WO2011067588A1

WO2011067588A1 - Cyclic sulphinyl esters of cytidine

Info

Publication number: WO2011067588A1
Application number: PCT/GB2010/051994
Authority: WO
Inventors: Vinayak Govind Gore; Laxmikant Patkar; Amit Bagul; Mahesh Edake
Original assignee: Generics [Uk] Limited; Mylan India Private Limited
Priority date: 2009-12-04
Filing date: 2010-11-30
Publication date: 2011-06-09

Abstract

The present invention relates to novel intermediates and to an improved process for the preparation of N- functionalised cytidine derivatives such as capecitabine, galocitabine and sapacitabine. Said intermediates are se from a copound of formula (A- 2), (A-3), (A-6), (A-7). wherein: R¹ and R³ arc each independendy selected from hydrogen, -F, -CI, -Br, -I, -CN, -NO₂, -N₃, -O-R⁷, -S-R⁷, -N(R⁷)₂, -N(R⁷)₃+ or -0-Si(R⁷)₃; R⁴ and R⁵ arc each independendy selected from hydrogen, -F, -CI, -Br and -I; R⁶ is selected from an alkyl, alkenyl, alkynyl, atyl, aiylalkyl, arylalkenyl, arylalkynyl, alkylaiyl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton; and each R⁷ is independendy selected from hydrogen, or an alkyl, alkenyl, alkynyl, atyl, aiylalkyl, arylalkenyl, arylalkynyl, alkylaiyl, alkenylaryl or alkynylaryl group, each of which may optionally he substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton, and wherein any two or more R⁷ groups may, together with rhe atom or atoms to which they are attached, form a cyclic alkyl, alkenyl, alkynyl, aryl, aiylalkyl, arylalkcnyl, arylalkynyl, alkylaiyl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton.

Description

CYCLIC SULPHINYL ESTERS OF CYTIDINE

Field of the invention

The present invention relates to novel intermediates and to an improved process for the preparation of N-functionalised cytidine derivatives such as capecitabine, galocitabine and sapacitabine.

Background of the invention

Capecitabine, represented by structural formula (1) and chemically named as 5'-deoxy-5- fluoro-N-[(pentyloxy)carbonyl]cytidine, is an anti-neoplastic agent and it is currently marketed as an orally administered chemotherapeutic agent used in the treatment of metastatic breast and colorectal cancers.

Other recently developed N-functionalised cytidine derivatives include galocitabine (2) and sapacitabine (3).

There are several processes disclosed in the prior art for the preparation of capecitabine. These processes are mainly based on the two approaches 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 chloro formate to afford intermediate (0103). Removal of the protecting group "PG" affords capecitabine (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 (1). Alternatively, if in intermediate (0202) A is pentyloxycarbonyl, intermediate (0102) subjected directly to suitable deprotection conditions to afford capecitabine (1).

Scheme 2

US 5,472,949 discloses a syndietic route, as depicted in Scheme 1, wherein the protecting groups "PG" are acyl groups, such as acetyl or benzoyl, or a silyl group, such as trimethylsilyl or tert-butyldimethylsilyl. Acylation of the hydroxyl groups is achieved by reaction of 5-fluoro-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 (1). However, this process requires purification by column chromatography at two stages.

US 5,476,932 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 (1). An alternative process, based on the approach depicted in Scheme 2, is disclosed in US 2005/0137392, US 7,365,188 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 (1).

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 (1) is the same as in Scheme 2.

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 (e.g. pyridine) or reagents (e.g. stannous chloride) 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 orthoformate are required; and/ or the processes afford capecitabine (1) in low to moderate overall yields.

In general, the purification procedures disclosed in the prior art processes were difficult and time consuming and did 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 (1) in the treatment of cancer, there is a great need to develop an improved process for the preparation of highly pure N-functionalised cytidine derivatives such as capecitabine (1), 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 N-functionalised cytidine derivatives such as capecitabine (1) with a high degree of chemical and optical purity.

Summary of the invention

The difficulties encountered in the prior art for the preparation of N-functionalised cytidine derivatives such as 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, polymorphic form, isomer, diastereomer or enantiomer thereof, unless otherwise specified.

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

For the purposes of the present invention, an N-functionalised cytidine derivative such as capecitabine, galocitabine or sapacitabine 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%. Similarly, intermediates such as (A-2), (A-3), (A-6), (A-7), (0402), (0502), (0503), (0301) and (0302) are "substantially free" of chemical impurities, if they comprise less than 3% impurity, preferably less than 2%, preferably less than 1%, preferably less than 0.5%, preferably less than 0.1%.

For the purposes of the present invention, an N-functionalised cytidine derivative such as capecitabine, galocitabine or sapacitabine is "substantially enantiomerically pure", if it comprises less than 3% of other isomers, preferably less than 2%, preferably less than 1%, preferably less than 0.5%, preferably less than 0.1% (as measured by specific optical rotation). Similarly, intermediates such as (A-2), (A-3), (A-6), (A-7), (0402), (0502), (0503), (0301) and (0302) are "substantially enantiomerically pure", if they comprise less than 3% of other isomers, preferably less than 2%, preferably less than 1%, preferably less than 0.5%, preferably less than 0.1% (as measured by specific optical rotation).

The present invention provides an efficient and economical synthesis of novel, crystalline intermediates, which are purified to a high state of purity and which can readily be converted to highly pure N-functionalised cytidine derivatives such as capecitabine (1) with minimal purification steps. The process of the present invention is high yielding and affords N-functionalised cytidine derivatives such as capecitabine (1) with very high chemical and optical purity on a commercial scale, without the need for cumbersome purification techniques.

Accordingly, in a first aspect, the present invention provides a process for the preparation of an N-functionalised cytidine derivative such as capecitabine, galocitabine or sapacitabine, comprising the use of a cyclic sulphonyl ester. In one embodiment of the first aspect of the present invention, the N-functionalised cytidine derivative is a com ound of formula (A):

or a salt, solvate, hydrate or tautomer thereof, wherein:

R¹, R² and R³ are each independently selected from hydrogen, -F, -CI, -Br, -I, -CN, -N0₂, -N₃, -O-R⁷, -S-R⁷, -N(R⁷)₂, -N(R⁷)₃ ⁺ or -0-Si(R⁷)₃;

R⁴ and R⁵ are each independentiy selected from hydrogen, -F, -CI, -Br and -I;

R⁶ is selected from an alkyl, alkenyl, alkynyl, aiyl, aiylalkyl, aiylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton; and

each R⁷ is independently selected from hydrogen, or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton, and wherein any two or more R⁷ groups may, together with the atom or atoms to which they are attached, form a cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton.

For the purposes of the present invention, an "alkyl" group is defined as a monovalent saturated hydrocarbon, which may be straight-chained or branched, or be or include cyclic groups. An alkyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of alkyl groups are methyl, ethyl, //-propyl, /-propyl, //-butyl, /- butyl, /-butyl and //-pentyl groups. Preferably an alkyl group is straight-chained or branched and does not include any heteroatoms in its carbon skeleton. Preferably an alkyl group is a C₁-C₁₂ alkyl group, more preferably an alkyl group is a C_1-C₆ alkyl group. An "alkylene" group is similarly defined as a divalent alkyl group.

An "alkenyl" group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon double bond, which may be straight-chained or branched, or be or include cyclic groups. An alkenyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of alkenyl groups are vinyl, allyl, but-l-enyl and but-2-enyl groups. Preferably an alkenyl group is straight-chained or branched and does not include any heteroatoms in its carbon skeleton. Preferably an alkenyl group is a C₂-C₁₂ alkenyl group, more preferably an alkenyl group is a C₂-C₆ alkenyl group. An "alkenylene" group is similarly defined as a divalent alkenyl group. An "alkynyl" group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon triple bond, which may be straight-chained or branched, or be or include cyclic groups. An alkynyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of alkynyl groups are ethynyl, propargyl, but-l-ynyl and but-2-ynyl groups. Preferably an alkynyl group is straight-chained or branched and does not include any heteroatoms in its carbon skeleton. Preferably an alkynyl group is a C₂-C₁₂ alkynyl group, more preferably an alkynyl group is a C₂-Q alkynyl group. An "alkynylene" group is similarly defined as a divalent alkynyl group.

An "aryl" group is defined as a monovalent aromatic hydrocarbon. An aryl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of aryl groups are phenyl, naphthyl, anthracenyl and phenanfhrenyl groups. Preferably an aryl group does not include any heteroatoms in its carbon skeleton. Preferably an aryl group is a C₄-C₁₄ aryl group, more preferably an aryl group is a Q-Qo aryl group. An "arylene" group is similarly defined as a divalent aryl group.

For the purposes of the present invention, where a combination of groups is referred to as one moiety, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule. A typical example of an arylalkyl group is benzyl.

