration of the aqueous solution and recrystallization from ethanol to obtain pure voglibose.
  • (1S)- (l(OH),2,4/l,3)-2,3,4-tri-O-benzoyl-l-C- (benzoyloxymethyl)-5-oxo-l,2,3,4- cyclohexanetetrol (tetra-O-benzoylvaliolone) has been purified by using column chromatography on silica gel with toluene and ethyl acetate.
  • (1S)- (l(OH),2,4Nl,3)-2,3,4-tri-O-benzyl-l-C-(benzyloxymethyl)-5-oxo-l,2,3,4- cyclohexanetetrol(tetra-O-benzylvaliolone) has been purified by using column chromatography on silica gel with toluene and ethyl acetate followed by treatment with a mixture of ethyl ether and petroleum ether.
  • processes for purifying voglibose which comprise the steps of: providing a solution of crude voglibose in one or more alcohols and optionally water, and recovering pure voglibose.
  • the processes may include one or more of the following embodiments.
  • the solution of crude voglibose can be obtained as a solution directly from a reaction mixture in which voglibose is prepared.
  • the solution of crude voglibose can be treated with activated carbon before recovering pure voglibose.
  • Recovering pure voglibose can comprise concentrating the solution of crude voglibose, crystallizing voglibose, precipitating voglibose, cooling the solution of crude voglibose or any combination thereof to obtain solid pure voglibose.
  • Recovering pure voglibose can also comprise concentrating the solution at elevated temperatures followed by cooling.
  • Recovering pure voglibose can also comprise adding one or more antisolvents to the solution. Suitable antisolvents can be one or more of a hydrocarbon, lower alkyl ether, ester, ketone or mixtures thereof.
  • Suitable hydrocarbons can be one or more of hexane, cyclohexane, toluene, heptane, octane or mixtures thereof.
  • processes for the purification of compounds of Formula I, Formula I wherein R is a protecting group comprising the steps of: contacting a crude compound of Formula I with one or more ethers to form a solution of a crude compound of Formula I, and recovering a pure compound of Formula I. These processes can include one or more of the following embodiments.
  • recovering pure compounds of Formula I can comprise concentrating the solution of a crude compound of Formula I, cooling the solution of a crude compound of Formula I, decanting to remove one or more ethers, layer separating to remove one or more ethers, filtering the compound of Formula I or any combination thereof to obtain solid a pure compound of Formula I.
  • the protecting group can be an optionally substituted C ⁇ - 6 straight or branched chain alkyl, an optionally substituted benzyl or benzoyl.
  • the one or more ethers can be di ethyl ether, diisopropyl ether, tert-butylethyl ether, tert-butylmethyl ether or mixtures thereof.
  • the solution of a crude compound Formula I can be stirred at a temperature of from about 40 °C to about 60 °C. Also provided herein are processes for the purification of compound of Formula II,
  • Formula II wherein R' is hydrogen or a protecting group, comprising the steps of: dissolving a crude compound of Formula II in one or more alcohols, ketones or mixtures thereof to form a solution of a crude compound of Formula II, and recovering a pure compound of Formula II.
  • recovering pure compounds of Formula II can comprise concentrating the solution of a crude compound of Formula II, crystallizing the compound of Formula II, precipitating the compound of Formula LT, cooling the solution of the crude compound of Formula II or any combination thereof to form solid a pure compound of Formula II.
  • the protecting group can be an optionally substituted C ⁇ - 6 straight or branched chain alkyl, an optionally substituted benzyl or benzoyl.
  • the solution of a crude compound of Formula LT can be obtained directly from a reaction mixture in which the crude compound of Formula II is prepared.
  • the one or more alcohols can be methanol, ethanol, isopropanol or mixtures thereof.
  • the one or more ketones can be acetone, methyl isobutyl ketone or mixtures thereof.
  • the crude compound of Formula II can be dissolved at a temperature of about 40 °C to reflux temperatures. Recovering a pure compound of Formula II by crystallizing comprises cooling the solution of the crude compound of Formula II to a temperature of about 10 °C to about 40 °C.
  • processes for the purification of voglibose comprising providing a solution of crude voglibose in one or more alcohols (particularly lower alcohols, e.g., methanol, ethanol, or propanol or isomers thereof and the like) and optionally water; and recovering pure voglibose.
