WO2011104540A1 - Procédé en une étape pour la préparation de la capécitabine - Google Patents

Procédé en une étape pour la préparation de la capécitabine Download PDF

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Publication number
WO2011104540A1
WO2011104540A1 PCT/GB2011/050351 GB2011050351W WO2011104540A1 WO 2011104540 A1 WO2011104540 A1 WO 2011104540A1 GB 2011050351 W GB2011050351 W GB 2011050351W WO 2011104540 A1 WO2011104540 A1 WO 2011104540A1
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WIPO (PCT)
Prior art keywords
optionally substituted
capecitabine
reagent
process according
pentyloxycarbonylation
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PCT/GB2011/050351
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English (en)
Inventor
Vinayak Govind Gore
Laxmikant Narahari Patkar
Rahul Bhalerao
Mahesh Gorakhnath Hublikar
Kiran Shivaji Pokharkar
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Generics [Uk] Limited
Mylan India Private Limited
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Application filed by Generics [Uk] Limited, Mylan India Private Limited filed Critical Generics [Uk] Limited
Publication of WO2011104540A1 publication Critical patent/WO2011104540A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical

Definitions

  • the present invention relates a one step process for the preparation of capecitabine and analogues thereof, such as galocitabine, sapacitabine, 5'-deoxy-5-fluoro-N- [(cyclohexyloxy)carbonyl]cytidine, and N-[(heptyloxy)carbonyl]cytarabine.
  • Capecitabine represented by structural formula 1 and chemically named as 5'-deoxy-5- fluoro-N-[(pentyloxy)carbonyl]cyudine, is an antineoplastic agent and it is currently marketed as an orally administered chemotherapeutic agent to be used in the treatment of metastatic breast and colorectal cancers.
  • Scheme 2 US 5472949 discloses a synthetic route, as depicted in Scheme 1, wherein the protecting groups "PG" are acyl groups, such as acetyl or benzoyl, or silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl.
  • acyl groups such as acetyl or benzoyl
  • silyl groups such as trimethylsilyl or tert-butyldimethylsilyl.
  • Acylation of the hydroxyl groups is achieved by reaction of 5-fluoiO-5'-deoxycytidine 0101 with acetic anhydride and pyridine as a solvent and base or alternatively with acetyl chloride.
  • intermediate 0103 is subjected to hydrolysis to remove the acyl protecting groups to afford capecitabine.
  • this process requires purification by column chromatography at two stages.
  • US 5476932 discloses a similar process, but with a slight variation in protecting group strategy, as the protecting groups used are pentyloxycarbonyl groups.
  • the hydroxyl functions are protected with n-pentyl chloroformate to directly afford intermediate 0103, which is then subjected to selective deprotection at the hydroxyl functions to afford capecitabine.
  • protecting group strategy for both the Scheme 1 and Scheme 2 type processes are disclosed in WO 2008/145403, WO 2008/144980, WO 2009/094847, WO 2009/082846, WO 2007/009303 and WO 2008/131062.
  • the protecting groups used are trialkylsilyl, acyl, ketals (such as isopropylidene), acetals (such as benzylidene and its derivatives), orthoesters and carbonates.
  • capecitabine as used herein throughout the description and claims means capecitabine and/or any salt, solvate, hydrate, tautomer or polymorphic form thereof, unless otherwise specified.
  • galocitabine as used herein throughout the description and claims means galocitabine and/or any salt, solvate, hydrate, tautomer or polymorphic form thereof, unless otherwise specified.
  • Japanese sarcitabine as used herein throughout the description and claims means sapacitabine and/or any salt, solvate, hydrate, tautomer or polymorphic form thereof, unless otherwise specified.
  • 5'-deoxy-5-fluoro-N-[(cyclohexyloxy)carbonyl]cytidine means 5'-deoxy-5-fluoro-N-[(cyclohexyloxy) carbonyljcytidine and/or any salt, solvate, hydrate, tautomer or polymorphic form thereof, unless otherwise specified.
  • N-[(heptyloxy)carbonyl]cytarabine as used herein throughout the description and claims means N-[(heptyloxy)carbonyl]cytarabine and/or any salt, solvate, hydrate, tautomer or polymorphic form thereof, unless otherwise specified.