For the purposes of this invention, an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, alkynylaryl or hydrocarbyl group may be substituted with one or more of -F, -CI, -Br, -I, -CF₃, -CC1₃, -CBr₃, -CI₃, -OH, -SH, -NH₂, -CN, -N0₂, -N₃, -COOH, -R'-O-R^ -R"-S-R^p, -R^«-SO-R^p, -R^a-S0₂-R^p, -R^a-S0₂-OR^p, -RO-S0₂-R^p, -R^a-S0₂-N(R^β)₂, -R"-NR^p-S0₂-R^p, -RO-S0₂-OR^p, -RO-S0₂-N(R^p)₂, -R^a-NR^l5-S0₂-OR^p, -R^a-NR^p-S0₂-N(R^p)₂, -R^a-N(R^P)₂, -R^a-N(R^P)₃ ⁺, -R^a-P(R^P)₂, -R^a-Si(R^p)₃, -R"-CO-R^p, -R^a-CO-OR^p, -RO-CO-R^p, -R^a-CO-N(R^p)₂, -R^H-NR^p-CO-R^p, -RO-CO-OR^p, -RO-CO-N(R^p)₂, -R^a-NR^p-CO-OR^p, -R^a-NR^p-CO-N(R^p)₂₎ -R^a-CS-R^p, -R^a-CS-OR^p, -RO-CS-R^P, -R^a-CS-N(R^p)₂, -R^a-NR^p-CS-R^p, -RO-CS-OR^p, -RO-CS-N(R , -R^a-NR^p-CS-OR^p, -R^a-NR^?-CS-N(R , -R^p, a bridging substituent such as -0-, -S-, -NR^P- or -R"-, or a π-bonded substituent such as =0, =S or =NR^P. In this context, -R^a- is independently a chemical bond, a C₁-C₁₀ alkylene, C,-C₁₀ alkenylene or C_rC₁₀ alkj^nylene group. -R¹³ is independently hydrogen, unsubstituted C ~C₆ allcyl or unsubstituted C₆-C₁₀ aryl. Optional substituent(s) are preferably taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituent(s). Preferably an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group is not substituted with a bridging substituent. Preferably an optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group is not substituted with a π- bonded substituent. Preferably a substituted group comprises 1, 2 or 3 substituents, more preferably 1 or 2 substituents, and even more 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, 4^th edition, 2006).

Preferably R¹ is hydrogen, -O-R⁷ or -0-Si(R⁷)₃. More preferably R¹ is hydrogen or -OH. Most preferably R¹ is hydrogen. Preferably R² is -O-R⁷ or -0-Si(R⁷)₃. More preferably R² is -OH.

Preferably R³ is -CN, -O-R⁷ or -0-Si(R⁷)₃. More preferably R³ is -CN or -OH. Most preferably R³ is -OH. Preferably R⁴ and R⁵ are each independently selected from hydrogen or -F. Preferably R⁴ is hydrogen and R⁵ is -F. Alternatively, both R⁴ and R⁵ may be hydrogen.

In one embodiment of the first aspect of the present invention, R⁶ contains from 1 to 30 carbon atoms. Preferably R⁶ contains from 3 to 20 carbon atoms. More preferably R⁶ contains from 4 to 16 carbon atoms.

Preferably R⁶ is an -O-alkyl, -alkyl or -aryl group, each of which may optionally be substituted. Most preferably, R⁶ is selected from a -0-C₅H_n, -C₁₅H₃₁, or 3,4,5-trimethoxyphenyl group.

Preferably each R⁷ is hydrogen. In one embodiment of the fkst aspect of the present invention, at least two of R¹, R² and R³ are -O-R⁷ or -0-Si(R⁷)₃. Preferably at least two of R¹, R² and R³ are -OH.

In another embodiment of the first aspect of the present invention, the N-functionalised cytidine derivative is a com ound of formula (B):

or a salt, solvate, hydrate or tautomer thereof, wherein R¹, R², R³, R⁴, R⁵ and R⁶ are defined above.

In yet another embodiment of the first aspect of the present invention, the functionalised cytidine derivative is a com ound of formula (C):

In still another embodiment of the first aspect of the present invention, the functionalised cytidine derivative is a com ound of formula (D):

or a salt, solvate, hydrate or tautomer thereof, wherein R¹, R², R³, R⁴, R⁵ and R⁶ defined above. In one embodiment of the fitst aspect of the present invention, the cyclic sulphinyl ester protects hydroxyl groups at the -R² and -R³ positions, such that in the cyclic sulphinyl ester -R² and -R³ together form the group -0-SO-0-. Preferably, in such a scenario, die hydroxyl groups at the -R² and -R³ positions are cis-.

In another embodiment of the first aspect of the present invention, the cyclic sulphinyl ester protects hydroxyl groups at the -R¹ and -R² positions, such that in the cyclic sulphinyl ester -R¹ and -R² together form the group -0-SO-0-. In one embodiment of the first aspect of the present invention, the cyclic sulphinyl ester is a compound of formula (A), (B), (C) or (D) as defined above, except that the -NH-CO-R⁶ group is instead a -NH₂ group, or a salt, solvate, hydrate or tautomer thereof, wherein -R¹ and -R², or -R² and -R³ together form the group -0-SO-0-. In another embodiment of the first aspect of the present invention, the cyclic sulphinyl ester is selected from a compound of formula (A-2), (A-3), (A-6), (A-7), and any salt, tautomer, solvate or hydrate thereof.

More preferably the cyclic sulphinyl ester is selected from intermediate (0301), intermediate (0302), and any salt, tautomer, solvate or hydrate tihereof. Most preferably the process of the first aspect of the present invention comprises the use of both, intermediate (0301) or a salt, tautomer, solvate or hydrate thereof, and intermediate (0302) or a salt, tautomer, solvate or hydrate thereof. Alternately the cyclic sulphinyl ester may be selected from intermediate (0301), intermediate (0402), and any salt, tautomer, solvate or hydrate thereof. Preferably such a process of the first aspect of the present invention comprises the use of both, intermediate (0301) or a salt, tautomer, solvate or hydrate thereof, and intermediate (0402) or a salt, tautomer, solvate or hydrate thereof.

Alternately still the cyclic sulphinyl ester may be selected from intermediate (0502), intermediate (0503), and any salt, tautomer, solvate or hydrate thereof. Preferably such a process of the first aspect of the present invention comprises the use of both, intermediate (0502) or a salt, tautomer, solvate or hydrate thereof, and intermediate (0503) or a salt, tautomer, solvate or hydrate thereof.

In a first preferred embodiment of the first aspect of the present invention, the process comprises one or more of the following steps:

(i) converting starting material (A-l) or a salt, tautomer, solvate or hydrate thereof, to cyclic sulfinyl ester (A-2) or a salt, tautomer, solvate or hydrate thereof:

(ii) converting cyclic sulfinyl ester (A-2) or a salt, tautomer, solvate or hydrate thereof, to c clic sulfinyl ester (A-3) or a salt, tautomer, solvate or hydrate thereof:

(iii) deprotection of cyclic sulfinyl ester (A-3) or a salt, tautomer, solvate or hydrate thereof, to obtain the N-functionalised cytidine derivative (A-4) or a salt, tautomer, solvate or h drate thereof:

wherein R , R , R and R' are as defined above. Preferably the process comprises two or more of steps (i) to (iii). For instance, the process may comprise at least steps (i) and (ii), or at least steps (ii) and (iii). More preferably the process comprises all three of steps (i) to (iii). Optionally, compounds (A-1), (A-2), (A-3) and (A-4) possess the same stereochemistry as compound (B) above. Preferably compounds (A-1), (A-2), (A-3) and (A-4) possess the same stereochemistry as compound (C) above.

Preferably, step (i) comprises treating starting material (A-1) with a reagent represented by general formula SOX₂, optionally in the presence of a base, wherein each X independently represents a suitable leaving group. Preferably each X is the same. Optionally, each X may independently be selected from a halogen, such as -CI, -Br or -I, or an imidazolyl group. Preferably, SOX₂ is selected from thionyl chloride, thionyl bromide and sulfinyl diimidazole, and most preferably SOX₂ is thionyl chloride.

The base used in step (i) of die first preferred embodiment of the first aspect of the present invention may be an organic base or ammonia. Preferably the base in step (i) is an organic base such as an amine, preferably selected from a toal lamine, such as triemylamine or clHsopropylemylarnine, or an aromatic amine, such as pyridine.

An "aromatic amine" refers to both amines which comprise an aryl group, such as aniline, and to amines in which the nitrogen atom forms part of the aromatic skeleton of an aryl group, such as pyridine, pyrrole, indole, isoindole, quinoline and the like. Preferably the term "aromatic amine" refers to amines in which the nitrogen atom forms part of the aromatic skeleton of an aryl group.

