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Title:
ONE STEP PROCESS FOR THE PREPARATION OF CAPECITABINE
Document Type and Number:
WIPO Patent Application WO/2011/104540
Kind Code:
A1
Abstract:
The present invention relates a one step process for the preparation of capecitabine and analogues thereof, such as galocitabine, sapacitabine, 5'-deoxy-5-fiuoro-N- [(cyclohexyloxy)carbonyl]cytidine, and N-[(heptyloxy)carbonyl]cytarabine.

Inventors:
GORE VINAYAK GOVIND (IN)
PATKAR LAXMIKANT NARAHARI (IN)
BHALERAO RAHUL (IN)
HUBLIKAR MAHESH GORAKHNATH (IN)
POKHARKAR KIRAN SHIVAJI (IN)
Application Number:
PCT/GB2011/050351
Publication Date:
September 01, 2011
Filing Date:
February 23, 2011
Export Citation:
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Assignee:
GENERICS UK LTD (GB)
MYLAN INDIA PRIVATE LTD (IN)
GORE VINAYAK GOVIND (IN)
PATKAR LAXMIKANT NARAHARI (IN)
BHALERAO RAHUL (IN)
HUBLIKAR MAHESH GORAKHNATH (IN)
POKHARKAR KIRAN SHIVAJI (IN)
International Classes:
C07H19/067
Domestic Patent References:
WO2005063786A22005-07-14
WO2008145403A12008-12-04
WO2008144980A12008-12-04
WO2009094847A12009-08-06
WO2009082846A12009-07-09
WO2007009303A12007-01-25
WO2008131062A22008-10-30
Foreign References:
EP0602454A11994-06-22
DE2634053A11978-02-23
DE2535512A11976-02-19
US4260765A1981-04-07
EP1767526A12007-03-28
US4304770A1981-12-08
US5472949A1995-12-05
US5476932A1995-12-19
US20050137392A12005-06-23
US7365188B22008-04-29
US20080300399A12008-12-04
Other References:
SHIMMA N ET AL: "The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, capecitabine", BIOORGANIC & MEDICINAL CHEMISTRY, PERGAMON, GB, vol. 8, no. 7, 1 July 2000 (2000-07-01), pages 1697 - 1706, XP002615020, ISSN: 0968-0896, DOI: DOI:10.1016/S0968-0896(00)00087-0
HE XUEJUN ET AL: "Graphical synthetic routes of capecitabine", ZHONGGUO YIYAO GONGYE ZAZHI - CHINESE JOURNAL OF PHARMACEUTICALS, SHANGHAI YIYAO GONGYE YANJIUYUAN, SHANGHAI, CN, vol. 40, no. 7, 1 January 2009 (2009-01-01), pages 549 - 551, XP009146842, ISSN: 1001-8255
JEAN IGOLEN AND CHRISTOPHE MORIN: "Rapid Syntheses of Protected 2'-Deoxycytidine Derivatives", JOURNAL OF ORGANIC CHEMISTRY, vol. 45, 1980, pages 4802 - 4804, XP002631381
CLAUDIA MERK ET AL.: "The 2-Cyanoethyl and (2-Cyanoethoxy)carbonyl Group for Base Protection in Nucleoside and Nucleotide Chemistry", HELVETICA CHIMICA ACTA, vol. 83, 2000, pages 3198 - 3210, XP002631382
MICHAEL C. PIRRUNG ET AL.: "Inverse Phosphotriester DNA Synthesis Using Photochemically-Removable Dimethoxybenzoin Phosphate Protecting Groups", JOURNAL OF ORGANIC CHEMISTRY, vol. 61, 1996, pages 2129 - 2136, XP002631383
LEN F. LEE, ET AL.: "Synthesies and Reactions of 2-Halo-5-thiazolecarboxylates", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 22, 1985, pages 1621 - 1630, XP002631384
T.W. GREENE; P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE
Attorney, Agent or Firm:
ELEND, Almut et al. (Byron HouseCambridge Business Park,Cowley Road, Cambridge Cambridgeshire CB4 0WZ, GB)
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Claims:
Claims

1. A process for the preparation of capecitabine 1, comprising reaction of 5-fiuoro-5'- deoxycytidine 0101 with a pentyloxycarbonylation reagent.

2. A process according to claim 1 , comprising reacting 5-fluoro-5'-deoxycytidine 0101 with a pentyloxycarbonylation reagent represented by general formula 0302, wherein X represents a suitable leaving group:

3. A process according to claim 2, wherein 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.

4. A process according to claim 3, wherein X is selected from an optionally substituted imidazolyl derivative such as imidazolyl.