  • processes for the purification of compounds of Formula I comprising providing a solution of crude voglibose in one or more alcohols (particularly lower alcohols, e.g., methanol, ethanol, or propanol or isomers thereof and the like) and optionally water; and recovering pure voglibose.
  • Formula II wherein R' is hydrogen or a protecting group, comprising dissolving crude compound of Formula JJ in a solvent (e.g., alcohols, ketones, or mixtures thereof) and recovering pure compound of Formula II.
  • a solvent e.g., alcohols, ketones, or mixtures thereof
  • the solution of "crude voglibose” may be obtained by dissolving crude voglibose obtained from any of the synthetic routes previously described, for example, in U.S. Patent Nos. 4,701,559; 4,824,943; 4,898,986; 6,150,568; J Org. Chem., 57:3651 (1992); andJ Med. Chem., 29:1038 (1986), in one or more alcohols (e.g., methanol) at room temperature or at higher temperatures up to reflux temperatures.
  • alcohols e.g., methanol
  • the solution of crude voglibose may also be obtained directly from a reaction mixture of the last step of a process in which voglibose is prepared, and used as such in the purification process.
  • the solvent of such a solution obtained directly from a reaction mixture
  • the solvent may be removed by conventional methods known in art (e.g., rotary evaporation, heating, vacuum) and the residue redissolved in one or more lower alcohols and optionally water.
  • Crude voglibose may contain corresponding anti-isomers, polymeric impurities or any other impurity, which may arise during production or storage, such as degradation products.
  • Alcoholic solutions of voglibose may be treated with activated carbon in some embodiments, particularly where decolorization is desired or necessary.
  • Methods of recovering pure voglibose include, for example, concentrating solutions of voglibose, crystallization, precipitation, cooling or any combination thereof, followed by separation and drying, if necessary. Precipitation may occur upon addition of one or more antisolvents, i.e., solvents in which voglibose is insoluble or sparingly soluble, to alcoholic solutions of voglibose.
  • precipitation can be induced by concentrating the solution of voglibose and/or reducing the temperature of the voglibose solution, particularly if the initial temperature is elevated (e.g., above room temperature).
  • the solution of voglibose can be concentrated by heating the solution to a sufficient temperature so that the alocoholic solvent evaporates, e.g., to temperatures near the boiling point of the alcohol, or lower temperatures if a vacuum is applied.
  • the temperature of the solution of voglibose can be lowered to temperatures sufficient to precipitate voglibose from solution, for example, from about 0 °C to about 40 °C or even from about 20 °C to about 30 °C.
  • Suitable antisolvents that may be added to precipitate pure voglibose include, but are not limited to, hydrocarbons (e.g., hexane, cyclohexane, toluene, heptane, octane or mixtures thereof); lower alkyl ethers (e.g., diethylether, diisopropylether or mixtures thereof); ketones (e.g., acetone, methyl isobutyl ketone or mixtures thereof); esters (e.g., ethylacetate, isopropylacetate or mixtures thereof); or mixtures thereof. Crystallization times and temperatures are not critical in obtaining pure voglibose.
  • the crystallization may be performed at temperatures sufficient to crystallilze voglibose, for example, from about 10 °C to about 40 °C for between about 30 minutes to about 2 hours in particular embodiments.
  • Methods of separating pure voglibose include, for example, decanting, filtering, centrifuging and similar processing methods for separating solids from liquids known in the art, or any combination of these separation methods.
  • Suitable protecting groups in compounds of Formula I and Formula II can be, for example, optionally substituted C ⁇ straight or branched chain alkyl, or optionally substituted benzyl and benzoyl groups.
  • Ci- 6 straight or branched chain alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, and the like.
  • Substituted benzyl groups include, for example, p-nitrobenzyl, p-methoxybenzyl, o-nitrobenzyl, p-bromobenzyl, 2,4,6- trimethylbenzyl, and the like.
  • Crude compounds of Formula I may be prepared by any synthetic routes known to one of ordinary skill in the art, including those described in U.S. Patent No. 4,824,943; U.S. Patent No. 6,150,568; andJ Org.