  • the capecitabine or analogue thereof is "substantially free” of chemical impurities, if it comprises less than 3% impurity, preferably less than 2%, preferably less than 1%, preferably less than 0.5%, preferably less than 0.1%, preferably as measured by HPLC.
  • the capecitabine or analogue thereof is “substantially free” of other optical isomers, if it comprises less than 3% of other optical isomers, preferably less than 2%, preferably less than 1%, preferably less than 0.5%, preferably less than 0.1%, preferably as measured by specific optical rotation or by chiral HPLC.
  • an optionally substituted group may be substituted with one or more of -F, -CI, -Br, -I, -CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -OH, -SH, -NH 2 , -CN, -N0 2 , -COOH, -R'-O-R 2 , -R'-S-R 2 , -R'-SO-R 2 , -R'-SCyR 2 , -R'-SO ⁇ OR 2 , -R'O-SO ⁇ R 2 , -R ⁇ SO ⁇ N ⁇ 2 ),, -R'-NR 2 -S0 2 -R 2 , -R 1 0-S0 2 -OR 2 , -R'O-SO ⁇ N ⁇ 2 ),, -R'-NR 2 -S0 2 -OR 2 , -R'O-SO ⁇ N ⁇ 2 ),, -R'-NR 2
  • -R 1 - is independentiy a chemical bond, a C r C 10 alkylene, C r C 10 alkenylene or C r C 10 alkynylene group.
  • -R 2 is independendy hydrogen, unsubstituted C r C 6 alkyl or unsubstituted Q-C 10 aryl.
  • Optional substituent(s) are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituent(s).
  • a substituted group comprises 1 , 2 or 3 substituents, preferably 1 or 2 substituents, preferably 1 substituent.
  • Any optional substituent may be protected.
  • Suitable protecting groups for protecting optional substituents are known in the art, for example from “Protective Groups in Organic Synthesis” by T.W. Greene and P.G.M. Wuts (Wiley-Interscience, 3 rd edition, 1999).
  • the present invention provides a process for the preparation of capecitabine 1, comprising reaction of 5-fiuoiO-5'-deoxycytidine 0101 with a pentyloxycarbonylation reagent.
  • the hydroxyl groups of the 5-fluoro-5'-deoxycytidine 0101 are not protected with protecting groups.
  • the pentyloxycarbonylation reagent is represented by general formula 0302, wherein X represents a suitable leaving group:
  • X is an optionally substituted aiyl, an optionally substituted -Y-aryl, an optionally substituted heteroaryl or an optionally substituted -Y-heteroaryl group, wherein Y is NH, O or S.
  • X is selected from an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted triazolyl, an optionally substituted benzotriazolyl or an optionally substituted phenoxy derivative.
  • X is not chloro.
  • X is selected from an optionally substituted imidazolyl derivative and more preferably is imidazolyl.
  • X is selected from an optionally substituted phenoxy derivative, such as 4- nitrophenoxy or pentafluorophenoxy.
  • X is selected from an optionally substituted benzotriazolyl derivative, which more preferably is 1-hydroxybenzotriazolyl.
  • X is selected from an optionally substituted thiazolyl derivative, preferably from an optionally substituted aminothiazolyl derivative, which more preferably is the ethyl 2- aminothiazolyl-5-carboxylate derivative 0302a.
  • the pentyloxycarbonylation reaction is carried out in the presence of a base or an acid.
  • the base is an organic base, preferably selected from a tnalkylamine such triethylamine or diisopropylethylamine, or an aromatic amine such as pyridine or dimemylaminopyridine. More preferably, the organic base is pyridine.
  • the acid is a mineral acid, which more preferably is hydrochloric acid.
  • the pentyloxycarbonylation reaction is carried out in the presence of an organic solvent, which is preferably selected from THF or acetonitrile or mixtures thereof.
  • the pentyloxycarbonylation reaction is carried out in the presence of 0.5 to 2.5 molar equivalents of the pentyloxycarbonylation reagent with respect to 5-fluoro-5'- deoxycytidine 0101, more preferably 0.8 to 1.2 molar equivalents of the pentyloxycarbonylation reagent, more preferably 0.9 to 1.1 molar equivalents, and most preferably about 1 molar equivalent.
  • the capecitabine formed is further purified, preferably by recrystallisation from a suitable solvent, such as ethyl acetate.
  • a second aspect of the present invention provides capecitabine when prepared by a process according to the first aspect of the present invention.