5. A process according to claim 3, wherein X is selected from an optionally substituted phenoxy derivative such as 4-nitrophenoxy or pentafluorophenoxy.

6. A process according to claim 3, wherein X is selected from an optionally substituted benzotriazolyl derivative such as 1-hydroxybenzotriazolyl.

7. A process according to claim 3, wherein X is selected from an optionally substituted aminothiazolyl derivative such as ethyl 2-aminothiazolyl-5-carboxylate derivative 0302a:

0302a

8. A process according to any one of claims 5 to 7, wherein the pentyloxycarbonylation reaction is carried out in the presence of a base.

9. A process according to claim 8, wherein the base is an organic base.

10. A process according to claim 9, wherein the organic base is selected from a ttiaUcylamine such as triethylarnine or cUisopropylemylamine, or an aromatic amine such as pyridine or 4-dimemylaminopyridine.

11. A process according to claim 4, wherein the pentyloxycarbonylation reaction is carried out in die presence of an acid.

12. A process according to claim 11, wherein the acid is a mineral acid such as hydrochloric acid.

13. A process according to any preceding claim, wherein the pentyloxycarbonylation reaction is carried out in the presence of an organic solvent.

14. A process according to claim 13, wherein the organic solvent is selected from THF or acetonitrile or mixtures thereof.

15. A process according to any preceding claim, wherein the pentyloxycarbonylation reaction is carried out in the presence of:

(i) 0.5 to 2.5 molar equivalents of the pentyloxycarbonylation reagent with respect to 5-fluoro-5'-deoxycytidine 0101; and/or

(ii) 0.8 to 1.2 molar equivalents of the pentyloxycarbonylation reagent with respect to 5-fluoro-5'-deoxycytidine 0101; and/or

(iii) 0.9 to 1.1 molar equivalents of the pentyloxycarbonylation reagent with respect to 5-fluoro-5'-deoxycytidine 0101; and/ or

(iv) about 1 molar equivalent of the pentyloxycarbonylation reagent with respect to 5- fluoro-5'-deoxycytidine 0101.

16. A process according to any preceding claim, wherein the capecitabine formed is further purified.

17. A process according to claim 16, wherein the capecitabine formed is recrystallised from ethyl acetate.

18. Capecitabine when prepared by a process according to any preceding claim.

19. Capecitabine substantially free of chemical impurities.

20. Capecitabine substantially free of other optical isomers of capecitabine.

21. Capecitabine according to any one of claims 18 to 20 for:

(i) use in medicine; and/ or

(ii) treating or preventing cancer; and/ or

(iii) treating or preventing metastatic breast or colorectal cancer.

22. A pharmaceutical composition comprising capecitabine according to any one of claims 18 to 21 and one or more pharmaceutically acceptable excipients.

23. A pharmaceutical composition according to claim 22 for:

(i) treating or preventing cancer; and/or

(ii) treating or preventing metastatic breast or colorectal cancer.

24. Use of capecitabine according to any one of claims 18 to 21 in the manufacture of a medicament for treating or preventing cancer.

25. A use according to claim 24, wherein the cancer is metastatic breast or colorectal cancer.

26. 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 any one of claims 18 to 21 or a therapeutically or prophylactically effective amount of the pharmaceutical composition according to claim 22 or 23.

27. A method according to claim 26, wherein the cancer is metastatic breast or colorectal cancer.

28. A method according to claim 26 or 27, wherein the patient is a mammal such as a human.

29. 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:

30. A reagent according to claim 29, wherein X is selected from an optionally substituted imidazolyl derivative such as imidazolyl.

31. A reagent according to claim 29, wherein X is selected from an optionally substituted phenoxy derivative such as 4-nitrophenoxy or pentafluorophenoxy.

32. A reagent according to claim 29, wherein X is selected from an optionally substituted benzotriazolyl derivative such as 1 -hydroxybenzotriazolyl.

33. A reagent according to claim 29, wherein X is selected from an optionally substituted aminothiazolyl derivative such as ethyl 2-aminothiazolyl-5-carboxylate derivative 0302a:

0302a

34. A process for the preparation of galocitabine 4, comprising reaction of 5-fiuoro-5'- deoxycytidine 0101 with a carbonylation reagent 0402, wherein X represents a suitable leaving group:

35. 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:

36. A process for the preparation of 5'-deoxy-5-fluoro-N-[(cyclohexyloxy) carbonyljcytidine 6, comprising reaction of 5-fiuoro-5'-deoxycytidine 0101 with a carbonylation reagent 0602, wherein Xrepresents a suitable leaving group:

37. 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:

Description:
ONE STEP PROCESS FOR THE PREPARATION OF CAPECITABINE

Field of the invention

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.

