PREPARATION OF CAPECITABINE

INTRODUCTION

Aspects of the present application relate to processes for preparing capecitabine. In aspects, the present disclosure also relates to processes for preparing 5'-deoxy-2',3'-0-acetyl-5-fluorocytidine, which is an intermediate for preparing capecitabine.

The drug compound having the adopted name "capecitabine" has a chemical name 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyljcytidine and has structural formula I.

This drug is a fluoropyrimidine carbamate with antineoplastic activity. The commercial product XELODA™ tablets from Roche Pharmaceuticals contains either 150 or 500 mg of capecitabine as the active ingredient.

U.S. Patent No. 4,966,891 describes capecitabine generically and a process for the preparation thereof. It also describes pharmaceutical compositions, and methods of treating sarcoma and fibrosarcoma.

Bioorganic & Medicinal Chemistry, Vol. 8, pp. 1697-1706 (2000) discloses a process for preparing 5'-deoxy-2',3'-0-acetyl-5-fluorocytidine and its conversion to capecitabine. The process for 5'-deoxy-2',3'-0-acetyl-5-fluorocytidine is represented in Scheme 1.

Scheme 1

International Application Publication No. WO 2010/065586 A2 discloses a process for preparing 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose and its conversion to capecitabine. The process for the preparation of the intermediate compound 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose involves:

a) reacting D-ribose with methanol and acetone in the presence of concentrated hydrochloric acid, to form methyl-2,3-0-isopropylidene-D-ribofuranoside (formula A);

b) reacting the compound of formula A with p-toluenesulfonyl chloride (PTS-CI) in the presence of triethylamine, to form methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside (formula B);

c) reacting the compound of Formula B with NaBH4 in the presence of dimethylsulfoxide (4 ml_ per gram of formula B) to provide methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside (formula C);

d) reacting the compound of formula C with 0.04N sulfuric acid and then neutralizing with solid sodium carbonate, followed by evaporation to produce a residue, which is further reacted with acetic anhydride in the presence of trimethylamine to produce 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose (formula D).

The process can be represented as Scheme 2.
P. Sairam et al., "Synthesis of 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose from D-ribose," Carbohydrate Research, Vol. 338(4), pp. 303-306, 2003 discloses a process for preparing 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose. The process for preparing 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose is summarized in Scheme 3.

Scheme 3

Based on the above disclosures, the present inventors found that the processes disclosed suffer from one or more serious drawbacks, which do not make the processes amenable to scale up for industrial production. In particular, low yields and low purity of steps a)-d) products, and use of large volumes of a polar aprotic solvent such as dimethylsulfoxide (DMSO), result in low yields of subsequent step products with lower purities.

The compound of formula D is a starting material for 5'-deoxy-2',3'-0-acetyl-5-fluorocytidine and its derivatives, hence purity of the intermediate plays an important role in increasing the yield and purity of 5'-deoxy-2',3'-0-acetyl-5-fluorocytidine and its derivatives.

Hence, there remains a need for an improved process to prepare 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose, which is economically viable and easy to handle at a commercial scale for preparing the intermediate compound 5'-deoxy-2',3'-0-acetyl-5-fluorocytidine of high purity which is useful in the preparation of capecitabine.

SUMMARY

An aspect of the present application provides processes for preparing 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose, embodiments comprising:

a) reacting D-ribose with 10% methanolic hydrochloric acid and methanol, followed by 10% methanolic hydrochloric acid and acetone, to provide methyl-2,3-0-isopropylidene-D-ribofuranoside (formula A);

b) reacting methyl-2,3-0-isopropylidene-D-ribofuranoside (formula A) with p-toluenesulfonyl chloride in the presence of a phase transfer catalyst and a suitable base, to form methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside (formula B);

c) reducing methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside (formula B), in the presence of a polar aprotic solvent, to form methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside (formula C); and

d) deprotecting methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside (formula C) with an acid to provide 5-deoxy-D-ribofuranose (triol), which is acetylated with acetic anhydride in the presence of triethylamine, to form 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose (formula D).