Step (ii) of the first preferred embodiment of the first aspect of die present invention optionally comprises treating cyclic sulfinyl ester (A-2) with R⁶-CO-Y, wherein R⁶ is as defined above and Y represents a suitable leaving group. Optionally step (ii) is performed in the presence of a base. Preferably, step (ii) comprises treating cyclic sulfinyl ester (A-2) with a reagent selected from R⁶-CO-Cl, R⁶-CO-0-CO-R⁶, p-nitrophenyl-CO-R⁶, imidazolyl-CO-R⁶, and R⁶-CO-0-CH₂CH₂-0-CO-R⁶, optionally in the presence of base. Preferably the reagent is R⁶-CO-Cl. The base used in step (ii) of the first preferred embodiment of the first aspect of the present invention may be an organic base or ammonia. Preferably the base used in step (ii) is an organic base such as an amine, preferably selected from a trialkylamine, such as triethylamine or diisopropylethylamine, or an aromatic amine, such as pyridine.

Optionally, the base used in step (ii) may be the same as the base used in step (i).

Preferably, step (iii) comprises treatment of cyclic sulfinyl ester (A-3) with an organic or inorganic base to obtain the N-functionalised cytidine derivative (A-4). Preferably the organic base is selected from ammonia or a trialklamine, such as triethylamine or diisopropylethylamine. More preferably the base is an inorganic base. Preferably the inorganic base is selected from a metal hydroxide or a metal carbonate, such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. Most preferably the base is sodium hydroxide.

Optionally, the intermediate cyclic sulfinyl ester (A-3), or a salt, tautomer, solvate or hydrate thereof, is prepared from the starting material (A-1), or a salt, tautomer, solvate or hydrate thereof, in a "one pot" process without isolation of the intermediate cyclic sulfinyl ester (A-2), or a salt, tautomer, solvate or hydrate thereof.

Alternately, the N-functionalised cytidine derivative (A-4) is prepared from the intermediate cyclic sulfinyl ester (A-2) or a salt, tautomer, solvate or hydrate thereof, in a "one pot" process without isolation of the intermediate cyclic sulfinyl ester (A-3), or a salt, tautomer, solvate or hydrate thereof.

Preferably the process according to the first preferred embodiment of the first aspect of the present invention is such that the N-functionalised cytidine derivative (A-4) is prepared in "one pot" without isolation of the intermediate cyclic sulfinyl esters (A-2) or (A-3) or a salt, tautomer, solvate or hydrate thereof.

As used herein, where an intermediate is used "without isolation", said intermediate is not purified save for the optional removal of the solvent and other volatile components of the reaction mixture. For example, said intermediate is not subjected to chromatography, recrystallisation or solvent extraction.

In a second preferred embodiment of the first aspect of the present invention, the process comprises one or more of the following steps:

(i) converting starting material (A-5) or a salt, tautomer, solvate or hydrate thereof, to cyclic sulfin l ester (A-6) or a salt, tautomer, solvate or hydrate thereof:

(ii) converting cyclic sulfinyl ester (A-6) or a salt, tautomer, solvate or hydrate thereof, to c clic sulfinyl ester (A-7) or a salt, tautomer, solvate or hydrate thereof:

(iii) deprotection of cyclic sulfinyl ester (A-7) or a salt, tautomer, solvate or hydrate thereof, to obtain the N-functionalised cytidine derivative (A-8) or a salt, tautomer, solvate or h drate thereof:

Preferably the process comprises two or more of steps (i) to (iii). For instance, the process may comprise at least steps (i) and (ii), or at least steps (ii) and (iii). More preferably the process comprises all three of steps (i) to (iii). Optionally, compounds (A-5), (A-6), (A-7) and (A-8) possess the same stereochemistry as compound (B) above. Preferably compounds (A-5), (A-6), (A-7) and (A-8) possess the same stereochemistry as compound (D) above.

Preferably, step (i) comprises treating starting material (A-5) with a reagent represented by general formula SOX₂, optionally in the presence of a base, wherein each X independently represents a suitable leaving group. Preferably each X is the same. Optionally, each X may independently be selected from a halogen, such as -CI, -Br or -I, or an imidazolyl group. Preferably, SOX₂ is selected from thionyl chloride, thionyl bromide and sulfinyl diimidazole, and most preferably SOX₂ is thionyl chloride.

The base used in step (i) of die second preferred embodiment of the first aspect of the present invention may be an organic base or ammonia. Preferably the base in step (i) is an organic base such as an amine, preferably selected from a triallcylamine, such as toethylamine or dusopropylethylamine, or an aromatic arnine, such as pyridine.

Step (ii) of the second preferred embodiment of the first aspect of the present invention optionally comprises treating cyclic sulfinyl ester (A-6) with R⁶-CO-Y, wherein R⁶ is as defined above and Y represents a suitable leaving group. Optionally step (ii) is performed in the presence of a base. Preferably, step (ii) comprises treating cyclic sulfinyl ester (A-6) with a reagent selected from R⁶-CO-Cl, R⁶-CO-0-CO-R⁶, p-nitrophenyl-CO-R⁶, imidazolyl-CO-R^rt, and R^CO-O-CH^CH^-O-CO-R⁶, optionally in the presence of base. Preferably the reagent is R⁶-CO-Cl.

The base used in step (ii) of the second preferred embodiment of the first aspect of the present invention may be an organic base or ammonia. Preferably the base used in step (ii) is an organic base such as an amine, preferably selected from a trialkylamine, such as triethylamine or dtisopropyletiiylamine, or an aromatic amine, such as pyridine.

Optionally, the base used in step (ii) may be the same as the base used in step (i). Preferably, step (iii) comprises treatment of cyclic sulfinyl ester (A-7) with an organic or inorganic base to obtain the N-functionalised cytidine derivative (A-8). Preferably the organic base is selected from ammonia or a ttialkylamine, such as triemylamine or dnsopropylemylamine. More preferably the base is an inorganic base. Preferably the inorganic base is selected from a metal hydroxide or a metal carbonate, such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. Most preferably the base is sodium hydroxide.

Optionally, the intermediate cyclic sulfinyl ester (A-7), or a salt, tautomer, solvate or hydrate thereof, is prepared from the starting material (A-5), or a salt, tautomer, solvate or hydrate thereof, in a "one pot" process without isolation of the intermediate cyclic sulfinyl ester (A-6), or a salt, tautomer, solvate or hydrate thereof.

Alternately, the N-functionalised cytidine derivative (A-8) is prepared from the intermediate cyclic sulfinyl ester (A-6) or a salt, tautomer, solvate or hydrate thereof, in a "one pot" process without isolation of the intermediate cyclic sulfinyl ester (A-7), or a salt, tautomer, solvate or hydrate thereof.

Preferably the process according to the second preferred embodiment of the first aspect of the present invention is such that the N-functionalised cytidine derivative (A-8) is prepared in "one pot" without isolation of the intermediate cychc sulfinyl esters (A-6) or (A-7) or a salt, tautomer, solvate or hydrate thereof.

A second aspect of the present invention provides a process for the preparation of capecitabine (1) comprising one or more of the following steps:

(i) converting 5-fluoro-5'-deoxycytidine (0101) or a salt, tautomer, solvate or hydrate thereof, to cychc sulfinyl ester (0301) or a salt, tautomer, solvate or hydrate thereof;

(ii) converting cyclic sulfinyl ester (0301) or a salt, tautomer, solvate or hydrate thereof, to cychc sulfinyl ester (0302) or a salt, tautomer, solvate or hydrate thereof; and

(iii) deprotection of cychc sulfinyl ester (0302) or a salt, tautomer, solvate or hydrate thereof, to obtain capecitabine (1). In one embodiment of the second aspect of the present invention, the process comprises two or more of steps (i) to (iii). For instance, the process may comprise at least steps (i) and

(ii) , or at least steps (ii) and (iii). Preferably the process comprises all three of steps (i) to

(iii) .

Preferably, step (i) comprises treating 5-fiuoro-5'-deoxycytidine with a reagent represented by general formula SOX₂, optionally in the presence of a base, wherein each X independently represents a suitable leaving group. Preferably each X is the same. In one embodiment of the second aspect of the present invention, each X is independently selected from a halogen, such as -CI, -Br or -I, or an imidazolyl group. Preferably, SOX₂ is selected from thionyl chloride, thionyl bromide and sulfinyl diimidazole, and most preferably SOX₂ is thionyl chloride. In one embodiment of the second aspect of the present invention, the base used in step (i) is an organic base or ammonia. Preferably the base in step (i) is an organic base such as an amine, preferably selected from a trialkylamine, such as triemylamine or diisopropylemylamine, or an aromatic amine, such as pyridine. In one embodiment of the second aspect of the present invention, the reaction of step (i) is performed at a temperature between -100°C and 100°C. Preferably the reaction of step (i) is performed at a temperature between -80°C and 80°C. More preferably the reaction of step (i) is performed at a temperature between -20°C and 50°C. Most preferably the reaction of step (i) is performed at a temperature between -5°C and 0°C.

In another embodiment of the second aspect of the present invention, the reaction of step (i) is performed in a dipolar aprotic solvent such as acetone, acetonitrile, dimethoxyethane, DMF, DMSO, 1,4-dioxane, pyridine, or THF. Most preferably, the reaction of step (i) is performed in acetonitrile.

