| Intermediate and process for preparing of beta- anomer enriched 21-deoxy,21,21-difluoro-d-ribofuranosyl nucleosides -> Monitor Keywords |
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  Intermediate and process for preparing of beta- anomer enriched 21-deoxy,21,21-difluoro-d-ribofuranosyl nucleosidesUSPTO Application #: 20070208170Title: Intermediate and process for preparing of beta- anomer enriched 21-deoxy,21,21-difluoro-d-ribofuranosyl nucleosides Abstract: The present invention provides a highly stereoselective, simple and economical glycosylation process for preparation of β-anomer enriched 21-deoxy-21,21-D-ribofuranosyl difluoronucleosides of formula (II), and physiologically acceptable slats thereof, in particular, the β-enriched anomer of gemcitabine hydrochloride of formula (IIb) in purity of >99% is provided through utilization of a novel trichloroacetimidate of formula (I). (end of abstract)
Agent: Schwegman, Lundberg, Woessner & Kluth, P.A. - Minneapolis, MN, US Inventors: Golak Chandra Maikap, Deependra Bhatt, Bijan Kumar Panda USPTO Applicaton #: 20070208170 - Class: 536028400 (USPTO) Related Patent Categories: Organic Compounds -- Part Of The Class 532-570 Series, Azo Compounds Containing Formaldehyde Reaction Product As The Coupling Component, Carbohydrates Or Derivatives, Nitrogen Containing, Dna Or Rna Fragments Or Modified Forms Thereof (e.g., Genes, Etc.), Phosphorus Containing N-glycoside Wherein The N Is Part Of An N-hetero Ring, The N-hetero Ring Is A 1,3-diazine Ring, Including Hydrogenated (e.g., Pyrimidines, Etc.) The Patent Description & Claims data below is from USPTO Patent Application 20070208170. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATION [0001] This application is a continuation application of U.S. patent application Ser. No. 11/332,830, filed Jan. 13, 2006, which application claims priority under 35 U.S.C. 119 to Indian Application No. 472/DEL/2005, filed Mar. 4, 2005, which applications are incorporated herein by reference in its entirety and made a part hereof FIELD OF THE INVENTION [0002] The present invention relates to a novel intermediate of formula (I), a process for preparation thereof and its use in the preparation of .beta.-enriched anomers of therapeutically and commercially valuable 2.sup.1-deoxy-2.sup.1, 2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II), and physiologically acceptable salts thereof. In particular, the present invention relates to a selective process for manufacture of the .beta.-enriched anomer of gemcitabine hydrochloride of formula (IIb) in high purity. BACKGROUND OF THE INVENTION [0003] 2.sup.1-deoxy-2.sup.1, 2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II), wherein the group R represents a base selected from a pyrimidine or purine derivative and P represents hydrogen or a hydroxy protective group possess useful therapeutic properties and one such 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleoside of therapeutic and commercial importance is gemcitabine hydrochloride of formula (IIb), first disclosed by Hertel et al. in U.S. Pat. No. 4,526,988; its continuation-in-part U.S. Pat. No. 4,692,434 and divisional, U.S. Pat. No. 4,808,614 as an useful antiviral and later by Grindey et al. in U.S. Pat. No. 5,464,826 as an useful anti-tumour agent for treatment of susceptible neoplasms in mammals. [0004] U.S. Pat. Nos. 4,526,988, 4,692,434 and 4,808,614 disclose a method for synthesis of the 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II) including gemcitabine hydrochloride of formula (IIb) comprising hydrolysis of an alkyl-3-dioxolanyl-2,2-difluoro-3-hydroxypropionate (1) to give a lactone (III), which after suitable protection of the hydroxyl groups is reduced to give the protected 2.sup.1-deoxy-2.sup.1,2.sup.1-difluororibose of formula (IV). The free hydroxy group of compound (IV) thus obtained is converted to a suitable derivative (2), in which the group L acts as a better leaving group for the coupling reaction with the appropriate base to give after removal of the hydroxy protective groups the 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II). The chemistry is summarized hereinbelow: [0005] Even though, U.S. Pat. Nos. 4,526,988, 4,692,434 and 4,808,614 mention that any protective group to which chemists are accustomed can be employed, however, the use of silyl hydroxy-protecting groups, specially the tert-butyldimethylsilyl group are preferred since these are difficult to cleave under normal conditions and can be removed only by contact with an hydrohalic acid. The reduction of the keto function of lactone (III) to the hydroxy compound (IV) is achieved using reducing agents such as diisobutyl aluminium hydride, lithium aluminium hydride, etc. [0006] The suitable leaving groups of compound (IV) for reaction with the base are those normally employed in organic synthesis such as methanesulfonyl, acetate, halo etc. [0007] However, the