Background of the invention

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.

There are several processes disclosed in the prior art for the preparation of capecitabine. These multi-step processes are mainly based on two approaches, with different protecting group strategies, as illustrated in Scheme 1 and Scheme 2.

In the first approach, outlined in Scheme 1, commercially available 5-fluoro-5'- deoxycytidine 0101 is subjected to hydroxyl function protection, followed by coupling of the protected derivative 0102 with n-pentyl chloroformate to afford intermediate 0103. Removal of the protecting group "PG" affords capecitabine.

Scheme 1

In the second approach, outlined in Scheme 2, the hydroxyl groups of 5-deoxyribose are protected with a protecting group "PG" to afford intermediate 0201. This intermediate is then coupled with cytosine derivative 0202 to afford protected intermediate 0102 (A = H) and the rest of the steps are similar to those in Scheme 1 to afford capecitabine. Alternatively, if A is pentyloxycarbonyl in intermediate 0202, intermediate 0102 can be subjected to suitable deprotection conditions to afford capecitabine.

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. 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. After introduction of the pentyloxycarbonyl group, intermediate 0103 is subjected to hydrolysis to remove the acyl protecting groups to afford capecitabine. However, 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. Starting with commercially available 5-fluoro-5'-deoxycytidine 0101, 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.

An alternative process, based on the approach depicted in Scheme 2, is disclosed in US 2005/0137392, US 7365188 and WO 2005/063786. This process is based on protection of 5-deoxyribose with acyl protecting groups to form intermediate 0201. This intermediate is then coupled with 5-fluorocytosine 0202 in the presence of hexamethyldisilazane and sodium iodide to form intermediate 0102. This intermediate is then reacted with n-pentyl chloroformate to afford intermediate 0103 and subsequent removal of the acyl protection with sodium hydroxide solution affords capecitabine.

A slight variation of the Scheme 2 approach is described in US 2008/0300399 and WO 2008/145403, wherein stannous chloride is used for the coupling of intermediates 0201 and 0202. The remainder of the reaction sequence to prepare capecitabine is the same as in Scheme 1.

Further variations of 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.

However, the above processes suffer from certain drawbacks such as: toxic solvents or reagents are used; column chromatography, which is unsuitable for large scale production, is required as the intermediates are not crystalline; relatively expensive protecting groups such as 2,2-dimethoxypropane or triethyl orfhoformate are required; and/ or the processes afford capecitabine in low to moderate overall yields.

In addition, the above processes suffer from the major disadvantage that all of them involve protection of the hydroxyl groups on the cytidine derivative and subsequent deprotection after the introduction of the pentyloxycarbonyl group. The protection- deprotection sequence adds two extra steps in the process, reducing the overall yield and increasing the time and cost of the process from a commercial production point of view.

In addition, the purification procedures disclosed in the prior art processes are difficult and time consuming and do not afford very pure product, particularly for commercial scale production.

In view of the above disadvantages associated with the prior art and of the importance of capecitabine in the treatment of cancer, there is a great need to develop an improved process for the preparation of highly pure capecitabine which does not involve multiple steps, uses relatively inexpensive reagents and further eliminates the need for cumbersome purification techniques. In addition, the improved process must be economical, high yielding and provide capecitabine with a high degree of chemical and optical purity.

Summary of the invention

The difficulties encountered in the prior art for the preparation of capecitabine 1 have been successfully overcome in the present invention. The term "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.

The term "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.

The term "sapacitabine" as used herein throughout the description and claims means sapacitabine and/or any salt, solvate, hydrate, tautomer or polymorphic form thereof, unless otherwise specified.

The term "5'-deoxy-5-fluoro-N-[(cyclohexyloxy)carbonyl]cytidine" as used herein throughout the description and claims means 5'-deoxy-5-fluoro-N-[(cyclohexyloxy) carbonyljcytidine and/or any salt, solvate, hydrate, tautomer or polymorphic form thereof, unless otherwise specified.

The term "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.

For the purposes of the present invention, 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.