DETAILED DESCRIPTION

An aspect of the present application provides processes for preparing 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose, embodiments comprising:

a) reacting D-ribose with 10% methanolic hydrochloric acid and methanol, followed by
10% methanolic hydrochloric acid and acetone, to provide methyl-2,3-0-isopropylidene-D-ribofuranoside (formula A);

b) reacting methyl-2,3-0-isopropylidene-D-ribofuranoside (formula A) with p-toluenesulfonyl chloride in the presence of a phase transfer catalyst and a suitable base, to form methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside (formula B);

c) reducing methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside (formula B), in the presence of a polar aprotic solvent, to form methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside (formula C); and

d) deprotecting methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside (formula C) with an acid to provide 5-deoxy-D-ribofuranose (triol), which is acetylated with acetic anhydride in the presence of triethylamine, to form 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose (formula D).

Individual steps are separately described below.

Step a) involves reacting D-ribose with 10% methanolic hydrochloric acid and methanol, followed by 10% methanolic hydrochloric acid and acetone, to provide methyl-2,3-0-isopropylidene-D-ribofuranoside (formula A);

The O-methylation and the hydroxyl group protection using acetone on D-ribose is carried out in two stages. Methanol is added to a reaction mass in the presence of methanolic hydrochloric acid, followed by acetone in the presence of methanolic hydrochloric acid being added to form methyl-2,3-0-isopropylidene-D-ribofuranoside.

Methanolic hydrochloric acid is added in increments to D-ribose, where the quantity of each portion can be 0.1 mole equivalents and 0.05 mole equivalents, per mole equivalent of D-ribose. In embodiments, methanolic hydrochloric acid may be prepared by purging anhydrous hydrogen chloride gas in methanol for a sufficient time period.

Suitable temperatures for conducting the reaction of D-ribose with methanol and acetone can be 20°C to 50°C. The reaction can be conducted until less than about 1% of the starting material remains. In general, this can require about 20 to about 25 hours.

After completion of the reaction, the reaction mass pH is adjusted to 7.5 to 8 with a base, such as sodium carbonate, sodium bicarbonate, or sodium hydroxide, and then the mass is evaporated completely to remove the methanol and acetone. The obtained residue is extracted into organic solvents, including, but not limited to: aromatic hydrocarbons, for example, toluene and xylene; aliphatic hydrocarbons, for example, hexane and heptane; halogenated hydrocarbons, for example, chloroform, ethylene dichloride, carbon tetrachloride and dichloromethane; ethers such as diethyl ether and diisopropyl ether; and any combinations thereof.

The resulting solution can be used directly in the subsequent reaction stage.

Step b) involves reacting methyl-2,3-0-isopropylidene-D-ribofuranoside (formula A) with p-toluenesulfonyl chloride in the presence of a phase transfer catalyst and a suitable base, to form methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside (formula B);

Suitable phase transfer catalysts for use in step b) include, but are not limited to, tetraalkylammonium or phosphonium halides such as tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulphate, crown ethers such as 15-crown-5 and 18-crown-6, and the like.

Suitable bases for use in step b) include, but are not limited to, inorganic bases, such as alkali metal hydroxides and alkali metal alkoxides. The alkali metal hydroxides include lithium hydroxide, sodium hydroxide, and potassium hydroxide, and alkali metal alkoxides include compounds such as sodium methoxide, sodium ethoxide, and potassium tertiary-butoxide. The base can be used in the form of an aqueous solution.

Suitable solvents for use in step b) include, but are not limited to: nitriles such as acetonitrile and propionitrile; halogenated hydrocarbons such as chloroform,
ethylene dichloride, carbon tetrachloride, dichloromethane, and the like; nitriles; ketones; aliphatic hydrocarbons; aromatic hydrocarbons such as toluene and xylene; dimethylsulfide; dimethylsulphoxide; and any mixtures thereof.