method disclosed U.S. Pat. Nos. 4,526,988, 4,692,434 and 4,808,614 utilizes expensive hydroxy protective group like tert-butyldimethylsilyl group and reducing agents like diisobutyl aluminium hydride, lithium aluminium hydride, which, moreover, are hazardous, requiring special handling care, thereby increasing the cost and risk of manufacture. [0008] Further, the lactone of formula (III), by virtue of having a chiral center is obtained as a mixture of erythro and threo enantiomers, of which the former one is preferred since it is the biologically more active one and provides a carbohydrate having the stereochemistry of naturally occurring ribose. More often than not, recourse to tedious and expensive chromatography procedures are taken to separate the said enantiomers. [0009] In addition, a second chiral centre is generated when the lactone (III) is reduced to the hydroxy compound (1V), affording a mixture of .alpha.- and .beta.-anomers, of which the latter i.e., the .beta.-anomer being more active biologically is preferred. The method disclosed U.S. Pat. Nos. 4,526,988, 4,692,434 and 4,808,614 produces protected 2.sup.1-deoxy-2.sup.1,2.sup.1-difluororibose of formula (IV) as a mixture of .alpha.- and .beta.-anomers in a ratio of 4:1, again more often than not, requiring elaborate purification techniques to remove the undesired .alpha.-anomer, further increasing the cost of manufacture of the desired .beta.-anomers of 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II). [0010] Many improvements have been reported for manufacture of 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II) and its intermediates, which are summarized hereinbelow: [0011] i) Chou et al. in U.S. Pat. No. 4,965,374 disclose a method for preparation of the erythro enantiomer of a lactone compound of formula (III), wherein the hydroxy protective group, P is benzoyl in greater than 95% purity comprising dissolution of a mixture of erythro and threo enantiomers in methylene chloride, cooling the solution to -5.degree. C. to +10.degree. C. and collecting the precipitated erythro enantiomer through filtration as such or optionally after addition of hexane. [0012] ii) Chou et al. in U.S. Pat. No. 5,223,608 teach a method for obtaining the .beta.-anomer of gemcitabine hydrochloride of formula (IIb) or the corresponding hydrobromide salt in a purity of about 80% comprising the steps of dissolving a 1:1 mixture of .alpha.- and .beta.-anomers in water at a temperature of about 50.degree. C. to 100.degree. C., followed by addition of acetone to the solution and collecting the said precipitated .beta.-anomer of 80% purity after cooling the mixture to about -10.degree. C. to 500 C. [0013] U.S. Pat. No. 5,223,608 also recites a method for enriching the purity of .beta.-anomer gemcitabine hydrochloride of formula (IIb) or the corresponding hydrobromide salt to 99% comprising subjecting the material of 80% purity as obtained by the abovementioned method to repeated purification utilizing the same purification method. [0014] U.S. Pat. No. 5,223,608 further discloses a method for obtaining .beta.-anomer enriched gemcitabine hydrochloride of formula (IIb) or the corresponding hydrobromide salt in a purity of 99% comprising the steps of dissolving a 1:1 mixture of .alpha.- and .beta.-anomers in water at a temperature of about 45.degree. C. to 90.degree. C., followed by adjusting the pH of the solution to about 7.0 to 9.0 and collecting the said precipitated .beta.-anomer of the free of 99% purity after cooling the mixture to about -10.degree. C. to 30.degree. C. The free base thus obtained is subjected to the same crystallization method in the presence of hydrogen chloride or hydrogen bromide to afford the desired gemcitabine hydrochloride of formula (IIb) or the corresponding hydrobromide salt in an anomeric purity of about 99% of the .beta.-anomer. [0015] The methods disclosed in U.S. Pat. No. 5,223,608, however, suffer from a disadvantage in that repeated crystallization steps are required to obtain the product of 99% purity, not only increasing the length but also the cost of manufacture. [0016] iii) Chou et al. in U.S. Pat. No. 5,252,756 disclose a stereoselective process for preparation of a .beta.-enriched anomer of compound of formula (2), wherein the leaving group L is selected from an arylsulfonate or substituted arylsulfonate comprising contacting the lactol of formula (IV) with a sulfonating reagent in an inert solvent in the presence of an acid scavenger. [0017] iv) Chou et al. in U.S. Pat. No. 5,256,797 further describe a method for separation of a mixture of .alpha.- and .beta.-anomers of compound of formula (2), wherein the leaving group L is selected from an alkylsulfonate or substituted alkylsulfonate comprising contacting the anomeric mixture with a solvent, heating the mixture and adding a counter-solvent, followed by lowering the temperature to effect separation of the two enantiomers. [0018] v) Chou et al. in U.S. Pat. No. 5,256,798 disclose a method for preparation of a a-anomer enriched anomer of compound (2), wherein the leaving group L is a sulfonate from the corresponding .beta.