For the purposes of the present invention, 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. For the purposes of the present invention, 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'-P(R 2 ) 2 , -R'-SiCR 2 ),, -R'-CO-R 2 , -R'-CO-OR 2 , -R'O-CO-R 2 , -R'-CO-N(R 2 ) 2 , -R'-NR -CO-R 2 , -R'O-CO-OR 2 , -R'O-CO-N R 2 ),, -R'-NR^CO-OR 2 , -R'-NR'-CO-N^ 2 )^ -R'-CS-R 2 , -R'-CS-OR 2 , -R ! 0-CS-R 2 , -R^CS-N R 2 ),, -R'-NR'-CS-R 2 , -R'O-CS-OR 2 , -R'0-CS-N(R 2 ) 2 , -R'-NR'-CS-OR 2 , -R'-NR'-CS-N^ 2 ), or -R 2 . In this context, -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). Preferably 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).

Accordingly, in a first aspect, 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.

Preferably, in the process according to the first aspect of the present invention, the pentyloxycarbonylation reagent is represented by general formula 0302, wherein X represents a suitable leaving group:

Preferably, 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. Preferably, 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. Preferably, X is not chloro.

Preferably, X is selected from an optionally substituted imidazolyl derivative and more preferably is imidazolyl.

Preferably, X is selected from an optionally substituted phenoxy derivative, such as 4- nitrophenoxy or pentafluorophenoxy.

Preferably, X is selected from an optionally substituted benzotriazolyl derivative, which more preferably is 1-hydroxybenzotriazolyl.

Preferably, 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.

0302a

Preferably, the pentyloxycarbonylation reaction is carried out in the presence of a base or an acid.

Preferably, 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.

Preferably, the acid is a mineral acid, which more preferably is hydrochloric acid. Preferably, the pentyloxycarbonylation reaction is carried out in the presence of an organic solvent, which is preferably selected from THF or acetonitrile or mixtures thereof.

Preferably, 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.

Preferably, in the process according to the first aspect of the present invention, 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.

Preferably, 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. Preferably, 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. Preferably the cancer is metastatic breast or colorectal cancer. Preferably 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.

Preferably, X is selected from an optionally substituted imidazolyl derivative, more preferably imidazolyl. Preferably, X is selected from an optionally substituted phenoxy derivative, more preferably 4-nitrophenoxy or pentafluorophenoxy. Preferably, X is selected from an optionally substituted benzotriazolyl derivative, more preferably 1- hydroxybenzotriazolyl. Preferably, 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.

Therefore 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. Preferably 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. Preferably 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. Preferably 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. Preferably X is as defined in relation to the first aspect of the present invention.

Detailed description of the 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.

The inventors found that attempts to prepare capecitabine directly in a one step process by reacting unprotected 5-fluoro-5'-deoxycytidine with typical pentyloxycarbonylation reagents, such n-pentyl chloroformate, were non selective. These reactions did afford the desired capecitabine, but only in low yield and in a complex mixture with several acylated products including N-acylated and/ or O-acylated products which were either tri-acylated, di-acylated (either di-O-acylated or a mixture of N-acylated and O-acylated) or mono-O- acylated. This mixture was very difficult to separate and the composition of the product mixture varied with different reaction conditions. Consequently, it was completely unacceptable as a process to prepare capecitabine.

However, the inventors surprisingly found that certain pentyloxycarbonylation reagents can be used to selectively form capecitabine from unprotected 5-fluoro-5'-deoxycytidine (i.e. without the need for protecting groups to protect the hydroxyl groups of the 5-fluoro-5'- deoxycytidine). It is very surprising that the reaction is so selective and affords capecitabine in such high yield and purity. The reagents themselves are novel and are surprisingly very useful for this type of reaction.

The use of 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.

Therefore 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.

Scheme 3

Thus, in the process of the present invention, high quality capecitabine can be obtained directly in just one synthetic step from 5-fluoro-5'-deoxycytidine 0101.

The 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. Preferably, in reagent 0302, X is not chloro. The leaving group X in reagent 0302 is preferably selected from the following moieties:

(a) any imidazolyl moiety, e.g. 1 ,3-imidazolyl

(b) any hydroxyl-l,2,3-triazolyl moiety, e.g. l-hydroxybenzotriazolyl

(c) any phenoxy group, preferably with an electron withdrawing group on the aryl ring, e.g. 4-nitrophenoxy or pentafluorophenoxy

(d) any thiazolyl moiety, particularly arninothiazolyl or hydroxyl-thiazolyl

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.