  • Such crude compounds of Formula I can be obtained as an isolated compound or as a solution obtained directly from a reaction mixture of the last step of a process in which voglibose is prepared and used as such in the process.
  • Suitable ethers when used in the purification of compounds of Formula I, include, for example, diethyl ether, diisopropyl ether, tert-butylethyl ether, tert-butylmethyl ether or mixtures thereof.
  • the term "contacting,” as used herein, includes slurrying, stirring, triturating or a combination thereof. Crude compounds of Formula I may be stirred in one or more ethers at about 40 °C to about 60 °C in particular embodiments.
  • Crude compounds of Formula II may be prepared by any synthetic route known to one of ordinary skill in the art, including, for example, those described in U.S. Patent Nos. 4,701,559; 4,824,943; 4,898,986 andJ Org. Chem., 57:3642 (1992). Crude compounds of Formula II may also be obtained as a solution directly from a reaction mixture of the last step of a process in which it is prepared and used as such in the process.
  • Suitable alcohols include, C ⁇ -C 6 alcohols, for example, methanol, ethanol, isopropanol or mixtures thereof.
  • Suitable ketones include, for example, acetone, methyl isobutyl ketone or mixtures thereof.
  • Crude compounds of Formula II may be dissolved in one or more alcohols or ketones at temperatures of about 40 °C to reflux temperatures in some particular embodiments.
  • Suitable methods of recovering pure compounds of Formula II include, for example, concentrating solutions of crude compounds of Formula II, crystallization, cooling or any combination thereof, followed by separation and drying. Crystallization times and temperatures are not critical in obtaining pure compounds of Formulae I or II.
  • the crystallization may be performed by stirring at temperatures of from about 10 °C to about 40 °C for between about 30 minutes to about 3 hours in some particular embodiments.
  • Suitable methods of separating of pure compounds of Formula II include, for example, decanting, filtering, centrifuging or other similar processing methods for separating solids from liquids known in the art, as well as any combination of these separation methods. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims. Examples Example 1: Preparation of pure (lSVfl(OH).2A5/l,3V5-rr2-hvdroxy-l-
  • the reaction mixture was filtered through a HYFLO bed and the HYFLO bed was washed with methanol (500 mL). Methanol (about 6 L) was distilled off and the concentrated solution was stirred at 25-30 °C for 1 hour. The obtained solid was filtered and washed with methanol. The product was dried at 45-50 °C under reduced pressure to yield the title compound as white crystals.
  • Example 3 Purification of riS)-ri(OH ⁇ 2.4/ 3V2,3.4-tri-O-benzyl-l-C- (benzyloxymethyl -5-oxo-l,2.3,4-cyclohexanetetrol (tetra-O-benzylvaliolone): Crude (lS)-(l(OH),2,4/l,3)-2,3,4-tri-O-benzyl-l-C- (benzyloxymethyl)- 5-oxo- 1,2,3,4-cyclohexanetetrol (tetra-O-benzylvaliolone, 140 g, HPLC purity: 78.5%) was dissolved in methanol (700 mL) at 45-50 °C and the mixture was cooled to 20-25 °C. The mixture was stirred for 2 hours at 20-25 °C. A precipitated solid was filtered, washed with methanol, and then dried at 35-40 °C under reduced pressure to yield the pure title compound.
  • methanol 700

Abstract

Processes for the purification of voglibose are provided. Also provided are processes for the purification of substituted or unsubstituted 5-oxo-1,2,3,4-cyclohexanetetrol and substituted 5-amino-1,2,3,4-cyclohexanetetrol, which compounds are useful intermediates in the preparation of voglibose.

Description

PROCESSES FOR THE PURIFICATION OF VOGLIBOSE AND INTERMEDIATES THEREOF
Field of the Invention Processes for the purification of voglibose are provided. Also provided are processes for the purification of substituted or unsubstituted 5-oxo- 1,2,3,4- cyclohexanetetrol and substituted 5-amino-l,2,3,4-cyclohexanetetrol, which compounds are useful intermediates in the preparation of voglibose.