The tosylation reaction is carried out by adding a solution of p-toluenesulfonyl chloride, in a solvent such as aromatic hydrocarbon, to the reaction mass at temperatures about 0-40°C and maintaining the reaction until less than about 5% of the starting material remains. Reaction times of about 3-8 hours can be required.

After completion of the reaction, the mass is separated into two layers. The organic layer is washed with warm water and then evaporated completely at a suitable temperature, for example, below about 50°C, or about 45-50°C. A solid is precipitated using an alcohol and petroleum ether. Alcohols such as methanol, ethanol, isopropyl alcohol, and the like are useful.

It has now been found that the use of an inorganic base in presence of a phase transfer catalyst provides a biphasic reaction mixture that reduces the formation of by-products such as p-toluenesulfonic acid.

The yield of the compound of formula B, obtained by the process described above, can be about 75%, and the purity can be about 99.5% as determined using high performance liquid chromatography.

Step c) involves reduction of methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside (formula B), in the presence of a polar aprotic solvent, to form methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside (formula C).

Suitable polar aprotic solvents include dimethylsulfoxide, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), and N-methylpyrrolidone (NMP). Typical quantities of polar aprotic solvent may range from about 2 to about 3.5 mL, per gram of starting material, or about 3 mL per gram.

Reduction is performed by reaction with sodium borohydride. Quantities of sodium
borohydride used are typically about 1.5-2 molar equivalents, per equivalent of the starting methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside reactant.

In general, the reduction reaction can be performed under an inert atmosphere, such as a nitrogen atmosphere. The reaction with sodium borohydride is highly exothermic, so addition of sodium borohydride can be in small portions over an extended time, such as over about 1 to 2 hours at ambient temperatures.

The reduction reaction may be performed in the presence of an organic base such as triethylamine, methylamine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, and the like, to reduce the requirements of polar aprotic solvent and sodium borohydride to minimum levels. The amount of base used may range from about 0.1 mole to about 1 mole, per mole equivalent of the starting reactant (formula B). Sodium borohydride used for the reduction, in the presence of an organic base, is below about 2 mole equivalents, or about 1.5 mole equivalents, per mole equivalent of starting reactant (formula B), and amounts of polar aprotic solvent used are less than about 2 ml_, per gram of starting reactant.

The temperature of the reaction can be gradually increased to 80-85°C in increments, to increase the formation of product with high purity. For example, the reaction mass can be heated to the temperatures 40-45°C, 50-55°C, 60-65°C, 70-75°C, and then 80-85°C, with 30 minutes being required to reach each higher temperature and the reaction being maintained for 1-2 hours at each temperature. If the reaction is not complete, the reaction mass can be stirred for an additional 4 to 6 hours at 80-85°C, until the content of unreacted starting material is below 1%.

After the desired extent of completion of the reaction, the reaction is quenched by mixing with aqueous acetic acid below 20°C, the product is extracted into an aromatic hydrocarbon such as toluene or xylene, and then the organic layer can be used directly in the next reaction stage.

The yield of methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside (formula C), obtained from the process of the present disclosure, is about 92% with respect to the compound of methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside (formula B). The purity of the compound of formula C is about 98% by gas chromatography.
Step d) involves deprotecting methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside (formula C) with an acid to provide 5-deoxy-D-ribofuranose (triol), which is acetylated with acetic anhydride in the presence of triethylamine to form 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose (formula D).

Acids that can be used for the preparation of the triol include mineral acids such as sulfuric acid and hydrochloric acid. The reaction can be performed at reflux temperature for about 9-12 hours, until the content of unreacted starting material is below 5%.
After completion of the reaction, the aqueous layer is separated and its pH is adjusted to about 4-7, or about 4-4.5, with an aqueous solution of a base, such as sodium hydroxide, sodium carbonate, sodium bicarbonate, and the like, and then the mass is evaporated completely. The residue is mixed with ethyl acetate and again subjected to evaporation, until the water content is below 3%.