In one embodiment of the second aspect of the present invention, step (ii) comprises treating cyclic sulfinyl ester (0301) with C₅H_irO-CO-Y, wherein Y represents a suitable leaving group. Optionally step (ii) is performed in the presence of a base. Preferably, step (ii) comprises treating cyclic sulfinyl ester (0301) with a reagent selected from n-pentyl chloroformate, n-pentyloxycarbonic anhydride, n-pentyl p-nitrophenyl carbonate, n- pentyloxycarbonyl imidazole and n-pentyloxycarbonyl-O-succinate, optionally in the presence of base. Preferably the reagent is n-pentyl chloroformate.

In one embodiment of the second aspect of the present invention, the base used in step (ii) is an organic base or ammonia. Preferably the base used in step (ii) is an organic base such as an amine, preferably selected from a trialkylamine, such as triethylamine or dtLsopropyled ylamine, or an aromatic amine, such as pyridine.

In one embodiment of the second aspect of the present invention, the reaction of step (ii) is performed at a temperature between -100°C and 100°C. Preferably the reaction of step (ii) is performed at a temperature between -80°C and 80°C. More preferably the reaction of step (ii) is performed at a temperature between -20°C and 50°C. Most preferably the reaction of step (ii) is performed at a temperature between -5°C and 0°C.

In another embodiment of the second aspect of die present invention, the reaction of step (ii) is performed in a dipolar aprotic solvent such as acetone, acetonitrile, dime hoxyethane, DMF, DMSO, 1,4-dioxane, pyridine, or THF, or in a chlorinated solvent such as chloroform or dichloromefhane. Most preferably, the reaction of step (ii) is performed in acetonitrile or dichloromethane. Optionally, the solvent used in step (ii) may be the same as the solvent used in step (i).

Preferably, step (iii) comprises treatment of cyclic sulfinyl ester (0302) with an organic or inorganic base to obtain capecitabine (1). Preferably the organic base is selected from ammonia or a t ialkylamine, such as triemylamine or dtisopropylemylamine. More preferably the base is an inorganic base. Preferably the inorganic base is selected from a metal hydroxide or a metal carbonate, such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. Most preferably the base is sodium hydroxide. In one embodiment of the second aspect of the present invention, the reaction of step (iii) is performed at a temperature between -100°C and 100°C. Preferably the reaction of step (iii) is performed at a temperature between -80°C and 80°C. More preferably the reaction of step (iii) is performed at a temperature between -20°C and 50°C. Most preferably the reaction of step (iii) is performed at a temperature between -5°C and 0°C.

In another embodiment of the second aspect of the present invention, the reaction of step (iii) is performed in a polar protic solvent such as acetic acid, methanol, ethanol, n- propanol or isopropanol. Preferably the polar protic solvent is not an acid. More preferably the polar protic solvent is an alcohol, preferably one containing from 1 to 6 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol or a mixture thereof. Most preferably the polar protic solvent is methanol.

In one embodiment of the second aspect of the present invention, the intermediate cyclic sulfinyl ester (0302), or a salt, tautomer, solvate or hydrate thereof, is prepared from the 5- fluor -5'-deoxycytidine (0101), or a salt, tautomer, solvate or hydrate thereof, in a "one pot" process without isolation of the intermediate cyclic sulfinyl ester (0301), or a salt, tautomer, solvate or hydrate thereof. In another embodiment of the second aspect of the present invention, the capecitabine (1) is prepared from the intermediate cyclic sulfinyl ester (0301) or a salt, tautomer, solvate or hydrate thereof, in a "one pot" process without isolation of the intermediate cyclic sulfinyl ester (0302), or a salt, tautomer, solvate or hydrate thereof. Preferably the process according to the second aspect of the present invention is such that the capecitabine (1) is prepared in "one pot" without isolation of the intermediate cyclic sulfinyl esters (0301) or (0302) or a salt, tautomer, solvate or hydrate thereof.

Preferably, in the process according to the second aspect of the present invention, the capecitabine (1) formed is further purified, for example by recrystallization, for example from ethyl acetate. A third aspect of the present invention provides a process for the preparation of galocitabine (2) comprising one or more of the following steps:

(i) converting 5-fluoro-5'-deoxycytidine (0101) or a salt, tautomer, solvate or hydrate thereof, to cyclic sulfinyl ester (0301) or a salt, tautomer, solvate or hydrate thereof:

converting cyclic sulfinyl ester (0301) or a salt, tautomer, solvate or hydrate thereof, cyclic sulfinyl ester (0402) or a salt, tautomer, solvate or hydrate thereof:

(iii) deprotection of cyclic sulfinyl ester (0402) or a salt, tautomer, solvate or hydrate thereof, to obtain galocitabine:

In one embodiment of the third aspect of the present invention, the process comprises two or more of steps (i) to (iii). For instance, the process may comprise at least steps (i) and (ii), or at least steps (ii) and (iii). Preferably the process comprises all three of steps (i) to (iii). Preferably, step (i) comprises treating 5-fluoro-5'-deoxycytidine with a reagent represented by general formula SOX₂, optionally in the presence of a base, wherein each X independently represents a suitable leaving group. Preferably each X is the same.

In one embodiment of the third aspect of the present invention, each X is independently selected from a halogen, such as -CI, -Br or -I, or an imidazolyl group. Preferably, SOX₂is selected from thionyl chloride, thionyl bromide and sulfinyl diimidazole, and most preferably SOX₂ is thionyl chloride.

In one embodiment of the third aspect of the present invention, the base used in step (i) is an organic base or ammonia. Preferably the base in step (i) is an organic base such as an amine, preferably selected from a ti½Utylamine, such as tiiethylamine or dnsopropylethylairiine, or an aromatic amine, such as pyridine.

In one embodiment of the third aspect of the present invention, the reaction of step (i) is performed at a temperature between -100°C and 100°C. Preferably the reaction of step (i) is performed at a temperature between -80°C and 80°C. More preferably the reaction of step (i) is performed at a temperature between -20°C and 50°C. Most preferably the reaction of step (i) is performed at a temperature between -5°C and 0°C. In another embodiment of the third aspect of the present invention, the reaction of step (i) is performed in a dipolar aprotic solvent such as acetone, acetonitrile, dimethoxyefhane, DMF, DMSO, 1,4-dioxane, pyridine, or THF. Most preferably, the reaction of step (i) is performed in acetonitrile. In one embodiment of the third aspect of the present invention, step (ii) comprises treating cyclic sulfinyl ester (0301) with (3,4,5-trimetlioxyphenyl)-CO-Y, wherein Y represents a suitable leaving group. Optionally step (ii) is performed in the presence of a base. Preferably, step (ii) comprises treating cyclic sulfinyl ester (0301) with a reagent selected from

In one embodiment of the third aspect of the present invention, the base used in step (ii) is an organic base or ammonia. Preferably the base used in step (ii) is an organic base such as an amine, preferably selected from a trialliylamine, such as tiie ylamine or diisopropylethylamine, or an aromatic amine, such as pyridine.

Optionally, the base used in step (ii) may be the same as the base used in step (i). In one embodiment of the third aspect of the present invention, the reaction of step (ii) is performed at a temperature between -100°C and 100°C. Preferably the reaction of step (ii) is performed at a temperature between -80°C and 80°C. More preferably the reaction of step (ii) is performed at a temperature between -20°C and 50°C. Most preferably the reaction of step (ii) is performed at a temperature between -5°C and 0°C.

In another embodiment of the third aspect of the present invention, the reaction of step (ii) is performed in a dipolar aprotic solvent such as acetone, acetonitrile, climethoxyethane, DMF, DMSO, 1,4-dioxane, pyridine, or THF, or in a chlorinated solvent such as chloroform or dichloromethane. Most preferably, the reaction of step (ii) is performed in acetonitrile or dichloromethane.

Optionally, the solvent used in step (ii) may be the same as the solvent used in step (i). Preferably, step (iii) comprises treatment of cyclic sulfinyl ester (0402) with an organic or inorganic base to obtain galocitabine (2). Preferably the organic base is selected from ammonia or a trialkylamine, such as triethylamine or diisopropylethylamine. More preferably the base is an inorganic base. Preferably the inorganic base is selected from a metal hydroxide or a metal carbonate, such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. Most preferably the base is sodium hydroxide.

In one embodiment of the third aspect of the present invention, the reaction of step (iii) is performed at a temperature between -100°C and 100°C. Preferably the reaction of step (iii) is performed at a temperature between -80°C and 80°C. More preferably the reaction of step (iii) is performed at a temperature between -20°C and 50°C. Most preferably the reaction of step (iii) is performed at a temperature between -5°C and 0°C.