Background of the Invention Chemically, voglibose is (lS)-(l(OH),2,4,5/l,3)-5-[[2-hydroxy-l-(hydroxymethyl) ethyl] amino]-l-C-(hydroxymethyl)-l, 2,3, 4-cyclohexanetetrol, which has excellent inhibitory activity against glucoside hydrolase. Several processes have been reported for the preparation of voglibose involving the use of ion-exchange chromatography with water as eluent, followed by concentration of the aqueous solution and recrystallization from ethanol to obtain pure voglibose. Such processes are difficult to perform and unsuitable at a commercial scale since it involves recovery of large amounts of water by prolonged heating, which subsequently results in low overall yields of the product. Further, the reported processes provide products that are initially hygroscopic and often convert to a sticky oil when exposed to the atmosphere. Purification of (lS)-(l(OH),2,4,5/l,3)-5-amino-l-C-(hydroxymethyl)-l,2,3,4- cyclohexanetetrol (valiolamine) by an ion-exchange chrornatograpbic method has also been disclosed. Purification of (lS)-(l(OH),2,4,5/l,3)2,3,4-tri-O-benzyl-5-amino-l-C- [(benzyloxy)methyl]-l,2,3,4-cyclohexanetetrol(tetra-O-benzylvaliolamine) by chromatography on silica gel using chloroform and methanol as eluent has also been disclosed. Other purification techniques have been disclosed. For example, (1S)- (l(OH),2,4/l,3)-2,3,4-tri-O-benzoyl-l-C- (benzoyloxymethyl)-5-oxo-l,2,3,4- cyclohexanetetrol (tetra-O-benzoylvaliolone) has been purified by using column chromatography on silica gel with toluene and ethyl acetate. In other disclosures, (1S)- (l(OH),2,4Nl,3)-2,3,4-tri-O-benzyl-l-C-(benzyloxymethyl)-5-oxo-l,2,3,4- cyclohexanetetrol(tetra-O-benzylvaliolone) has been purified by using column chromatography on silica gel with toluene and ethyl acetate followed by treatment with a mixture of ethyl ether and petroleum ether. Further, ion exchange column chromatography has been used for the purification of (1S)-(1(0H),2,4/1,3)- 1-C- (hydroxymethyl)- 5-oxo-l,2,3,4-cyclohexanetetrol (valiolone). In light of the above, there remains a need for an improved process that avoids chromato graphic purification techniques of voglibose, which minimizes or eliminates the above problems and is convenient to operate on a commercial scale.
Summary of the Invention Provided herein are processes for purifying voglibose, which comprise the steps of: providing a solution of crude voglibose in one or more alcohols and optionally water, and recovering pure voglibose. The processes may include one or more of the following embodiments. For example, the solution of crude voglibose can be obtained as a solution directly from a reaction mixture in which voglibose is prepared. Also, the solution of crude voglibose can be treated with activated carbon before recovering pure voglibose. Recovering pure voglibose can comprise concentrating the solution of crude voglibose, crystallizing voglibose, precipitating voglibose, cooling the solution of crude voglibose or any combination thereof to obtain solid pure voglibose. Recovering pure voglibose can also comprise concentrating the solution at elevated temperatures followed by cooling. Recovering pure voglibose can also comprise adding one or more antisolvents to the solution. Suitable antisolvents can be one or more of a hydrocarbon, lower alkyl ether, ester, ketone or mixtures thereof. Suitable hydrocarbons can be one or more of hexane, cyclohexane, toluene, heptane, octane or mixtures thereof. Also provided herein are processes for the purification of compounds of Formula I,
Figure imgf000004_0001
Formula I wherein R is a protecting group, comprising the steps of: contacting a crude compound of Formula I with one or more ethers to form a solution of a crude compound of Formula I, and recovering a pure compound of Formula I. These processes can include one or more of the following embodiments. For example, recovering pure compounds of Formula I can comprise concentrating the solution of a crude compound of Formula I, cooling the solution of a crude compound of Formula I, decanting to remove one or more ethers, layer separating to remove one or more ethers, filtering the compound of Formula I or any combination thereof to obtain solid a pure compound of Formula I. The protecting group can be an optionally substituted Cι-6 straight or branched chain alkyl, an optionally substituted benzyl or benzoyl. The one or more ethers can be di ethyl ether, diisopropyl ether, tert-butylethyl ether, tert-butylmethyl ether or mixtures thereof. The solution of a crude compound Formula I can be stirred at a temperature of from about 40 °C to about 60 °C. Also provided herein are processes for the purification of compound of Formula II,
Figure imgf000004_0002