  • a third aspect of the present invention provides capecitabine substantially free of chemical impurities.
  • a fourth aspect of the present invention provides capecitabine substantially free of other optical isomers of capecitabine.
  • the capecitabine according to the second, third or fourth aspects of the present invention is suitable for use in medicine, preferably for the treatment or prevention of cancer, more preferably for the treatment or prevention of metastatic breast or colorectal cancer.
  • a fifth aspect of the present invention provides a pharmaceutical composition comprising capecitabine according to the second, third or fourth aspects of die present invention and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition is suitable for the treatment or prevention of cancer, more preferably for the treatment or prevention of metastatic breast or colorectal cancer.
  • a sixth aspect of the present invention provides use of capecitabine according to the second, third or fourth aspects of the present invention or use of the pharmaceutical composition according to the fifth aspect of the present invention in the manufacture of a medicament for treating or preventing cancer, preferably for treating or preventing metastatic breast or colorectal cancer.
  • a seventh aspect of the present invention provides a method of treating or preventing cancer comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of capecitabine according to the second, third or fourth aspects of the present invention or a therapeutically or prophylactically effective amount of the pharmaceutical composition according to the fifth aspect of the present invention.
  • the cancer is metastatic breast or colorectal cancer.
  • the patient is a mammal, more preferably a human.
  • An eighth aspect of the present invention provides a pentyloxycarbonylation reagent represented by general formula 0302, wherein X represents a suitable leaving group selected from an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted triazolyl, an optionally substituted benzotriazolyl or an optionally substituted phenoxy derivative.
  • X is selected from an optionally substituted imidazolyl derivative, more preferably imidazolyl.
  • X is selected from an optionally substituted phenoxy derivative, more preferably 4-nitrophenoxy or pentafluorophenoxy.
  • X is selected from an optionally substituted benzotriazolyl derivative, more preferably 1- hydroxybenzotriazolyl.
  • X is selected from an optionally substituted thiazolyl derivative, preferably from an optionally substituted aminotbiazolyl derivative, more preferably ethyl 2-aminothiazolyl-5-carboxylate derivative 0302a.
  • the process of the present invention can be easily adapted for the preparation of compounds, which are analogous to capecitabine 1, such as galocitabine 4, sapacitabine 5, 5'-deoxy-5-fluoro-N-[(cyclohexyloxy)carbonyl]cytidine 6, and N-[(heptyloxy)carbonyl] cytarabine 7.
  • a ninth aspect of the present invention provides a process for the preparation of galocitabine 4, comprising reaction of 5-fluoro-5'-deoxycytidine 0101 with a carbonylation reagent 0402, wherein X represents a suitable leaving group.
  • X is as defined in relation to the first aspect of the present invention.
  • a tenth aspect of the present invention provides a process for the preparation of sapacitabine 5, comprising reaction of 5'-deoxy-5'-(S)-cyano-cytidine 0501 with a carbonylation reagent 0502, wherein X represents a suitable leaving group.
  • X is as defined in relation to the first aspect of the present invention.
  • An eleventh aspect of the present invention provides a process for the preparation of 5'- deoxy-5-fluoro-N-[(cyclohexyloxy)carbonyl]cytidine 6, comprising reaction of 5-fiuoro-5'- deoxycytidine 0101 with a caibonylation reagent 0602, wherein X represents a suitable leaving group.
  • X is as defined in relation to the first aspect of the present invention.
  • a twelfth aspect of the present invention provides a process for the preparation of N- [(heptyloxy)carbonyl]cytarabine 7, comprising reaction of cytarabine 0701 with a carbonylation reagent 0702, wherein X represents a suitable leaving group.
  • X is as defined in relation to the first aspect of the present invention.
  • the present invention provides a simple, convenient one step method for the preparation of enantiomerically and chemically pure capecitabine 1.
  • the products obtained from the process of the present invention are surprisingly very pure without the need for cumbersome purification techniques.
  • the advantages of the present invention are the use of inexpensive, non-hazardous synthetic agents and a simple and convenient one step process which affords the resultant product with very high chemical and optical purity, whilst avoiding the multi-step processes disclosed in the prior art.
  • protecting groups adds two steps (protection and deprotection) to the chemical synthesis and hence the present invention is particularly advantageous for commercial production processes, as it avoids the expense of the extra steps involved and the expense of the reagents for adding the protecting groups.