In another embodiment of the third aspect of the present invention, the reaction of step (iii) is performed in a polar protic solvent such as acetic acid, methanol, ethanol, n- propanol or isopropanol. Preferably the polar protic solvent is not an acid. More preferably the polar protic solvent is an alcohol, preferably one containing from 1 to 6 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol or a mixture thereof. Most preferably the polar protic solvent is methanol. In one embodiment of the third aspect of the present invention, the intermediate cyclic sulfinyl ester (0402), or a salt, tautomer, solvate or hydrate thereof, is prepared from the 5- fluoro-5'-deoxycytidine (0101), or a salt, tautomer, solvate or hydrate thereof, in a "one pot" process without isolation of the intermediate cyclic sulfinyl ester (0301), or a salt, tautomer, solvate or hydrate thereof.

In another embodiment of the third aspect of the present invention, the galocitabine (2) is prepared from the intermediate cyclic sulfinyl ester (0301) or a salt, tautomer, solvate or hydrate thereof, in a "one pot" process without isolation of the intermediate cyclic sulfinyl ester (0402), or a salt, tautomer, solvate or hydrate thereof.

Preferably the process according to the third aspect of the present invention is such that the galocitabine (2) is prepared in "one pot" without isolation of the intermediate cyclic sulfinyl esters (0301) or (0402) or a salt, tautomer, solvate or hydrate thereof.

Preferably, in the process according to the third aspect of the present invention, the galocitabine (2) formed is further purified, for example by recrystallization, for example from ethyl acetate.

A fourth aspect of the present invention provides a process for the preparation of sapacitabine (3) comprising one or more of the following steps:

(i) converting the nucleoside (0501) or a salt, tautomer, solvate or hydrate thereof, to c clic sulfinyl ester (0502) or a salt, tautomer, solvate or hydrate thereof:

(ii) converting cyclic sulfinyl ester (0502) or a salt, tautomer, solvate or hydrate thereof, to cyclic sulfinyl ester (0503) or a salt, tautomer, solvate or hydrate thereof:

(iii) deprotection of cyclic sulfinyl ester (0503) or a salt, tautomer, solvate or hydrate thereof to obtain sapacitabine:

In one embodiment of the fourth aspect of the present invention, the process comprises two or more of steps (i) to (iii). For instance, the process may comprise at least steps (i) and (ii), or at least steps (ii) and (iii). Preferably the process comprises all three of steps (i) to

Preferably, step (i) comprises treating the nucleoside (0501) with a reagent represented by general formula SOX₂, optionally in the presence of a base, wherein each X independently represents a suitable leaving group. Preferably each X is the same. In one embodiment of the fourdi aspect of the present invention, each X is independently selected from a halogen, such as -CI, -Br or -I, or an imidazolyl group. Preferably, SOX₂ is selected from thionyl chloride, thionyl bromide and sulfinyl diimidazole, and most preferably SOX₂ is thionyl chloride. In one embodiment of the fourth aspect of the present invention, the base used in step (i) is an organic base or ammonia. Preferably the base in step (i) is an organic base such as an amine, preferably selected from a toalkylamine, such as trietiiylamine or diisopropylethykmine, or an aromatic amine, such as pyridine. In one embodiment of the fourth aspect of the present invention, the reaction of step (i) is performed at a temperature between -100°C and 100°C. Preferably the reaction of step (i) is performed at a temperature between -80°C and 80°C. More preferably the reaction of step (i) is performed at a temperature between -20°C and 50°C. Most preferably the reaction of step (i) is performed at a temperature between -5°C and 0°C.

In another embodiment of the fourth aspect of the present invention, the reaction of step

(i) is performed in a dipolar aprotic solvent such as acetone, acetonitrile, dimethoxyethane, DMF, DMSO, 1,4-dioxane, pyridine, or THF. Most preferably, the reaction of step (i) is performed in acetonitrile.

In one embodiment of the fourth aspect of the present invention, step (ii) comprises treating cyclic sulfinyl ester (0502) with C₁₅H₃₁-CO-Y, wherein Y represents a suitable leaving group. Optionally step (ii) is performed in the presence of a base. Preferably, step (ii) comprises treating cyclic sulfinyl ester (0502) with a reagent selected from palmitoyl chloride, palmitic anhydride, p-nitrophenyl palmitate, palmitoyl imidazole and palmitoyl O- succinate, optionally in the presence of base. Preferably the reagent is palmitoyl chloride.

In one embodiment of the fourth aspect of the present invention, the base used in step (ii) is an organic base or ammonia. Preferably the base used in step (ii) is an organic base such as an amine, preferably selected from a trialkylamine, such as trieuiylamine or dUsopropylethylamine, or an aromatic amine, such as pyridine.

In one embodiment of the fourth aspect of d e present invention, the reaction of step (ii) is performed at a temperature between -100°C and 100°C. Preferably the reaction of step (ii) is performed at a temperature between -80°C and 80°C. More preferably the reaction of step (ii) is performed at a temperature between -20°C and 50°C. Most preferably the reaction of step (ii) is performed at a temperature between -5°C and 0°C.

(ii) is performed in a dipolar aprotic solvent such as acetone, acetonitrile, dimethoxyethane, DMF, DMSO, 1,4-dioxane, pyridine, or THF, or in a chlorinated solvent such as chloroform or dichloromethane. Most preferably, the reaction of step (ii) is performed in acetonitrile or dichloromethane. Optionally, the solvent used in step (ii) may be the same as the solvent used in step (i).

Preferably, step (iii) comprises treatment of cyclic sulfinyl ester (0503) with an organic or inorganic base to obtain sapacitabine (3). Preferably the organic base is selected from ammonia or a triaU^lamine, such as triethylamine or dnsopropylethylamine. More preferably the base is an inorganic base. Preferably the inorganic base is selected from a metal hydroxide or a metal carbonate, such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. Most preferably the base is sodium hydroxide.

In one embodiment of the fourth aspect of the present invention, the reaction of step (iii) is performed at a temperature between -100°C and 100°C. Preferably the reaction of step (iii) is performed at a temperature between -80°C and 80°C. More preferably the reaction of step (iii) is performed at a temperature between -20°C and 50°C. Most preferably the reaction of step (iii) is performed at a temperature between -5°C and 0°C. In another embodiment of the fourth aspect of the present invention, the reaction of step (iii) is performed in a polar protic solvent such as acetic acid, methanol, ethanol, n- propanol or isopropanol. Preferably the polar protic solvent is not an acid. More preferably the polar protic solvent is an alcohol, preferably one containing from 1 to 6 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol or a mixture thereof. Most preferably the polar protic solvent is methanol.

In one embodiment of the fourth aspect of the present invention, the intermediate cyclic sulfinyl ester (0503), or a salt, tautomer, solvate or hydrate thereof, is prepared from the nucleoside (0501), or a salt, tautomer, solvate or hydrate thereof, in a "one pot" process without isolation of the intermediate cyclic sulfinyl ester (0502), or a salt, tautomer, solvate or hydrate thereof. In another embodiment of the fourth aspect of the present invention, the sapacitabine (3) is prepared from the intermediate cyclic sulfinyl ester (0502) or a salt, tautomer, solvate or hydrate thereof, in a "one pot" process without isolation of the intermediate cyclic sulfinyl ester (0503), or a salt, tautomer, solvate or hydrate thereof.

Preferably the process according to the fourth aspect of the present invention is such that the sapacitabine (3) is prepared in "one pot" without isolation of the intermediate cyclic sulfinyl esters (0502) or (0503) or a salt, tautomer, solvate or hydrate thereof. Preferably, in the process according to the fourth aspect of the present invention, the sapacitabine (3) formed is further purified, for example by recrystallization, for example from ethyl acetate.

A fifth aspect of the present invention provides an N-functionalised cytidine derivative when prepared by a process according to any of the preceding aspects of the present invention. Preferably the N-functionalised cytidine derivative and all process intermediates are obtained on a commercial scale, preferably in batches of 1kg or more, 10kg or more, 100kg or more, 500kg or more, or 1000kg or more. Preferably the N-functionalised cytidine derivative and all process intermediates are substantially free of chemical impurities.

For instance, the fifth aspect of the present invention may provide capecitabine (1) when prepared by a process according to the first or second aspect of the present invention. Preferably the capecitabine (1) of the fifth aspect of the present invention is obtained on a commercial scale, preferably in batches of 1kg or more, 10kg or more, 100kg or more, 500kg or more, or 1000kg or more. Preferably the capecitabine (1) of the fifth aspect of the present invention is substantially free of chemical impurities.

Alternately, the fifth aspect of the present invention may provide galocitabine (2) when prepared by a process according to the first or third aspect of the present invention. Preferably the galocitabine (2) of the fifth aspect of the present invention is obtained on a commercial scale, preferably in batches of 1kg or more, 10kg or more, 100kg or more, 500kg or more, or 1000kg or more. Preferably the galocitabine (2) of the fifth aspect of the present invention is substantially free of chemical impurities.