The compound is acetylated with acetic anhydride in the presence of a reagent such as triethylamine at ambient temperature, such as about 25-30°C, for times about 1-5 hours.
The acetylation reaction can also by performed with acetic anhydride, in the presence of sodium acetate, zinc chloride, or dimethylaminopyridine.

After completion of the reaction, the reaction is quenched with water and the product is extracted into an aromatic hydrocarbon, such as toluene or xylene. The organic layer is washed with 10% dilute hydrochloric acid solution, followed by sodium bicarbonate solution, and then is evaporated completely below 45°C, until the content of toluene is below 1%.

The overall yield of 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose, obtained from the present process, can be about 80-85% with respect to the compound methyl-2,3-O-isopropylidene-5-O-tosyl-D-ribofuranoside (formula B).

The purity of the compound, 2,3-tri-0-acetyl-5-deoxy-D-ribofuranose, obtained from the present process, can be greater than about 98.5% by high performance liquid chromatography.

The resultant pure compound 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose (formula D) is used for the preparation of 2',3'-di-0-acetyl-5'-deoxy-5-fluorocytidine, which is an intermediate for capecitabine according to the process disclosed in WO 2010/065586 A2.
It has now been found that the use of pure 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose (formula D) as a starting material results in substantially pure 2',3'-di-0-acetyl-5'-deoxy-5-fluorocytidine, "Substantially pure" indicates purity at least about 98% by weight or having contents of impurities at RRTs (relative retention times) about 1.56 and 1.28-1.3, up to less than about 1%, or less than about 0.5% by weight using the high performance liquid chromatography (HPLC). This may avoid any further additional purification steps in subsequent stages of process for preparing Capecitabine.

HPLC analysis of a compound having Formula D and associated impurities can be performed using an instrument with an INERTSIL ODS 2.250x4.6 mm, 5 fim column, and the following parameters:

Wavelength of detection: 240 nm.
Flow rate: 1.0 mL/minute.
Buffer: 1.0 mL of glacial acetic acid in 1000 mL of milli-Q water.
Eluent A: 60% buffer, 35% methanol, and 5% acetonitrile (by volume).
Eluent B: 15% buffer, 80% methanol, and 5% acetonitrile (by volume).
Injection volume: 10 uL
Column temperature: 40±2°C.
Gradient program (values are volume percent):

Embodiments of the processes of the present application provide 2',3'-di-0-acetyl-5'-deoxy-5-fluorocytidine (formula D) having purities equal to or greater than about 98%, or greater than about 99%, and containing less than about 0.5% of 5-fluorocytosine, less than about 0.2% of 2',3'5'-th-0-acetyl-5-fluorocytidine, less than about 0.1% of a compound at about 1.56 RRT, less than about 0.2% of any other individual impurity; and less than about 2%, or less than about 1%, of total impurities, as determined using the above HPLC method.

Certain specific aspects and embodiments of the disclosure will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES EXAMPLE 1: Preparation of methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside.

D-ribose (100 g), methanol (300 mL) and 10% hydrogen chloride in methanol (24 g) are charged into a round bottom flask and stirred for 10 minutes at 25-30°C.

The solution is heated to 30-35°C and stirred for 4 hours. Acetone (400 mL) and 10% hydrogen chloride in methanol (12 g) are added at 30-35°C. The mass is heated to 35-40°C and stirred for about 24 hours. After reaction completion, the mass is cooled to 25-30°C and pH is adjusted to 7.5-8 with aqueous sodium carbonate solution (8 g of sodium carbonate in 80 mL of water). The mass is stirred for 15 minutes at 25-30°C and then is evaporated under vacuum (~600-650 mmHg) at a temperature below 45°C, and then is cooled to 25-30°C. Toluene (300 mL) is added and the mass is stirred for 10 minutes. The organic layer is separated and the aqueous layer is extracted with toluene (100 mL). The combined organic layers are washed with brine solution (10 g sodium chloride in 100 mL of water).