-anomer of formula comprising treating the latter with a source of conjugate anion of a sulfonic acid at elevated temperatures in an inert solvent. [0019] vi) Chou et al. in U.S. Pat. No. 5,371,210 and U.S. Pat. No. 5,401,838 describe a stereoselective fusion glycosylation process for preparation of .beta.-anomer of 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II), wherein R and P are as defined hereinbefore comprising reacting a difluorocarbohydrate of formula (2), wherein L is an aryl/alkyl sulfonoyloxy group as a mixture of .alpha.- and .beta.-anomers in a ratio equal to greater than 1:1 with an excess of at least 3 molar equivalents of amino/hydroxy protected base, R at elevated temperatures of between 100.degree. C. to 160.degree. C., in the absence of a catalyst followed by removal of the amino/hydroxyl protective groups to give the .beta.-anomer of 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II). [0020] The method, however, is lengthy since it involves protection and deprotection of functional groups; requires large excess of the base R and, moreover, is not highly suitable for commercial manufacture since it requires elevated temperatures for carrying out the reaction. [0021] vii) Chou et al. in U.S. Pat. No. 5,401,861 describes a method for producing an .alpha.-enriched anomer of the intermediate compound (2), wherein the leaving group is a sulfonoyloxy group comprising treating a solution of a mixture of .alpha.- and .beta.-anomers of the lactol compound (1V) with an amine base at very low temperature and adding a sulfonating reagent. [0022] The method, however, suffers from a limitation in that very low temperatures ranging from between -40.degree. C. to -120.degree. C. is employed for achieving the separation of the .alpha.- and .beta.-anomers. [0023] viii) Britton et al. in U.S. Pat. No. 5,420,266 disclose a process for anomerizing an .alpha.-anomer of formula (II) to the .beta.-anomer by treatment with a hydroxide base in an organic solvent or vice versa. [0024] However, the product obtained contains an anomeric ratio of the .alpha.- and .beta.-anomers in a ratio ranging between 62:38 to 97:3, which needless to mention, would require further crystallization(s) to obtain the .beta.-anomer of at least 99% purity. [0025] ix) Jones in U.S. Pat. No. 5,424,416 discloses a process for preparation of a .beta.-enriched anomer of compound (II) comprising the steps of contacting a solution of the lactol of formula (IV) with a base at a temperature in the range of -40.degree. C. to -120.degree. C., followed by addition of a sulfonating reagent to produce an .alpha.-enriched anomer of formula (2), wherein L is a fluoroalkylsulfonoyloxy or fluoroarylsulfonoyloxy group. The compound (2) thus obtained is reacted with a conjugate anion of a sulfonic acid to give the corresponding .beta.-enriched anomer (2), wherein L is an alkyl/arylsulfonyloxy group. The .beta.-enriched anomer (2) thus obtained is heated to a temperature of between 50.degree. C. to 120.degree. C. to give the corresponding .alpha.-enriched anomer (2), wherein L is an alkyl/arylsulfonyloxy group, which on contact with a nucleobase anion, R in an inert solvent at a temperature of between 23.degree. C. to 170.degree. C. gives the .beta.-enriched compound of formula (II). [0026] However, the length of synthesis, the very low and very elevated temperatures are major limitations of the method. [0027] x) Kjell in U.S. Pat. No. 5,426,183 describes a catalytic stereoselective process for preparation of .alpha.- and .beta.-enriched anomers of 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II), wherein R and P are as defined hereinbefore comprising reacting a difluorocarbohydrate of formula (2), wherein L is a sulfonyloxy, cyano, halo, carboalkoxy groups etc. as a mixture of .alpha.- and .beta.-anomers in a ratio equal to or greater than 1:1 with the requisite amino/hydroxy protected base, R at elevated temperatures of between 50.degree. C. to 100.degree. C., in the presence of a catalyst selected from potassium/barium/cesium trialkyl ammonium salts of trifluoromethanesulfonic acid, nanofluorobutanesulfonic acid, sulfuric acid, perchloric acid, nitric acid, trifluoroacetic acid etc. followed by removal of the amino/hydroxyl protective groups to give the .beta.-anomer of 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II). [0028] xi) Hertel et al. in U.S. Pat. No. 5,480,992 and its divisional U.S. Pat. No. 5,541,345 describe another process for preparation of 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II), wherein R and P are as defined hereinbefore comprising reacting a amine of formula (3) with an acyclic compound of formula (4), wherein the group Y is hydrogen, alkyl or halo followed by cyclization and deprotection to give compound (II). [0029] xii) Chou et al. in U.S. Pat. No. 5,453,499 describe a stereoselective process for preparation of .alpha.