Formula II wherein R' is hydrogen or a protecting group, comprising the steps of: dissolving a crude compound of Formula II in one or more alcohols, ketones or mixtures thereof to form a solution of a crude compound of Formula II, and recovering a pure compound of Formula II. These processes can include one or more of the following embodiments. For example, recovering pure compounds of Formula II can comprise concentrating the solution of a crude compound of Formula II, crystallizing the compound of Formula II, precipitating the compound of Formula LT, cooling the solution of the crude compound of Formula II or any combination thereof to form solid a pure compound of Formula II. The protecting group can be an optionally substituted Cι-6 straight or branched chain alkyl, an optionally substituted benzyl or benzoyl. The solution of a crude compound of Formula LT can be obtained directly from a reaction mixture in which the crude compound of Formula II is prepared. The one or more alcohols can be methanol, ethanol, isopropanol or mixtures thereof. The one or more ketones can be acetone, methyl isobutyl ketone or mixtures thereof. The crude compound of Formula II can be dissolved at a temperature of about 40 °C to reflux temperatures. Recovering a pure compound of Formula II by crystallizing comprises cooling the solution of the crude compound of Formula II to a temperature of about 10 °C to about 40 °C.
Detailed Description of the Invention In one aspect, provided herein are processes for the purification of voglibose comprising providing a solution of crude voglibose in one or more alcohols (particularly lower alcohols, e.g., methanol, ethanol, or propanol or isomers thereof and the like) and optionally water; and recovering pure voglibose. In another aspect, provided herein are processes for the purification of compounds of Formula I,
Figure imgf000005_0001
Formula I wherein R is a protecting group, comprising contacting crude compound of Formula I with one or more ethers and recovering pure compound of Formula I. In yet another aspect, provided herein are processes for the purification of compounds of Formula LT,
Figure imgf000006_0001
Formula II wherein R' is hydrogen or a protecting group, comprising dissolving crude compound of Formula JJ in a solvent (e.g., alcohols, ketones, or mixtures thereof) and recovering pure compound of Formula II. The solution of "crude voglibose" may be obtained by dissolving crude voglibose obtained from any of the synthetic routes previously described, for example, in U.S. Patent Nos. 4,701,559; 4,824,943; 4,898,986; 6,150,568; J Org. Chem., 57:3651 (1992); andJ Med. Chem., 29:1038 (1986), in one or more alcohols (e.g., methanol) at room temperature or at higher temperatures up to reflux temperatures. The solution of crude voglibose may also be obtained directly from a reaction mixture of the last step of a process in which voglibose is prepared, and used as such in the purification process. In cases where the solvent (of such a solution obtained directly from a reaction mixture) is not an alcohol (e.g., methanol), the solvent may be removed by conventional methods known in art (e.g., rotary evaporation, heating, vacuum) and the residue redissolved in one or more lower alcohols and optionally water. Crude voglibose may contain corresponding anti-isomers, polymeric impurities or any other impurity, which may arise during production or storage, such as degradation products. Alcoholic solutions of voglibose may be treated with activated carbon in some embodiments, particularly where decolorization is desired or necessary. Methods of recovering pure voglibose include, for example, concentrating solutions of voglibose, crystallization, precipitation, cooling or any combination thereof, followed by separation and drying, if necessary. Precipitation may occur upon addition of one or more antisolvents, i.e., solvents in which voglibose is insoluble or sparingly soluble, to alcoholic solutions of voglibose. • Alternatively, precipitation can be induced by concentrating the solution of voglibose and/or reducing the temperature of the voglibose solution, particularly if the initial temperature is elevated (e.g., above room temperature). For example, the solution of voglibose can be concentrated by heating the solution to a sufficient temperature so that the alocoholic solvent evaporates, e.g., to temperatures near the boiling point of the alcohol, or lower temperatures if a vacuum is applied. For cooling, the temperature of the solution of voglibose can be lowered to temperatures sufficient to precipitate voglibose from solution, for example, from about 0 °C to about 40 °C or even from about 20 °C to about 30 °C. Suitable antisolvents that may be added to precipitate pure voglibose include, but are not limited to, hydrocarbons (e.g., hexane, cyclohexane, toluene, heptane, octane or mixtures thereof); lower