Alternately still, the fifth aspect of the present invention may provide sapacitabine (3) when prepared by a process according to the first or fourth aspect of the present invention. Preferably the sapacitabine (3) of the fifth aspect of the present invention is obtained on a commercial scale, preferably in batches of 1kg or more, 10kg or more, 00kg or more, 500kg or more, or 1000kg or more. Preferably die sapacitabine (3) of the fifth aspect of the present invention is substantially free of chemical impurities.

A sixth aspect of the present invention provides an N-functionalised cytidine derivative substantially free of chemical impurities. For instance, the sixth aspect of the present invention may provide capecitabine (1), galocitabine (2) or sapacitabine (3) substantially free of chemical impurities.

Preferably the N-functionalised cytidine derivative, such as the capecitabine (1), galocitabine (2) or sapacitabine (3), according to the fifth or sixth aspects of the present invention is substantially enantiomerically pure. Preferably the N-functionalised cytidine derivative, such as the capecitabine (1), galocitabine (2) or sapacitabine (3), according to the fifth or sixth aspects of the present invention is suitable for the treatment or prevention of cancer, preferably for the treatment or prevention of metastatic breast or colorectal cancers. A seventh aspect of the present invention provides a pharmaceutical composition comprising the N-functionalised cytidine derivative, such as the capecitabine (1), galocitabine (2) or sapacitabine (3), according to the fifth or sixth aspects of the present invention. Preferably the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. Preferably die pharmaceutical composition is suitable for the treatment or prevention of cancer, preferably for the treatment or prevention of metastatic breast or colorectal cancers. An eighth aspect of the present invention provides a method of treating or preventing cancer comprising administering a therapeutically or prophylactically effective amount of the N-functionalised cytidine derivative, such as the capecitabine (1), galocitabine (2) or sapacitabine (3), according to the fifth or sixth aspects of the present invention or a therapeutically or prophylactically effective amount of the pharmaceutical composition according to the seventh aspect of the present invention to a patient in need thereof. Preferably the cancer is metastatic breast or colorectal cancer. Preferably the patient is a mammal, and most preferably die mammal is a human. A ninth aspect of the present invention provides cyclic sulfinyl ester (A-2) or a salt, tautomer, solvate or hydrate thereof. Preferably the ninth aspect of the present invention provides cyclic sulfinyl ester (0301) or a salt, tautomer, solvate or hydrate thereof.

A tenth aspect of the present invention provides cyclic sulfinyl ester (A-3) or a salt, tautomer, solvate or hydrate thereof. Preferably the tenth aspect of the present invention provides cyclic sulfinyl ester (0302) or a salt, tautomer, solvate or hydrate thereof, or the cyclic sulfinyl ester (0402) or a salt, tautomer, solvate or hydrate thereof.

An eleventh aspect of the present invention provides cyclic sulfinyl ester (A-6) or a salt, tautomer, solvate or hydrate thereof. Preferably die eleventh aspect of the present invention provides cyclic sulfinyl ester (0502) or a salt, tautomer, solvate or hydrate thereof.

A twelfth aspect of the present invention provides cyclic sulfinyl ester (A-7) or a salt, tautomer, solvate or hydrate thereof. Preferably the twelfth aspect of the present invention provides cyclic sulfinyl ester (0503) or a salt, tautomer, solvate or hydrate thereof.

For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention. In addition, insofar as is practicable it is to be understood that any preferred or optional embodiment of any aspect of the present invention should also be considered as a preferred or optional embodiment of any other aspect of die present invention. Detailed description of the invention

The present invention provides a simple, convenient and inexpensive method for the preparation of enantiomerically pure N-functionalised cytidine derivatives such as capecitabine (1). The products obtained from the process of the present invention are surprisingly very pure without the need for cumbersome purification techniques due to the properties of the novel synthetic intermediates.

The advantages of the present invention are the use of inexpensive, non-hazardous synthetic agents, and simple and convenient process conditions which afford the resultant products in very high chemical and optical purity.

The inventors have found that a sulfinyl group can be employed as protecting group for selectively protecting the hydroxyl groups at the 2- and 3-positions in 5-fiuoro-5'- deoxycytidine (0101) to form a cyclic sulfinyl ester intermediate. The sulfinyl protecting group can be introduced under wide ranging reaction conditions and with a variety of reagents. After introduction of the pentyloxycarbonyl moiety on the nitrogen at the 5- position, the sulfinyl protecting group can advantageously be removed very easily and conveniently with a variety of organic and inorganic bases to afford capecitabine (1).

The present invention is particularly advantageous as the sulfinyl group can serve as a selective, convenient and relatively inexpensive protecting group for the hydroxyl function of 5-fluoro-5'-deoxycytidine (0101) and, surprisingly, the intermediates (0301) and (0302), by virtue of being crystalline and solid, can be easily purified by crystallization or precipitation if necessary. Hence, the intermediates are very suitable for commercial production processes.

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 reactions are not limited by these reagents and solvents. Any suitable alternatives can be used and preferred alternatives are discussed below.

In a particularly preferred embodiment of the present invention, the three step synthetic sequence exemplified in Scheme 3 can be carried out in "one pot" without isolation of any of the intermediates and hence is very convenient, particularly for commercial production.

The sulfinyl protecting group can be introduced by reacting (0101) with a suitable sulfinylating reagent, such as thionyl chloride, thionyl bromide or sulfinyl <diimidazole. Optionally, the reaction is performed in the presence of an organic base, such as triethylamine, pyridine or diisopiOpylethylan ine.

A preferred embodiment of the procedure comprises the following steps:

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

(2) addition of a sulfinylating reagent to the solution or suspension obtained in step (1) at a temperature ranging between -20 to 50°C; optionally adding organic base to the solution or suspension obtained in step (2) at a temperature ranging between -20 to 50°C;

isolating the product either by removal of solvent or by quenching the reaction mixture with water, adjusting the pH to 6-8, extraction with organic solvent and removal of solvent or filtration of the solid that precipitates out during adjustment of the pH to between 6-8; and

optional crystallization of the product (0301) from a suitable solvent system.

In the above procedure, if organic base is not added in step (3), the hydrogen chloride salt of intermediate (0301) is obtained on removal of solvent. In an alternative procedure, the hydrogen chloride salt of (0101) also affords intermediate (0301) when subjected to steps (1) to (5). In step (4), if solid precipitate is filtered, exclusively one of the two possible diastereomers is obtained. If extraction is done, a mixture of the two diastereomers in varying ratio is typically obtained.

Intermediate (0301) is preferably treated with a pentyloxycarbonylating reagent to provide intermediate (0302). The following pentyloxycarbonylating reagents are suitable for this transformation:

(a) n-pentyl chloroformate

(b) n-pentyloxycarbonic anhydride

(c) n-pentyl p-nitrophenyl carbonate

(d) n-pentyloxycarbonyl imidazole

(e) n-pentyloxycarbonyl-O-succinate

A preferred embodiment of the procedure comprises the following steps:

(1) dissolving or suspending intermediate (0301) in a suitable organic solvent system;

(2) addition of organic base to the solution or suspension of step (1);

(3) addition of any of the pentyloxycarbonylating reagents (a) to (e) listed above;

(4) isolating the product (0302) either by removal of solvent, addition of water to the residual reaction mixture, extraction with organic solvent and removal of solvent; or by removal of solvent, addition of water and filtration of the precipitated solid; or by addition of water to the reaction mixture, layer separation of organic solvent, washing of the organic solvent layer with water and removal of solvent; and (5) optional crystallization of product (0302) from a suitable solvent system.

In step (1) of the above procedure, the hydrogen chloride salt of (0301) could also be employed with an increase in the amount of organic base added in step (2).

Removal of the sulfinyl protecting group from intermediate (0302) affords capecitabine (1). This deprotection can be readily achieved with organic or inorganic base. Suitable bases employed for this deprotection are as follows:

(a) sodium hydroxide

(b) potassium hydroxide

(c) sodium carbonate

(d) potassium carbonate

(e) ammonia

(£) triethylamine

A preferred embodiment of the procedure comprises the following steps:

(1) dissolving or suspending intermediate (0302) in a suitable organic solvent system;

(2) addition of any one of bases (a) to (f) listed above at a temperature ranging between 0 to 60°C;

(3) isolating the product, capecitabine (1), by quenching the reaction mixture with water, adjusting the pH to 4-6, extraction with organic solvent and removal of solvent; and

(4) purification of the crude product, capecitabine (1), by crystallization from a suitable solvent system.

In an alternative procedure, steps (1) and (2) above could be reversed to obtain the product capecitabine (1).

The deprotection step to afford capecitabine (1) is typically carried out under aqueous conditions or in solvent grade hydroxylic solvents, such as methanol or ethanol, such that hydrolysis of the sulfinyl ester is efficiently achieved. Preferably the process of the present invention can be carried out in a "single pot", without isolation of intermediates, to afford capecitabine (1) in a very good yield and a short time. This is particularly advantageous for commercial production, where the process to obtain capecitabine from (0101) is reduced to just two steps— a one pot three step route (as illustrated in Scheme 3) and purification of crude capecitabine (1).