-anomer of a halo compound of formula (2), wherein the group L is a halogen from the corresponding .beta.-anomeric compounds 5 wherein the group L is a sulfonyloxy group comprising treating the latter with a source of halide ions in an inert solvent. The halo compounds are intermediates for compound of formula (II). [0030] xiii) Wildfeur in U.S. Pat. No. 5,521,294 describes a method for gemcitabine of formula (IIb) comprising reacting the requisite cytosine with an intermediate of formula (5). [0031] xiv) Wirth et al. in U.S. Pat. No. 5,559,222 and its divisional, U.S. Pat. No. 5,608,043 disclose a process for preparation of gemcitabine hydrochloride of formula (IIb), which is essentially an improvement of the one described in U.S. Pat. No. 4,526,988; U.S. Pat. No. 4,692,434 and U.S. Pat. No. 4,808,614, the improvement comprising converting the lactol compound of formula (IV) to the 5-O-triphenylmethyl derivative (6), followed by reaction with methanesulfonyl chloride to give the mesyl derivative (7). The mesyl derivative (7) is then reacted with a silylated pyrimidine base, followed by removal of protective groups to give a gemcitabine derivative as a mixture of anomers, which on treatment with a base gives the .beta.-anomer of 98% purity. [0032] However, the overall yield reported for the process is only 1.3% from compound (IV), which renders it not at all attractive on a commercial scale. [0033] xv) Chou in U.S. Pat. No. 5,594,124 discloses a stereoselective process for preparation of a .beta.-enriched anomer of compound (II) comprising glycosylation of compound (2), wherein the group L is sulfonyloxy with the nucleobase, R at a temperature ranging from -120.degree. C. to 25.degree. C. in a low freezing inert solvent selected from dichloromethane, 1,2-dichloroethane, dichlorofluoromethane, acetone, toluene, anisole, chlorobenzene or mixture thereof. However, utilization of very low temperatures is a limitation of this process. [0034] xvi) In a variation, of the above process, Chou et al. in U.S. Pat. No. 5,606,048 recite a glycosylation process wherein it is carried out in a high boiling inert solvent selected from toluene, xylenes, 1,2-dichloroethane, 1,1,2-trichloroethane, glyme, diglyme, dichlorobromoethane, dibromochloromethane, tribromomethane, dibromomethane, anisole and mixtures thereof. The method, however, is lengthy since it involves protection and deprotection of functional groups; requires large excess of the base R and moreover, is not highly suitable for commercial manufacture since it requires elevated temperatures for carrying out the reaction. [0035] xvii) Kjell in U.S. Pat. No. 5,633,367 recites a process for preparation of compound of formula (II) comprising reacting 2-ketonucleoside of formula (8) with diethylammonium sulfur trifluoride (DAST) in the presence of 5 catalytic amount of pyridinium hydrofluoride and a non-reactive halogenated hydrocarbon. [0036] xviii) Berglund in U.S. Pat. No. 5,637,688 and its continuation U.S. Pat. No. 5,808,048 discloses a method for preparation of gemcitabine hydrochloride of formula (IIb) comprising removal of the benzoyl protective group of the .beta.-anomer of 1-(2.sup.1-deoxy-2.sup.1,2.sup.1-difluoro-3.sup.1,5.sup.1-di-O-benzoyl-D-- ribofuranosyl)-4-aminopyrimidin-2-one (9) with a catalytic amount of an alkylamine in the presence of methanol or ethanol in an environment free of water, followed by treatment of the deblocked nucleoside with hydrochloric acid and an antisolvent selected from acetone, acetonitrile, tetrahydrofuran, propanol, butanol, isobutanol, sec-butanol and isopropanol and recovering gemcitabine hydrochloride (IIb) from thereof. The method has a severe limitation in that the deblocking reaction requires strictly anhydrous conditions with all reagents and solvents used free of water. [0037] In addition, as per the disclosure of U.S. Pat. No. 4,965,374; U.S. Pat. No. 5,223,608; U.S. Pat. No. 5,434,254; and U.S. Pat. No. 5,945,547 and as described in Examples 7, 8, 9, 10, 11, 12, and 13 therein for synthesis of gemcitabine hydrochloride of formula (IIb) it would be further evident that: [0038] a) The removal of the benzoyl protective group of the di-O-benzoyl protected gemcitabine obtained as per the method described in Examples 7 and 11 is achieved through bubbling ammonia gas through a solution of the said di-O-benzoyl protected gemcitabine in methanol, followed by evaporation of methanol and extraction of the oily residue in ethyl acetate to give gemcitabine as a 1:1 mixture of .alpha.- and .beta.