alkyl ethers (e.g., diethylether, diisopropylether or mixtures thereof); ketones (e.g., acetone, methyl isobutyl ketone or mixtures thereof); esters (e.g., ethylacetate, isopropylacetate or mixtures thereof); or mixtures thereof. Crystallization times and temperatures are not critical in obtaining pure voglibose. For example, the crystallization may be performed at temperatures sufficient to crystallilze voglibose, for example, from about 10 °C to about 40 °C for between about 30 minutes to about 2 hours in particular embodiments. Methods of separating pure voglibose include, for example, decanting, filtering, centrifuging and similar processing methods for separating solids from liquids known in the art, or any combination of these separation methods. Suitable protecting groups in compounds of Formula I and Formula II can be, for example, optionally substituted C^ straight or branched chain alkyl, or optionally substituted benzyl and benzoyl groups. Optionally substituted Ci-6 straight or branched chain alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, and the like. Substituted benzyl groups include, for example, p-nitrobenzyl, p-methoxybenzyl, o-nitrobenzyl, p-bromobenzyl, 2,4,6- trimethylbenzyl, and the like. Crude compounds of Formula I may be prepared by any synthetic routes known to one of ordinary skill in the art, including those described in U.S. Patent No. 4,824,943; U.S. Patent No. 6,150,568; andJ Org. Chem., 57:3651 (1992). Such crude compounds of Formula I can be obtained as an isolated compound or as a solution obtained directly from a reaction mixture of the last step of a process in which voglibose is prepared and used as such in the process. Suitable ethers, when used in the purification of compounds of Formula I, include, for example, diethyl ether, diisopropyl ether, tert-butylethyl ether, tert-butylmethyl ether or mixtures thereof. The term "contacting," as used herein, includes slurrying, stirring, triturating or a combination thereof. Crude compounds of Formula I may be stirred in one or more ethers at about 40 °C to about 60 °C in particular embodiments. Recovery of pure compoimds of Formula I may be accomplished by concentrating solutions of crude compounds of Formula I, cooling, decanting, layer separation, filtration or any combination thereof, followed by drying. Crude compounds of Formula II may be prepared by any synthetic route known to one of ordinary skill in the art, including, for example, those described in U.S. Patent Nos. 4,701,559; 4,824,943; 4,898,986 andJ Org. Chem., 57:3642 (1992). Crude compounds of Formula II may also be obtained as a solution directly from a reaction mixture of the last step of a process in which it is prepared and used as such in the process. Suitable alcohols include, Cι-C6 alcohols, for example, methanol, ethanol, isopropanol or mixtures thereof. Suitable ketones include, for example, acetone, methyl isobutyl ketone or mixtures thereof. Crude compounds of Formula II may be dissolved in one or more alcohols or ketones at temperatures of about 40 °C to reflux temperatures in some particular embodiments. Suitable methods of recovering pure compounds of Formula II include, for example, concentrating solutions of crude compounds of Formula II, crystallization, cooling or any combination thereof, followed by separation and drying. Crystallization times and temperatures are not critical in obtaining pure compounds of Formulae I or II. For example, the crystallization may be performed by stirring at temperatures of from about 10 °C to about 40 °C for between about 30 minutes to about 3 hours in some particular embodiments. Suitable methods of separating of pure compounds of Formula II include, for example, decanting, filtering, centrifuging or other similar processing methods for separating solids from liquids known in the art, as well as any combination of these separation methods. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims. Examples Example 1: Preparation of pure (lSVfl(OH).2A5/l,3V5-rr2-hvdroxy-l-
(hvdroxymethyl ethyl] amino]- 1 -C-(hvdroxymethyl - 1.2.3.4-cyclohexanetetrol (voglibose): Crude (lS)-(l(OH),2,4,5/l,3)-5-[[2-hydroxy-l-(hydroxymethyl) ethyl]amino]-l-C- (hydroxymethyl)-l,2,3,4-cyclohexanetetrol (voglibose, 109 g, HPLC purity: 97.5%) was dissolved in methanol (6.6 L) and heated to reflux temperatures. Charcoal (4 g) was then added to the solution at 50 °C and stirred for 30 minutes at 50 °C. The reaction mixture was filtered through a HYFLO bed and the HYFLO bed was washed with methanol (500 mL). Methanol (about 6 L) was distilled off and the concentrated solution was stirred at 25-30 °C for 1 hour. The obtained solid was filtered and washed with methanol. The product was dried at 45-50 °C under reduced pressure to yield the title compound as white crystals.