Water (400 ml) and the organic layer are charged into a round bottom flask to at 25-30°C and cooled to 10-15°C. Sodium hydroxide solution (82.56 g in 130 mL of water) is added over 45-60 minutes and the mass is stirred for 10-15 minutes. Tetrabutyl ammonium bromide (TBAB) (3 g) is added. A solution of p-toluenesulphonyl chloride (217 g) in toluene (300 mL) is added over 2 hours and the mass is stirred for 3 hours at 10-15°C. The mass is allowed to 28-32°C and maintained for 4 hours. The organic layer is separated and the aqueous layer is extracted with toluene (200 mL). The organic layer is washed with warm water (40-45°C, 100 mL), then is evaporated under vacuum (~650-700 mmHg) at 45-50°C. Isopropyl alcohol (100 mL) is added to the residue and then evaporated under vacuum (~650-700 mmHg) below 50°C. Another quantity of isopropyl alcohol (200 mL) is added to the residue and stirred for 30 minutes. Petroleum ether (600 mL) is added at 45-50°C, mass is cooled to 25-30°C and stirred for 30 minutes. The mass is further cooled to -5 to 0°C and stirred for 4 hours. The formed solid is filtered and washed with pre-cooled (0-5°C) isopropyl alcohol (30 mL) and petroleum ether (180 mL). The solid is dried at 35-40°C under vacuum (~ 600 mmHg) for 6 hours.
Yield: 181.5 g (76%), purity: 99.62% by HPLC.

EXAMPLE 2: Preparation of methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside. Methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside (100 g) and dimethylsulfoxide (300 mL) are charged into a round bottom flask at 25-30°C. Sodium borohydride (21 g) is added in 10 portions over 90 minutes, at 25-35°C under a nitrogen atmosphere and the mass is stirred for 90 minutes at 40-45°C under a nitrogen atmosphere. The mass is heated to 50-55°C, 60-65°C, and 70-75°C sequentially, with 25 -30 minutes to reach each new temperature and maintenance for 60-90 minutes at each temperature. The mass was heated to 80-85°C within 25-30 minutes and maintained for 4-5 hours. After reaction completion, the mass is cooled to 10-15°C and the reaction is quenched with dilute acetic acid solution (25 mL glacial acetic acid in 500 mL of water) below 15°C. The mass is heated to 25-30°C and stirred for 15 minutes. Toluene (300 mL) is added and the mass is stirred for 15 minutes. The organic layer is separated and the aqueous layer is extracted with toluene (100 mL). The organic layers are combined and washed with water (200 mL).

Yield (compound in solution): 50.8 g (96.94%), Purity by gas chromatograpgy (GC): 98.47%

EXAMPLE 3: Preparation of methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside.
Methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside (50 g) in dimethyl sulfoxide (75 mL) and triethylamine (9.7; d: 0.77) are charged into a round bottom flask at 25-30°C and stirred to obtain a solution. Sodium borohydride (7.9 g) is slowly added over 80 minutes under a nitrogen atmosphere. The mass is heated to 50-55°C, 60-65°C, and 70-75°C sequentially and maintenance for 60 minutes at each temperature. The mass is then heated to 80-85°C and maintained for 4-5 hours. After reaction completion, the mass is cooled to 0 to 5°C and the reaction is quenched with aqueous acetone (25 mL of acetone in 150 mL of water) at 0-5°C. The pH is adjusted to 4-4.5 by adding dilute sulphuric acid solution and the mass is stirred for 2 hours. The mass is heated to 25-30°C and maintained for 15-25 minutes. Toluene (150 mL) is added and the mass is stirred for 15 minutes. The organic layer is separated and the aqueous layer is extracted with toluene (100 mL). The organic layers are combined and washed with brine solution.
Yield (compound in solution): 92%, Purity by HPLC: 98.48%