-anomers. [0039] Use of ammonia gas requires special handling and safety precautions, thereby increasing the cost and risk of manufacture. [0040] b) The gemcitabine obtained from step (a) above is invariably obtained as an oil and is converted to the hydrochloride salt by dissolving the oil in hot isopropanol (60.degree. C.), followed by addition of Reagent Grade hydrochloric acid and allowing the solution to cool under refrigerated conditions overnight, wherein solid gemcitabine hydrochloride as a 1:1 mixture of .alpha.- and .beta.-anomers separates out and is collected [0041] c) The hydrochloride salt obtained in step (b) requires further purification steps as mentioned hereinbefore, viz. repeated crystallization from acetone-water mixture at 50.degree. C. 100.degree. C., repeated crystallization from water at a pH of 7.0 to 9.9 etc. to obtain a material of pharmaceutical grade, all the above-mentioned unit operations resulting in the H-anomer of gemcitabine hydrochloride in a yield of about 0.14% to 0.33% only. [0042] Further, it might be noted that a manufacturing process for the .beta.-anomer of gemcitabine or its salts is invariably associated with formation of by-products, specially the corresponding .alpha.-anomer and cytosine of formula (V). [0043] Pharmacopoeial specifications world over are very stringent on the level of the abovementioned impurities present in gemcitabine hydrochloride, which should not be more than 0.1% each. [0044] From the foregoing it would be noticed that the prior art methods for synthesis of 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II), and gemcitabine hydrochloride of formula (IIb) suffer from anyone or more of the following limitations, viz., [0045] i) utilization of expensive hydroxy protective group like tert-butyldimethylsilyl group and reducing agents like diisobutyl aluminium hydride, lithium aluminium hydride, which, moreover, are hazardous, requiring special handling care, thereby increasing the cost and risk of manufacture; [0046] ii) utilization of multiple protection and deprotection steps not only increasing the length and cost of manufacture; [0047] iii) utilization of high boiling solvents and elevated reaction temperatures necessitating high energy consumption; [0048] iv) utilization of very low temperatures of about -120.degree. C., which is not practical on a commercial scale; [0049] v) utilization of large excess of the nucleoside base, which while adding to the cost also necessitates elaborate methods for removal of the excess reagent; [0050] vi) utilization of gaseous ammonia and strictly anhydrous conditions for removal of certain protective groups, necessitating special handling and safety precautions; [0051] vii) more often than not, resulting in formation of predominant amounts of the undesired .alpha.-anomers; [0052] viii) utilization of expensive and tedious chromatographic procedures and multiple crystallization techniques for obtaining the therapeutically desirable .beta.-enriched anomers, not only increasing the length and cost of manufacture; and [0053] ix) production of the object 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II), and gemcitabine hydrochloride of formula (IIb) in rather poor yields. [0054] A need, therefore, exists for an improved method for manufacture of 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II), in particular gemcitabine hydrochloride of formula (IIb), which is free of and not associated with the limitations of the prior art and provides the object compounds in higher yields and conforming to pharmacopoeial specifications. OBJECTS OF THE INVENTION [0055] An object of the present invention is to provide a process for preparation of 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II), in particular gemcitabine hydrochloride of formula (IIb), which is free of the limitations of the prior art methods. [0056] Another object of the present invention is to provide a novel intermediate for preparation of 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II), in particular gemcitabine hydrochloride of formula (IIb). [0057] Yet another object of the present invention is to provide a process for preparation of the novel intermediate for 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II), in particular gemcitabine hydrochloride of formula (IIb). [0058] A further object of the present invention is to provide a process for preparation of the 1-enriched anomer of 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II), in particular gemcitabine hydrochloride of formula (IIb), which is simple, cost-effective and avoids use of hazardous and expensive reagents and solvents and moreover, does not require strictly anhydrous conditions and special handling and safety precautions. [0059] Yet further object of the present invention is to provide a process for preparation of 2.sup.1-deoxy-2.sup.1,2.sup.1-D-ribofuranosyl difluoronucleosides of formula (II), in particular gemcitabine hydrochloride of formula (IIb) in higher yields. Continue reading... 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