In a preferred embodiment, the procedure comprises the following steps:

(1) dissolving or suspending 0101 in an organic solvent;

(2) addition of reagent 0302 to the reaction mixture;

(3) optionally adding catalyst to the above solution or suspension and heating at a temperature between 0 to 110°C;

(4) isolating the product by a suitable work up procedure;

(5) optional (re)crystallization of product (capecitabine) from a suitable solvent system.

In step (3) above, the catalyst may be an organic base, such as pyridine or 4- dimethylaminopyridine, or a mineral acid, such as hydrochloric acid. However, other organic bases or commonly available acids can also be employed to catalyse the above transformation.

Preferably, 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.

Preferably, 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 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.

Scheme 4

In the process of the present invention, 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.

Preferably, 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.

Preferably, the capecitabine 1 is obtained substantially free of chemical impurities.

Preferably, 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. As described above, 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, microcrystalline cellulose or polyacrylin potassium; one or more different glidants or lubricants such as magnesium stearate, calcium stearate, zinc stearate, calcium behenate, sodium stearyl fumarate, talc, magnesium trisilicate, stearic acid, palmitic acid, carnauba wax or silicon dioxide.

If required, the pharmaceutical composition of the present invention may also include surfactants and other conventional excipients.

If the solid pharmaceutical formulation is in the form of coated tablets, 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.

Experimental details of preferred examples of the invention are given below. Examples

Example 1

(a) Preparation of pentyloxycarbonyl-l-hydroxybenzotriazole (0302, X = -OBt)

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.

Yield = 31.18 g (84%)

lH NMR [300 MHz]

Aromatic protons = 8.16 ppm to 7.61 ppm (4 protons)

CH 2 -0 proton = 4.50 ppm to 4.48 ppm (2 protons)

CH 2 proton = 1.84 ppm to 1.36 ppm (6 protons)

CH j proton = 0.93 ppm to 0.89 ppm (3 protons)

(b) Preparation of capecitabine 1 by reaction of 5-fluoro-5'-deoxycytidine (0101) with pentyloxycarbonyl-l-hydroxybenzottiazole (0302, X = -OBt)

5-Fluoro-5'-deoxycytidine (5 g, 1 mol equivalent) and pentyloxycarbonyl-1- hydroxybenzotriazole (0302, X = -OBt, 5.45 g, 1 mol equivalent) were added to THF (100 ml, 20 vol) and stirred at 25-30°C for 15 minutes. The reaction mixture was heated to reflux for 9-10 hours before the solvent was removed by vacuum distillation. Water (100 ml) was added to the residue followed by the addition of ethyl acetate (150 ml). After stirring for 15 minutes, the organic layer was separated and washed with sodium bicarbonate solution (100 ml, 2.5 w/w). The solvent was removed under vacuum cUstillation from the organic layer to afford a gummy residue. The residue was dissolved in ethyl acetate (5 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.

Yield = 4.8 g (66%)

Specific Optical Rotation: [oc] 20 D = +96.93° (c = lOmg/ml, MeOH)

[which is within the USP 32 range of [o ] 20 D = +96.0° to +100.0° (c = lOmg/ml, MeOH)]

HPLC: RT matches with USP standard

HPLC Purity = 98.8% Example 2

(a) Preparation of pentyloxycarbonyl-imidazole (0302, X = imidazolyl)

Imidazole (5 g, 1 mol equivalent) was added to THF (50 ml) and the mixture was cooled to 0-5°C before n-pentyl chloroformate (5.5 g, 0.5 mol equivalent) in THF (10 ml) was added dropwise over a period of 15 minutes. After stirring for 1 hour, water (100 ml) and ethyl acetate (100 ml) were added and the mixture stirred vigo ously for 0 minutes. The organic layer was separated and the solvent removed by vacuum distillation to afford an oily residue.

Yield = 4.7 g (70%)

*H NMR [300 MHz] (CDC1 3 solvent)

Aromatic protons = 8.14 ppm to 7.07 ppm (3 protons)

CH 2 -0 proton = 4.43 ppm to 4.39 ppm (2 protons)

CH 2 proton = 1.82 ppm to 1.35 ppm (6 protons)

CH 3 proton = 0.96 ppm to 0.88 ppm (3 protons)

(b) Preparation of capecitabine 1 by reaction of 5-fluoro-5'-deoxycytidine (0101) with pentyloxycarbonyl-imidazole (0302, X = imidazolyl)

5-Fluoro-5'-deoxycytidine (3 g, 1 mol equivalent) was added to acetonitrile (60 ml) and stirred at 25-30°C for 15 minutes. To the stirring suspension, 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. Ethyl acetate (10 ml) was added to the residue and stirred vigorously before the organic layer was decanted and then cooled to 0-5°C for 30 minutes to afford capecitabine 1 as a white solid which was isolated by filtration and drying in a vacuum oven at 50-55°C for 8 hours.