  • the present invention provides a novel one step process with improved yields and time cycle, which is a simple, economical and commercially feasible process for the synthesis of capecitabine with commercially acceptable yields and high purity.
  • a preferred embodiment of the present invention is illustrated in Scheme 3.
  • the reagents and solvents illustrated in Scheme 3 are merely illustrative of the present invention and the reaction schemes are not limited by these reagents and solvents. Any suitable alternatives can be used and preferred alternatives are discussed below.
  • the inventors have found that the exocyclic nitrogen in the cytosine base of 0101 can be selectively pentyloxycarbonylated with specific reagents (represented by general structure 0302), without the need to protect the hydroxyl groups of compound 0101. After reaction work up, capecitabine can be isolated in very good yield and purity.
  • the crude product may be optionally purified further, but only a simple purification such as recrystallisation is required.
  • high quality capecitabine can be obtained directly in just one synthetic step from 5-fluoro-5'-deoxycytidine 0101.
  • reagents represented by general structure 0302 react with 5-fluoiO-5'-deoxycytidine 0101 in the presence or absence of a catalyst and under suitable reaction conditions to directly afford capecitabine.
  • X is not chloro.
  • the leaving group X in reagent 0302 is preferably selected from the following moieties:
  • any phenoxy group preferably with an electron withdrawing group on the aryl ring, e.g. 4-nitrophenoxy or pentafluorophenoxy
  • the reagent 0302 has a suitable leaving group X to carry out the selective reaction with 5- fluoro-5'-deoxycytidine 0101.
  • Particularly preferred leaving groups are selected from thiazolyl, hydroxyl-l,2,3-triazolyl, phenoxy and imidazolyl moieties or free radical leaving groups.
  • the procedure comprises the following steps:
  • the catalyst may be an organic base, such as pyridine or 4- dimethylaminopyridine, or a mineral acid, such as hydrochloric acid.
  • organic bases or commonly available acids can also be employed to catalyse the above transformation.
  • the pentyloxycarbonylation reaction is carried out in the presence of 0.5 to 2.5 molar equivalents of the pentyloxycarbonylation reagent with respect to 5-fluoro-5'- deoxycytidine 0101, more preferably 0.8 to 1.2 molar equivalents of the pentyloxycarbonylation reagent, more preferably 0.9 to 1.1 molar equivalents, and most preferably about 1 molar equivalent.
  • the reaction is carried out at a temperature of between about 20 to 140°C, more preferably between about 20 to 80°C, more preferably between about 20 to 50°C.
  • the preparation of reagents 0302 is typically carried out by reaction of X-H with a n-pentyl haloformate, such as n-pentyl chloroformate, optionally in the presence of a base.
  • a n-pentyl haloformate such as n-pentyl chloroformate
  • a preferred process for the preparation is outlined in Scheme 4, wherein Y can be halo, such as chloro, bromo or iodo, and X is as defined above.
  • the capecitabine 1 is preferably obtained in a yield of 70% or more, preferably 80% or more, preferably 90% or more, preferably 95% or more, from 5-fluoro-5'-deoxycytidine 0101.
  • the capecitabine 1 is obtained on a commercial scale, preferably in batches of lkg or more, 10kg or more, 100kg or more, 500kg or more, or 1000kg or more.
  • the capecitabine 1 is obtained substantially free of chemical impurities.
  • the capecitabine 1 is obtained substantially free of other optical isomers of capecitabine.
  • the process of the present invention can be easily adapted for the preparation of compounds, which are analogous to capecitabine 1, such as galocitabine 4, sapacitabine 5, 5'-deoxy-5-fluoiO-N-[(cyclohexyloxy)carbonyl]cytidine 6, and N-[(heptyloxy)carbonyl] cytarabine 7.
  • the pharmaceutical composition according to the fifth aspect of the present invention can be a solution or suspension form, but is preferably a solid oral dosage form.
  • Preferred dosage forms in accordance with the invention include tablets, capsules and the like which, optionally, may be coated if desired. Tablets can be prepared by conventional techniques, including direct compression, wet granulation and dry granulation. Capsules are generally formed from a gelatine material and can include a conventionally prepared granulate of excipients in accordance with the invention.
  • the pharmaceutical composition according to the present invention typically comprises one or more conventional pharmaceutically acceptable excipient(s) selected from the group comprising a filler, a binder, a disintegrant, a lubricant and optionally further comprises at least one excipient selected from colouring agents, adsorbents, surfactants, film-formers and plasticizers.