Yield: 99 g
HPLC Purity: 99.6%
1HNMR (D2O, 300MHz), δ: 1.55 (1H, dd, J=2.1, 15Hz), 2.10 (1H, dd, J=2.7, 15Hz), 2.90 (1H, m), 3.40-3.55 (2H, m), 3.59 (2H,m), 3.64-3.80 (5H, m), 3.88 (1H, t, J=9.6Hz) Example 2: Synthesis of pure (lS)-d(OH12,4,5/1.3V2.3.4-tri-O-benzyl-5-amino-l-C- rbenzyloxymethyll - 1.2,3 ,4-cvclohexanetetrol(tetra-O-benzyl valiolamine : Ammonium acetate (75 g, 0.97 mol) and sodium cyanoborohydride (20 g, 0.318 mol) was added to a solution of pure (1S)-(1(0H),2,4 /l,3)-2,3,4-tri-O-benzyl-l-C- (benzyloxymethyl)-5-oxo-l,2,3,4-cyclohexanetetrol (tetra-O-benzylvaliolone, 50 g, 0.09 mol) in methanol (500 mL). The reaction mixture was stirred overnight at 30-35 °C. The solvent was distilled off under reduced pressure and water (250 mL) was added to the reaction mixture followed by extraction with ethyl acetate (250 mL). The organic layer was washed with water followed by brine solution, and concentrated to yield tetra-O- benzyl valiolamine as a colorless syrup (HPLC purity: 74.7%). The syrup was stirred with diisopropylether (100 mL) at 45-50 °C for 30 minutes. The lower thick layer of tetra-O- benzylvaliolamine was separated and then stirred with diisopropylether (100 mL) at 45-50 °C for 30 minutes. The lower layer was separated and then concentrated to dryness to yield a pure tetra-O-benzyl valiolamine as a colorless foamy solid. Yield: 99 g
HPLC Purity: 88.1%
1HNMR (CDC13 + D2O, 300MHz), δ: 1.76 (1H, dd, J=2.6, 14.6Hz), 1.80 (1H, dd, J=2.5, 14.6Hz), 3.20-3.60 (5H, m), 4.18 (1H, t, J=9.6Hz), 4.40 (2H,s), 4.60-4.91 (6H, m), 7.25- 7.36 (20H, m)
Example 3: Purification of riS)-ri(OH\2.4/ 3V2,3.4-tri-O-benzyl-l-C- (benzyloxymethyl -5-oxo-l,2.3,4-cyclohexanetetrol (tetra-O-benzylvaliolone): Crude (lS)-(l(OH),2,4/l,3)-2,3,4-tri-O-benzyl-l-C- (benzyloxymethyl)- 5-oxo- 1,2,3,4-cyclohexanetetrol (tetra-O-benzylvaliolone, 140 g, HPLC purity: 78.5%) was dissolved in methanol (700 mL) at 45-50 °C and the mixture was cooled to 20-25 °C. The mixture was stirred for 2 hours at 20-25 °C. A precipitated solid was filtered, washed with methanol, and then dried at 35-40 °C under reduced pressure to yield the pure title compound.