Yield = 2.1 g (50%)

Specific Optical Rotation: within the USP 32 range of [oc] 20 D = +96.0° to +100.0° (c = lOmg/ml, MeOH)]

HPLC: RT matches with USP standard

HPLC Purity = 99.20% Example 3

(a) Preparation of pentyloxycarbonyl-4-nitrophenoxy (0302, X = -O-4-nitrophenyl)

4- Nitrophenol (5 g, 1 mol equivalent) and tiiethylamine (5 ml, 1 mol equivalent) were added to THF (50 ml) and cooled to 0-5°C. n-Pentyl chloroformate (6.2 ml, 1.2 mol equivalent) in THF (50 ml) was added dropwise over a period of 30 minutes. After stirring for 2 hours, water (100 ml) was added followed by the addition of ethyl acetate (150 ml) and stirred vigorously for 10 minutes. The organic layer was separated and washed with 2.5% sodium bicarbonate solution. The organic solvent was removed under vacuum to afford an oily residue.

Yield = 8.1 g (89%)

'H NMR [300 MHz]

Aromatic protons = 8.34 ppm to 7.55 ppm (4 protons)

CH 2 -0 proton = 4.26 ppm to 4.19 ppm (2 protons)

CH 2 proton = 1.71 ppm to 1.64 ppm (6 protons)

CH 3 proton = 0.91 ppm to 0.84 ppm (3 protons)

(b) Preparation of capecitabine 1 by reaction of 5-fluoro-5'-deoxycytidine (0101) with pentyloxycarbonyl-4-nitrophenoxy (0302, X = -O-4-nitrophenyl)

5- Fluoro-5'-deoxycytidine (3 g, 1 mol equivalent) was added to THF (60 ml) before pentyloxycarbonyl-4-nitrophenoxy (3.1 g, 1 mol equivalent) and pyridine (0.9 ml, 1 mol equivalent) were added. The reaction mixture was heated to reflux for 9-10 hours before the solvent was removed by vacuum distillation. Water (100 ml) was added to the residue followed by addition of ethyl acetate (150 ml). After stirring for 15 minutes, the organic layer was separated and washed with sodium bicarbonate solution (100 ml, 2.5 w/w). The solvent was removed under vacuum distillation from the organic layer to afford a gummy residue, which 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.

Yield = 2.4 g (55%)

Specific Optical Rotation: within the USP 32 range of [oc] 0 D = +96.0° to +100.0° (c = lOmg/ml, MeOH)]

HPLC: RT matches with USP standard HPLC Purity = 99.2% Example 4

(a) Preparation of pentyloxycarbonyl-pentafluorophenoxy (0302, X = -O- pentafluorophenyl)

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. After stirring for 2 hours, water (100 ml) was added followed by the addition of ethyl acetate (150 ml) and stirred vigorously for 10 minutes. 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.

Yield = 22.8 g (94%)

(b) Preparation of capecitabine 1 by reaction of 5-fluoro-5'-deoxycytidine (0101) with pentyloxycarbonyl-pentafiuorophenoxy (0302, X = -O-pentafiuorophenyl)

5-Fluoro~5'-deoxycytidine (4 g, 1 mol equivalent) was added to THF (80 ml) before pentyloxycarbonyl-pentafluorophenoxy (9.7 g, 2.5 mol equivalent) and pyridine (1.3 ml, 1 mol equivalent) were added. The reaction mixture was heated to reflux for 9-10 hours before the solvent was removed by vacuum distillation. Water (100 ml) was added to the residue followed by addition of ethyl acetate (150 ml). After stirring for 15 minutes, the organic layer was separated and washed with sodium bicarbonate solution (100 ml, 2.5 w/w). The solvent was removed under vacuum distillation to afford a gummy residue. The residue 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.

Yield = 3.9 g (67%)

Specific Optical Rotation: within the USP 32 range of [oc] 20 D = +96.0° to +100.0° (c = lOmg/ml, MeOH)]

HPLC: RT matches with USP standard

HPLC Purity = 99.10% It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.