  • the pharmaceutical composition of the invention typically comprises one or more fillers such as microcrystalline cellulose, lactose, sugars, starches, modified starches, mannitol, sorbitol and other polyols, dextrin, dextran or maltodextrin; one or more binders such as lactose, starches, modified starch, maize starch, dextrin, dextran, maltodextrin, microcrystalline cellulose, sugars, polyethylene glycols, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxye hyl cellulose, methyl cellulose, carboxymethyl cellulose, gelatine, acacia gum, tragacanth, polyvinylpyrrolidone or crospovidone; one or more disintegrating agents such as croscarmellose sodium, cross- linked polyvinylpyrrolidone, crospovidone, cross-linked carboxymethyl starch, starches, micro
  • the pharmaceutical composition of the present invention may also include surfactants and other conventional excipients.
  • the coating may be prepared from at least one film-former such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose or methacrylate polymers which optionally may contain at least one plasticizer such as polyethylene glycols, dibutyl sebacate, diethyl citrate, and other pharmaceutical auxiliary substances conventional for film coatings, such as pigments, fillers and others.
  • film-former such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose or methacrylate polymers
  • plasticizer such as polyethylene glycols, dibutyl sebacate, diethyl citrate, and other pharmaceutical auxiliary substances conventional for film coatings, such as pigments, fillers and others.
  • Triethylamine (21.5 ml, 1.2 mol equivalent w.r.t. HOBt) and HOBt (20 g, 1 mol equivalent) were added to THF (100 ml) with stirring, and cooled to 0-5°C for 15 minutes.
  • n-Pentyl chloroformate (22.8 ml, 1.2 mol equivalent) was added dropwise over 30 minutes.
  • a thick white slurry was obtained and after stirring for 1 hour, the THF was removed by vacuum distillation.
  • Water (200 ml) and ethyl acetate (200 ml) were added to the residue. After stirring vigorously for 10 minutes, the organic layer was separated and the aqueous layer was further extracted with ethyl acetate (100 ml).
  • the combined organic layers were removed under vacuum distillation and the residue was treated with hexane (100 ml), followed by stirring at 25- 30°C for 30 minutes, to afford a free flowing white solid which was isolated by filtration.
  • Aromatic protons 8.16 ppm to 7.61 ppm (4 protons)
  • Aromatic protons 8.14 ppm to 7.07 ppm (3 protons)
  • 5-Fluoro-5'-deoxycytidine (3 g, 1 mol equivalent) was added to acetonitrile (60 ml) and stirred at 25-30°C for 15 minutes.
  • DCM HCl solution (5% w/w of HCl gas in DCM, 10 ml) was added and stirred for 30 minutes.
  • Pentyloxycarbonyl- imidazole (2.45 g, 1 mol equivalent) was added and the reaction mixture was heated at reflux for 5 hours. The solvent was removed under vacuum to afford a gummy residue.
  • Aromatic protons 8.34 ppm to 7.55 ppm (4 protons)
  • Pentafluorophenol (15 g, 1 mol equivalent) and potassium t-butoxide (9.1 g, 1 mol equivalent) were added to THF (50 ml) and the mixture was cooled to 0-5°C.
  • n-Pentyl chloroformate (12.3 ml, 1.2 mol equivalent) in THF (50 ml) was added dropwise over a period of 30 minutes.
  • water 100 ml
  • ethyl acetate 150 ml
  • the organic layer was separated, washed with 2.5% sodium bicarbonate solution and the organic solvent was removed under vacuum to afford an oily residue.
  • capecitabine 1 was dissolved in ethyl acetate (10 ml) and then cooled to 0-5°C to give capecitabine 1 as a white solid which was isolated by filtration and drying in a vacuum oven at 50-55°C for 8 hours.

Abstract

La présente invention concerne un procédé en une étape pour la préparation de la capécitabine et des analogues de celle-ci, tels que la galocitabine, la sapacitabine, la 5'-déoxy-5-fluoro-N- [(cyclohexyloxy)carbonyl]cytidine, et la N-[(heptyloxy)carbonyl]cytarabine.
PCT/GB2011/050351 2010-02-24 2011-02-23 Procédé en une étape pour la préparation de la capécitabine WO2011104540A1 (fr)

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