In still another aspect of the present invention, steps (1) and (2) depicted in Scheme 3 could be done in one pot and the rest of the steps individually. This could also be convenient from a scale up point of view due to higher yield and reduced time for the process.

Isolation and purification of intermediate (0301) or (0302) leads to very pure capecitabine (1)· Preferably the process of the present invention is carried out without the use of chromatography.

Preferably the intermediate and final products are obtained in a yield of 70% or more, preferably 80% or more, preferably 90% or more, preferably 95% or more.

Preferably capecitabine (1) and intermediates (0301) and (0302) are obtained on a commercial scale, preferably in batches of 1kg or more, 10kg or more, 100kg or more, 500kg or more, or 1000kg or more. Preferably capecitabine (1) and intermediates (0301) and (0302), if isolated, are obtained substantially free of chemical impurities.

Preferably capecitabine (1) and intermediates (0301) and (0302), if isolated, are obtained substantially enantiomerically pure.

The process of the present invention can be easily adapted for the preparation of compounds, which are analogous to capecitabine (1), such as galocitabine (2) and sapacitabine (3). The pharmaceutical composition according to 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, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, gelatin, acacia gum, tragacanth, polyvinylpyrrolidone or crospovidone; one or more disintegrating agents, such as croscarmellose sodium, cross- linked polyvinylpyrrolidone, crospovidone, cross-linked carboxymethyl starch, starches, rnicrocrystalline cellulose or polyacrylin potassium; and 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, triethyl 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

Protection of 5-fluoro-5'-deoxycytidine (0101) with thionyl chloride to form cyclic sulfinyl ester (0301).

5-Fluoro-5'-deoxycytidine (0101) (5.0 g, 1 equivalent, 0.020 mol) was added to acetonitrile (50 ml) and stirred at 25-30°C for 15 minutes. A colourless mass was observed. The mixture was cooled to -5°C to 0°C and thionyl chloride (4.45 ml, 3 equivalents, 0.061 mol) was added dropwise in about 15 minutes. Pyridine (3.3 ml, 2 equivalents, 0.0407 mol) was also added dropwise in about 20-25 minutes, whilst maintaining the temperature at -5°C to 0°C. The reaction mixture was stirred for another 2 hours and after completion of the reaction, water (75 ml, 15 vol) was added to the turbid reaction mass to give a clear solution. The pH of the reaction mass was adjusted to pH 6 to 7 using NaHCO_j and at this stage a solid started precipitating out. The slurry was stirred for another 30 minutes, before filtration afforded the single isomer of cyclic sulfinyl ester (0301).

Yield (molar) = 3.6 g (60%)

M.P. = 190-192°C

In an alternate isolation procedure, the reaction mass was extracted with ethyl acetate (75 ml, 15 vol) after adjusting the pH. After removal of the solvent, a mixture of the two isomers of cyclic sulfinyl ester (0301) was obtained.

Yield (molar) = 5.04 g (85%)

NMR: δ Values: 1.35 (t, 3H), 4.08 (m, 1H), 5.42 (t, 1H), 5.74 (t, 1H), 5.81 (t, 1H), 7.74 and 8.01 (bd, 2H), 8.04 (d, 1H) Example 2

Preparation of cyclic sulfinyl ester (0302) via coupling of cyclic sulfinyl ester (0301) with n- pentyl chloro formate.

Cyclic sulfinyl ester (0301) (2.0 g, 1 equivalent, 0.007 mol) was added to dichloromethane (40 ml) and stirred at 25-30°C for 15 minutes. A colourless mass was observed. The mixture was cooled to -5°C to 0°C and pyridine (1.1 ml, 2 equivalents, 0.014 mol) was added dropwise in about 20-25 minutes, whilst maintaining the temperature at -5°C to 0°C. N-pentyl chloroformate (1.01 ml, 1 equivalent, 0.007 mol) was also added dropwise in about 20-25 minutes, whilst maintaining the temperature at -5°C to 0°C. The reaction mixture was stirred for 15 minutes, before the reaction mass was allowed to warm to ambient temperature gradually. The mixture was stirred for a further 2 hours, before the reaction mass was quenched with water (100 ml, 50 vol). The organic layer was separated and then washed with water (100 ml, 50 vol), dried on sodium sulfate and the solvent removed to afford cyclic sulfinyl ester (0302).

Yield (molar) = 2.36 g (85%)

NMR: δ Values: 0.88 (t, 3H), 1.30 (m, 4H), 1.31 (t, 2H), 1.32 (d, 3H), 4.10 (t, 2H), 4.10 (m, 1H), 5.42 (t, 1H), 5.85 (t, 1H), 8.34 (bs, 1H), 10.65 (bs, 1H)

M. P. = 84-86°C

Example 3

Preparation of capecitabine (1) via deprotection of cyclic sulfinyl ester (0302).

Cyclic sulfinyl ester (0302) (2 g, 1 equivalent, 0.0049 mol) was added to methanol (20 ml, 10 vol) and stirred at 25-30°C for 15 minutes. The mixture was cooled to -5°C to 0°C and IN NaOH (13.6 ml) was added dropwise in about 20-25 minutes, whilst maintaining d e temperature at -5°C to 0°C. The reaction mixture was stirred for 1 hour. After stirring for 1 hour, water was added (20 ml, 10 vol), the pH of the reaction was adjusted to 4 to 6 using HC1 and the reaction mixture was then stirred for a further 30 minutes. Dichloromethane (20 ml, 10 vol) was added to the reaction mass and the mixture was stirred for a further 30 minutes. The organic layer was separated and the aqueous layer further extracted with dichloromethane (2 x 20 ml, 2 x 10 vol). Removal of the DCM extracts afforded capecitabine (1).

Yield (molar) = 1.45 g (82%) Specific Optical Rotation [oc]²⁰ _D = +97. (c = 1, MeOH)

HPLC Purity = 97.2 %

This solid (1.45 g, 1 equivalent) was further purified by dissolving in ethyl acetate (7.25 ml, 5 vol) at 25-30°C and stirring for 30 minutes. A white precipitation was observed and stirred for 30 minutes. The slurry was filtered and washed with 1:1 ethyl acetate : n-hexane (4 vol) and dried to afford white coloured capecitabine (1).

Yield (molar) = 1.16 g (80%)

Specific Optical Rotation [oc]²⁰ _D = +97.73° (c = 1, MeOH)

HPLC: RT matches with USP standard

HPLC Purity = 98.8 %

Example 4

Preparation of cyclic sulfinyl ester (0302) from 5-fluoro-5'-deoxycytidine (0101) in a one pot synthesis without isolation of cyclic sulfinyl ester intermediate (0301).

5-Fluoro-5'-deoxycytidine (0101) (5.0 g, 1 equivalent, 0.020 mol) was added to acetonitrile (50 ml) and stirred at 25-30°C for 15 minutes. A colourless mass was observed and the mixture was cooled to -5°C to 0°C. Thionyl chloride (4.45 ml, 3 equivalents, 0.061 mol) was added dropwise in about 15 minutes and pyridine (6.6 ml, 4 equivalents, 0.0814 mol) was also added dropwise in about 20-25 minutes, whilst mamtaining the temperature at -5°C to 0°C. The reaction mixture was stirred for 2 hours and, after completion of the reaction was observed by TLC, the mixture was cooled to -5°C to 0°C. N-Pentyl chloroformate (3.03 ml, 1 equivalent, 0.020 mol) was also added dropwise in about 20-25 minutes, whilst ma taining the temperature at -5°C to 0°C. The reaction mixture was then stirred for 15 minutes and the reaction mass was allowed to warm to ambient temperature gradually, and then stirred for a further 2 hours. Acetonitrile was removed by vacuum distillation at 40°C and the residue was quenched with ice cold water (250 ml, 50 vol) and stirred for 30 minutes. Dichloromefhane (50 ml, 10 vol) was added and the mixture was stirred vigorously before the organic layer was separated and then washed with water (250 ml, 50 vol). The organic layer was dried on sodium sulfate and the solvent removed to afford cyclic sulfinyl ester (0302).

Yield (molar) = 7.02 g (85%) Example 5

Preparation of capecitabine (1) from 5-fluoro-5'-deoxycytidine (0101) in a one pot synthesis without isolation of cyclic sulfinyl ester intermediates (0301) and (0302).