Yield: 95 g HPLC Purity: 94.7%
M.P.: 98 - 99°C
1HNMR (CDC13), δ: 2.39 (brs, IH), 2.47 (IH, d, J=14.4Hz), 2.84 (IH, d, J = 14.7Hz), 3.15, 3.53 (IH each, ABq, J=8.4Hz), 4.01-4.14 (3H, m), 4.42-4.57 (4H, m), 4.74 (IH, d, J=l 0.8Hz), 4.93-5.0 (3H, m), 7.16-7.38 (20H, m)
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

WE CLAIM: 1. A process for the purification of voglibose comprising the steps of: providing a solution of crude voglibose in one or more alcohols and optionally water, and recovering pure voglibose. 2. The process according to claim 1, wherein the solution of crude voglibose is obtained as a solution directly from a reaction mixture in which voglibose is prepared. 3. The process according to claim 1, wherein the solution of crude voglibose is treated with activated carbon before recovering pure voglibose. 4. The process of claim 1, wherein recovering pure voglibose comprises concentrating the solution of crude voglibose, crystallizing voglibose, precipitating voglibose, cooling the solution of crude voglibose or any combination thereof to obtain solid pure voglibose. 5. The process according to claim 1, wherein recovering pure voglibose comprises concentrating the solution at elevated temperatures followed by cooling. 6. The process according to claim 1, wherein recovering pure voglibose comprises adding one or more antisolvents to the solution. 7. The process according to claim 6, wherein the one or more antisolvents are one or more of a hydrocarbon, lower alkyl ether, ester, ketone or mixtures thereof. 8. The process according to claim 7, wherein the hydrocarbon is one or more of hexane, cyclohexane, toluene, heptane, octane or mixtures thereof.9. A process for the purification of compound of Formula I,
Figure imgf000012_0001
Formula I wherein R is a protecting group, comprising the steps of: contacting a crude compound of Formula I with one or more ethers to form a solution of a crude compound of Formula I, and recovering a pure compound of Formula I. 10. The process of claim 9, wherein recovering pure compounds of Formula I comprises concentrating the solution of the crude compound of Formula I, cooling the solution of the crude compound of Formula I, decanting to remove one or more ethers, layer separating to remove one or more ethers, filtering the compound of Formula I or any combination thereof to obtain solid a pure compound of Formula I. 11. The process according to claim 9, wherein the protecting group comprises an optionally substituted Cι-6 straight or branched chain alkyl, an optionally substituted benzyl or benzoyl. 12. The process according to claim 9, wherein the one or more ethers comprise diethyl ether, diisopropyl ether, tert-butylethyl ether, tert-butylmethyl ether or mixtures thereof. 13. The process of claim 9, wherein the solution of a crude compound Formula I is stirred at a temperature of from about 40 °C to about 60 °C. 14. A process for the purification of compound of Formula II,
Figure imgf000013_0001
Formula II wherein R' is hydrogen or a protecting group, comprising the steps of: dissolving a crude compound of Formula II in one or more alcohols, ketones or mixtures thereof to form a solution of a crude compound of Formula LT, and recovering a pure compound of Formula II. 15. The process of claim 14, wherein recovering pure compounds of Formula II comprise concentrating the solution of the crude compound of Formula II, crystallizing the compound of Formula II, precipitating the compound of Formula II, cooling the solution of the crude compound of Formula LT or any combination thereof to form solid a pure compound of Formula II. 16. The process according to claim 14, wherein the protecting group comprises an optionally substituted Cι-6 straight or branched chain alkyl, an optionally substi"tuted benzyl or benzoyl. 17. The process according to claim 14, wherein the solution of a crude compound of Formula II is obtained directly from a reaction mixture in which the crude compound of Formula II is prepared. 18. The process according to claim 14, wherein the one or more alcohols comprise methanol, ethanol, isopropanol or mixtures thereof. 19. The process according to claim 14, wherein the one or more ketones comprise acetone, methyl isobutyl ketone or mixtures thereof. 20. The process according to claim 14, wherein the crude compound of Formula II is dissolved at a temperature of about 40 °C to reflux temperatures. 21. The process according to claim 20, wherein recovering a pure compound of Formula II by crystallizing comprises cooling the solution of the crude compound of Formula II to a temperature of about 10 °C to about 40 °C.
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WO2008092327A1 (en) * 2007-01-26 2008-08-07 Pharmaxyn Laboratories Ltd. Half-hydrated crystal of voglibose, the preparation thereof and pharmaceutical composition containing the same
CN102050846B (en) * 2009-11-02 2013-09-11 上海天伟生物制药有限公司 Amino sugar, and preparation method and use thereof

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008092327A1 (en) * 2007-01-26 2008-08-07 Pharmaxyn Laboratories Ltd. Half-hydrated crystal of voglibose, the preparation thereof and pharmaceutical composition containing the same
CN102050846B (en) * 2009-11-02 2013-09-11 上海天伟生物制药有限公司 Amino sugar, and preparation method and use thereof

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