EXAMPLE 4: Preparation of 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose.
Methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside in toluene (465 mL), obtained according to the process of Examples 2 and 0.04N sulphuric acid (500 mL) are charged into a round bottom flask at 25-30°C and stirred for 25-30 minutes. The reaction mass pH is maintained at 1.5-2 using 0.04N sulphuric acid and the mass is heated to 80-85°C and stirred for 12 hours. After reaction completion, the mass is cooled to 25-30°C and the organic layer is separated. The aqueous layer pH is adjusted to 4-4.5 using 10% sodium carbonate solution, the solution is stirred for 25-30 minutes, and reaction mass is concentrated at a temperature below 45°C under reduced pressure to obtained a residue. To the residue, ethyl acetate (150 mL) is added and evaporated. The ethyl acetate addition and evaporation is repeated two more times until the water content is below 3% w/w. Toluene (260 mL) and triethylamine (192 mL) are added to the residue, and the mixture is stirred for 15 minutes and then cooled to 10-15°C. Acetic anhydride (152 g) is added below 20°C under a nitrogen atmosphere. The mass is heated to 25-30°C stirred for 2 hours at 25-30°C under a nitrogen atmosphere. After reaction completion, water (100 mL) is added below 30°C and the mass is stirred for 30 minutes at 25-30°C. The organic layer is separated and the aqueous layer is extracted with toluene (100 mL) at 25-30CC. The organic layers are combined, stirred with 10% dilute hydrochloric acid solution (45 mL of concentrated hydrochloric acid in 115 mL of water) for 10-15 minutes at 25-30°C, and the organic layer is separated. The organic layer is washed with sodium bicarbonate solution (15.8 g of sodium bicarbonate dissolved in 158 mL of water) and then with water (100 mL). The organic layer is concentrated below 45°C under vacuum (~ 550 to 600 mmHg). Yield: 58.20 g, Purity: 98.88% by GC

EXAMPLE 5: Preparation of 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose.
Methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside in toluene (461 mL), obtained according to a process of Examples 2 or 3 and 0.04N sulphuric acid (500 mL) are charged into a round bottom flask at 25-30°C and stirred for 25-30 minutes. The mass is heated to 80-85°C and stirred for 11 hours. After completion of the reaction, the mass is cooled to 25-30°C and the organic layer is separated. The aqueous layer pH is adjusted to 4-4.5 using 10% sodium carbonate solution (12 mL), the mass is stirred for 25-30 minutes, and solvent is evaporated below 45°C under reduced pressure. To the residue, ethyl acetate (150 mL) is added and evaporated. The ethyl acetate addition and evaporation is repeated two more times until the water content is below 3% w/w. Acetic anhydride (170 g) and sodium acetate (3.4 g) are added to the residue, and the mass is heated to 55-60°C and stirred for 4 hours under a nitrogen atmosphere. After completion of the reaction, the reaction is quenched with ice cold water (100 mL) and toluene (150 mL) is added. The organic layer is separated and the aqueous layer is extracted with toluene (100 mL) at 25-30°C. The organic layers are combined and washed with 10% sodium bicarbonate solution (100 mL). The organic layer is washed with water (2x100 mL) and then is concentrated below 45°C under vacuum (~550-600 mmHg). Yield: 59.40 g (81.8%), Purity: 99.36% by GC

EXAMPLE 6: Preparation of N,0-(disilylated)-5-fluorocytosine and 2',3'-di-0-acetyl-5'-deoxy-5-fluorocytidine.

5-fluorocytosine (24 g), hexamethyldisilazane (38.5 mL), and trimethylsilyl chloride (4.25 mL) and toluene (150 mL) are charged into a round bottom flask at 25-30°C and heated to 110-115°C. The mixture is stirred for 1 hour and then cooled to 50-55°C. The solvent is evaporated at 50-60°C under vacuum and the residue is cooled to 25-30°C. Dichloromethane (1000 mL) is added to the residue and the mixture is cooled to 0-5°C. A solution of 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose (50 g) in dichloromethane (50 mL) is added over 30 minutes. SnCI4 (24 mL) is added, the temperature is allowed to rise to 25-30°C, and the mixture is stirred for 2 hours. Sodium bicarbonate (82 g) and water (30 mL) are added, maintained the reaction mass for about 2 hours. The mixture is filtered and the filtrate is washed with 5% sodium bicarbonate solution (250 mL). The clear organic layer is evaporated under vacuum below 45°C. Isopropyl alcohol (50 mL) is mixed with the residue and evaporated. Isopropyl alcohol (125 ml) is added to the residue and the mixture is heated to 40-50°C. The mixture is cooled to 0-5°C and stirred for 1 hour. The formed solid is filtered, washed with isopropyl alcohol (25 mL), and dried at 40-45°C under vacuum for 4-5 hours, to afford 47.5 g of the title compound.
Purity: 99.39% by HPLC, 1.54 RRT impurity: 0.052%.

Claims:

1. A process for preparing 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose, comprising the steps of:

a) reacting D-ribose with 10% methanolic hydrochloric acid and methanol, followed by 10% methanolic hydrochloric acid and acetone, to provide methyl-2,3-0-isopropylidene-D-ribofuranoside (formula A);

b) reacting methyl-2,3-0-isopropylidene-D-ribofuranoside (formula A) with p-toluenesulfonyl chloride in the presence of a phase transfer catalyst and a suitable base, to form methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside (formula B);

c) reducing methyl-2,3-0-isopropylidene-5-0-tosyl-D-ribofuranoside (formula B), in the presence of a polar aprotic solvent, to form methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside (formula C); and

d) deprotecting methyl-5-deoxy-2,3-0-isopropylidene-D-ribofuranoside (formula C) with an acid to provide 5-deoxy-D-ribofuranose (triol), which is acetylated with acetic anhydride in the presence of triethylamine, to form 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose (formula D).

2. The process of claim 1, wherein methanolic hydrochloric acid in step a) is added in portions to D-ribose, wherein the quantity of each portion is 0.1 mole equivalents and 0.05 mole equivalents, per mole equivalent of D-ribose.

3. The process of claim 1, wherein the phase transfer catalyst used in step b) is selected from tetraalkylammonium or phosphonium halides such as tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulphate and crown ethers such as 15-crown-5, 18-crown-6.

4. The process of claim 1, wherein the base used in step b) is an inorganic base selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tertiary-butoxide.

5. The process of claim 1, wherein step b) is carried out in the presence of solvent selected from nitriles such as acetonitrile and propionitrile, halogenated hydrocarbons such as chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane, ketones, aliphatic hydrocarbons, aromatic hydrocarbons such as toluene and xylene, dimethylsulfide, dimethylsulphoxide and mixtures thereof.

6. The process of claim 1, wherein the reduction in step c) is carried out using sodium borohydride and an organic base selected from triethylamine, methylamine, tetramethylammonium hydroxide and tetrabutylammonium hydroxide.

7. The process of claim 1, wherein the polar aprotic solvent used in step c) is selected from dimethylsulfoxide, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), and N-methylpyrrolidone (NMP).

8. The process of claim 1, wherein the acid used in step d) is selected from mineral acids such as sulfuric acid and hydrochloric acid and the reaction of step d) is performed at reflux temperatures.

9. 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose (formula D) produced according to the process of claims 1-8 and having a purity of greater than about 98.5% by high performance liquid chromatography.

10. Use of 1,2,3-tri-0-acetyl-5-deoxy-D-ribofuranose (formula D) produced according to the process of any one of the claims 1-8 in the process for the preparation of capecitabine.