5-Fluoro-5'-deoxycytidine (0101) (5.0 g, 1 equivalent, 0.020 mol) was added to acetonitrile (50 ml) and stirred at 25-30°C for 15 minutes. A colourless mass was observed. The mixture was cooled to -5°C to 0°C and thionyl chloride (4.45 ml, 3 equivalents, 0.061 mol) was added dropwise in about 15 minutes. Pyridine (6.6 ml, 4 equivalents, 0.0814 mol) was also added dropwise in about 20-25 minutes, whilst maintaining the temperature at -5°C to 0°C. The reaction mixture was stirred for a further 2 hours and, after completion of the reaction was observed by TLC, the mixture was cooled to -5°C to 0°C. N-Pentyl chloro formate (3.03 ml, 1 equivalent, 0.020 mol) was then added dropwise in about 20-25 minutes, whilst maintaining the temperature at -5°C to 0°C. The reaction mixture was stirred for 15 minutes, before it was allowed to warm to ambient temperature gradually, and then stirred for a further 2 hours. The solvent was removed under vacuum at 40°C, methanol (50 ml, 10 vol) was added and the mixture stirred at 25-30°C for 15 minutes. The mixture was cooled to -5°C to 0°C before IN NaOH (70 ml) was added dropwise in about 20-25 minutes, whilst mamtaining the temperature at -5°C to 0°C. The reaction mixture was stirred for 1 hour. After stirring for 1 hour, water was added (50 ml, 10 vol), the pH of the reaction mixture was adjusted to 4 to 6 using HC1 and the reaction mixture was then stirred for 30 minutes. Dichloromethane (50 ml, 10 vol) was added and the mixture stirred for 30 minutes before separating the organic layer. The aqueous layer was further extracted with dichloromethane (2 x 50 ml, 2 x 10 vol) and removal of the solvent from the combined DCM layers afforded capecitabine (1).

Yield (molar) = 5.86 g (80%)

Specific Optical Rotation [oc]²⁰ _D = +98.0° (c = 1, MeOH)

HPLC Purity > 99.50 %

This solid (5.86 g, 1 equivalent) was further purified by dissolving in ethyl acetate (29.3 ml, 5 vol) at 25-30°C and stirring for 30 minutes. The white precipitation observed was stirred for a further 30 minutes before it was filtered and washed with 1:1 ethyl acetate : n-hexane (4 vol). The solid was dried to give white coloured capecitabine (1).

Yield (molar) = 4.69 g (80%)

Specific Optical Rotation [oc]²⁰ _D = +98.1° (c = 1, MeOH) HPLC Purity > 99.90 %

No trace of any chemical impurities were observed by HPLC in the capecitabine (1), when prepared following the process of the present invention.

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.

Claims

1. A process for the preparation of an N-functionalised cytidine derivative, such as capecitabine, galocitabine or sapacitabine, comprising the use of a cyclic sulphinyl ester.

2. A process according to claim 1, wherein the N-functionalised cytidine derivative is a compound of formula (A):

or a salt, solvate, hydrate or tautomer thereof, wherein:

R¹, R² and R³ are each independently selected from hydrogen, -F, -CI, -Br, -I, -CN,

-N0₂, -N₃, -O-R⁷, -S-R⁷, -N(R⁷)₂, -N(R⁷)₃ ⁺ or -0-Si(R⁷)₃;

R⁴ and R⁵ are each independently selected from hydrogen, -F, -CI, -Br and -I;

R⁶ is selected from an alkyl, alkenyl, alkynyl, ar l, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton; and

3. A process according to claim 1 or 2, wherein the cyclic sulphinyl ester is selected from a compound of formula (A-2), (A-3), (A-6), (A-7), and any salt, tautomer, solvate or hydrate thereof:

4. A process for the preparation of capecitabine comprising one or more of the following steps:

(ii) converting cyclic sulfinyl ester (0301) or a salt, tautomer, solvate or hydrate thereof, to cyclic sulfinyl ester (0302) or a salt, tautomer, solvate or hydrate thereof:

; and (iii) depi-otection of cyclic sulfinyl ester (0302) or a salt, tautomer, solvate or hydrate thereof, to obtain capecitabine:

5. A process according to claim 4, comprising all three of steps (i) to (iii).

6. A process according to claim 4 or 5, wherein step (i) comprises treating 5-fluoro-5'- deoxycytidine with a reagent represented by general formula SOX₂, optionally in the presence of a base, wherein each X independently represents a suitable leaving group.

7. A process according to claim 6, wherein SOX₂ is selected from thionyl chloride, thionyl bromide and sulfinyl diimidazole.

8. A process according to claim 7, wherein SOX₂ is thionyl chloride.

9. A process according to any one of claims 6 to 8, wherein the base is an organic base.

10. A process according to claim 9, wherein the organic base is selected from a toaUcylamine, such as triemylamine or diisopropylemylamine, or an aromatic amine, such as pyridine.

11. A process according to any one of claims 4 to 10, wherein step (ii) comprises treating cyclic sulfinyl ester (0301) with a reagent selected from n-pentyl chloroformate, n- pentyloxycarbonic anhydride, n-pentyl p-nitrophenyl carbonate, n-pentyloxycarbonyl imidazole and n-pentyloxycarbonyl-O-succinate, optionally in the presence of base.

12. A process according to claim 11, wherein step (ii) comprises treating cyclic sulfinyl ester (0301) with the reagent n-pentyl chloroformate.

13. A process according to claim 11 or 12, wherein the base used in step (ii) is an organic base.

14. A process according to claim 13, wherein the organic base is selected from a triaUcylamine, such as triethylamine or diisopropylethylamine, or an aromatic amine, such as pyridine.

15. A process according to any one of claims 4 to 14, wherein step (iii) comprises treatment of cyclic sulfinyl ester (0302) with an organic or inorganic base to obtain capecitabine.

16. A process according to claim 15, wherein the organic base is selected from ammonia or a trialkykmine, such as triemylamine or dusopropylemylamine.

17. A process according to claim 15, wherein the inorganic base is selected from a metal hydroxide or a metal carbonate, such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

18. A process according to any preceding claim, wherein the capecitabine is prepared in "one pot" without isolation of the intermediate cyclic sulfinyl esters (0301) or (0302).

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

20. A process according to claim 19, wherein the capecitabine formed is recrystallized from ethyl acetate.

21. A process for die preparation of galocitabine (2) comprising one or more of the following steps:

(ii) converting cyclic sulfinyl ester (0301) or a salt, tautomer, solvate or hydrate thereof, to cyclic sulfinyl ester (0402) or a salt, tautomer, solvate or hydrate thereof:

22. A process for the preparation of sapacitabine (3) comprising one or more of the following steps:

(i) converting the nucleoside (0501) or a salt, tautomer, solvate or hydrate thereof, to cyclic sulfinyl ester (0502) or a salt, tautomer, solvate or hydrate thereof:

(iii) deprotection of cyclic sulfinyl ester (0503) or a salt, tautomer, solvate or hydrate thereof, to obtain sapacitabine:

23. An N-functionalised cytidine derivative when prepared by a process according to any preceding claim, such as:

(a) capecitabine when prepared by a process according to any one of claims 1 to 20;

(b) galocitabine when prepared by a process according to any one of claims 1 to 3 or claim 21; or

(c) sapacitabine when prepared by a process according to any one of claims 1 to 3 or claim 22.

24. An N-functionalised cytidine derivative, such as capecitabine, galocitabine or sapacitabine, substantially free of chemical impurities.

25. An N-functionalised cytidine derivative, such as capecitabine, galocitabine or sapacitabine, according to claim 23 or 24, for the treatment or prevention of cancer.

26. An N-functionalised cytidine derivative, such as capecitabine, galocitabine or sapacitabine, according to claim 25, for the treatment or prevention of metastatic breast or colorectal cancer.

27. A pharmaceutical composition comprising an N-functionalised cytidine derivative, such as capecitabine, galocitabine or sapacitabine, according to any one of claims 23 to 26.

28. A pharmaceutical composition according to claim 27, for the treatment or prevention of cancer.

29. A pharmaceutical composition according to claim 28, for the treatment or prevention of metastatic breast or colorectal cancer.

30. A method of treating or preventing cancer, comprising administering a therapeutically or prophylactically effective amount of an N-functionalised cytidine derivative, such as capecitabine, galocitabine or sapacitabine, according to any one of claims 23 to 26 or a therapeutically or prophylactically effective amount of the pharmaceutical composition according to any one of claims 27 to 29 to a patient in need thereof.

31. A method according to claim 30, wherein the cancer is metastatic breast or colorectal cancer.

32. A method according to claim 30 or 31, wherein the patient is a mammal.

33. A method according to claim 32, wherein the mammal is a human.

34. A cyclic sulfinyl ester selected from a compound of formula (A-2), (A-3), (A-6), (A-7), and any salt, tautomer, solvate or hydrate thereof:

wherein:

R¹ and R³ are each independently selected from hydrogen, -F, -CI, -Br, -I, -CN, -N0₂, -N_j, -O-R⁷, -S-R⁷, -N ⁷)₂, -N(R⁷)₃ ⁺ or -0-Si(R⁷)₃;

R⁴ and R⁵ are each independendy selected from hydrogen, -F, -CI, -Br and -I;

R^c is selected from an alkyl, alkenyl, alkynyl, aiyl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton; and

35. A cyclic sulfinyl ester selected from a compound of formula (0301), (0302), (0402), (0502), (0503), and any salt, tautomer, solvate or hydrate thereof: