Compound (1) [Rl = H, lower alkyl, F, Cl, I, CF3 : R4 = H, alkyl, aryl : Rus = H, alkyl, aryl] Description of the Prior Art Hepatitis B virus (HBV) causing the acute and chronic inflammation of the liver is one of the main causes which give rise to the worldwide hygienic and sanitary problems. Today, it is known that the number of the chronic hepatitis patients infected by HBV amounts to over two hundred millions.

HBV, a double-stranded DNA virus, of which the polymerase can synthesize its DNA using both DNA and RNA as a template. This is why the medication effective against HBV infection has not been developed as yet and the vaccine treatment just for

avoiding HBV infection is known as the best alternative.

Interferon-a or a nucleoside analog such as adenine arabinoside or its phosphate (ara-AMP) has been prescribed to the HBV-infected persons, with no remarkable efficacy. Further, 3'-azido-3'-deoxythymidine, acyclovir, foscarnet and the like are also reported not so effective.

Recently, it has been revealed that 2', 3'-dideoxynucleoside derivatives effectively work on HBV in culture state. Especially, 2'3'-dideoxy-3'-thiacytidine and 2'3'-dideoxycytidine derivatives, with less toxicity, have proved to be superior to others in blocking the proliferation of HBV.

Meanwhile, it has further been disclosed that the proliferation of human immunodeficiency virus (HIV) causing acquired immunodeficiency syndrome (AIDS) can also be blocked by nucleoside derivatives such as 2', 3'-didehydro-3'- deoxythymidine, 2 \3"-didehydro-2', 3'-dideoxyguanosine, 3'-azido-2', 3 - dideoxyguanosine, 2', 3'-dideoxyinosine, 3'-fluoro-2', 3'-dideoxyadenosine and 2', 3 '-didehydro-2', 3'-dideoxycytidine (hereinafter, referred to as"DDC"). At present, some nucleoside derivatives including DDC are used for HIV treatment.

Conventional synthetic methods of 2 \3'-didehydro-2', 3'-dideoxycytidine derivatives can generally be classified into three different methods according to starting materials or reaction intermediates : (1) the method in which the corresponding cytidine or 2'-deoxycytidine derivatives is used as starting materials, @) the method which uses coupling between ribose derivatives and nucleobase, and (3) the method in which uridine or 2'-deoxyuridine derivatives is first synthesized.

(1) Some examples representing the synthetic methods which start from cytidine

or 2'-deoxycytidine derivatives are given below: 1) examples in that the acetate intermediate is reduced by Zn as a catalyst according to the formula of (USP 4900828; J. Org. Chem. 1992,57,3473; Synthesis 1993,303; J. Org. Chem. 1995,60,7902; Collect. Czech.

Chem. Commun. 1996,61,645; J. Org. Chem. 1992,44,1404; USP 3817982).

2) examples in that Barton deoxygenation is used (USP 5455339).

3) examples in that Corey-Winter reaction is used (EP 342422; J. Org. Chem.

1992,57,3473).

4) examples in that the sulfonate intermediate is formed (J. Org. Chem. 1967,32, 817; EP 409,227; Chem. Pharm. Bull. 1989,37,2547; Nucleosides & Nucleotides 1990, 9,1061).

In the above methods, however, the price of cytidine or 2'-deoxycytidine derivatives is higher than that of uridine or 2'-deoxyuridine derivatives; protection and deprotection of-NH2 group of cytidine derivatives are indispensably required during the synthetic process; heavy metals or highly toxic materials are used in some of the processes, all which are obstacles to the large-scale synthesis.

(2) There are problems in the method of coupling of ribose derivatives and nucleobases (WO 96/22778; USP 5905070; USP 5703058; USP 5220003) in terms of selectivity and purification because the isomeric mixture (a and f3 types) results from the coupling.

(3) The following examples are of the method starting from uridine or 2'- deoxyuridine derivatives.

1) examples of amination of uracil rings after synthesis of 2'3'-didehydro-2', 3'-dideoxyuridine (D4U) derivatives (Biochemical Pharmacology 1987,36,311; EP 261595; Org. Prep. Proc. Int. 1990,22,265; J. Med. Chem. 1990,33,1833; J. Pharm. Sci.

1994,83,339; Tetrahedron Lett. 1994,35,3477).

The processes of protection and deprotection of 5'-OH group should be essential to this method. Further, D4U derivatives are generally unstable to acid, base and heat, so that they are easily decomposed into the corresponding bases and 2', 3'- didehydro-2', 3'-dideoxyribose. Moreover, cytidine rings are formed from these unstable D4U derivatives through complicated processes, with low yield.

2) examples of D4C syntheses from the intermediate of D4U derivatives (Org.

Prep. Proc. Int. 1990,22,265; J. Med. Chem. 1996,39,1758; USP 5627160; USP 583088; USP 5631239; WO 93/23413; EP 204264).

This method has a disadvantage in that it cannot be adapted to large-scale synthesis because it takes about 70 hours to convert uracil ring to cytosine ring; the reagents are too expensive; and the reaction intermediates and final products should be separated and purifie only by chromatography.

SUMMARY OF THE INVENTION

Accordingly, the objective of the present invention is to provide a synthetic process of compound (1), which allows the cost-effective and large-scale synthesis thanks to the easy reaction and purification.

DETAILED DESCRIPTION OF THE INVENTION To achieve the above objective, the present invention provides the synthetic process of compound (1) comprising 5 steps; sulfonylation, oxetane-ring formation, activation of 4-C, amination, and double-bond formation.

Each step will be explained in the following.

(1) Sulfonylation In this step, compound (3) is prepared by converting 3'-and 5'-OH groups of compound (2) to sulfonyl groups through the action of R2SO2X and an organic base such as amine in an organic solvent. Here, X represents a halogen atom. 0 0 R R _ R2S02X N O N O HO R202S0 O Base OH R202SO Compound (2) Compound (3) [R'= H, lower alkyl, F, Cl, I, CF3: R2SO2 = organic sulfonyl : R = alkyl, aryl]

R2 represents a lower alkyl or aryl group. R2SO2C1 is a lower alkylsulfonyl chloride with R2 having 1-4 of carbon number such as methanesulfonyl chloride, trifluoromethanesulfonyl chloride, etc. or an arylsulfonyl chloride such as toluenesulfonyl chloride or benzenesulfonyl chloride, etc.

The base useable in this step may include pyridine, triethyleneamine (TEA) or N-methylmorphorline.

The solvent used in this step is preferably an aprotic organic solvent such as chloroform, dichloromethane, acetone or acetonitrile.

The ratio of compound (2): R2SO2X : organic base is 1: (2-10) : (2-20) by weight, preferably, 1: (2-4) : (2-10).

After an organic base and organic solvent are added to compound (2), the admixture is cooled to 0 ~ 5 C. R2SO2X is added dropwise and the reaction admixture is warmed to room temperature and stirred for 3-6 hours. Then, compound (2) is converted to compound (3) through the displacement of 3'-and 5'-OH groups by organic sulfonate. To this reaction admixture, water is added 3-20 times as much by volume, to solidify compound (3). After filtration of the solidified compound (3), the cake of compound (3) is obtained.

(2) Oxetane-Rins Formation In this step, the oxetane ring consisting of 3'-, 4'-and 5'-C is formed by the reaction of compound (3) with an alkali reagent in an aqueous solvent.

Any kind of inorganic base may be used for an alkali reagent but NaOH, KOH and the like is preferred. Compared with the conventional method in which the

refluxing of ethanol at 78°C is indispensably required, the stirring at 20-50°C alone can complete the reaction in the present invention.

First, an alkali reagent is added to water and 10-50% of compound (3) with respect to the amount of alkaline water is added by 1 ~ 10 portions with the time interval of 30-60min. At this stage of addition, the temperature should be kept at 20~50 C while stirring. After the reaction is completed, the reaction admixture is cooled to 0- 10°C and its pH is adjusted to 5.5-7.5. After additional stirring for 2-5 hours, the reaction admixture is filtered to obtain the solid, i. e. compound (4) which has an oxetane ring consisting of 3'-C, 4'-C, and 5'-C of compound (3). 0 pi JJ 0 Y"NH pi U Base ruz \NH \ NH N XO Base N XO R202SOutg 0 O R202SO Compound (3) Compound (4) [R'= H, lower alkyl, F, Cl, I, CF3: R2SO2 = organic sulfonyl : R2 = alkyl, aryl] (3) Activation of 4-C In this step, compound (5) is obtained by converting 4-C carbonyl group of compound (4) into organic sulfonyl group using R3SO2X in an organic solvent containing NaH, K2CO3 or a tertiary amine. Here, X represents a halogen atom.

A tertiary amine as aforementioned may include TEA, diisopropylethylamine (DIEA), etc., which works as a base. R3 in R3SO2X represents an aryl group such as

benzene, toluene, etc.

An organic solvent used in this step may include acetonitrile (AN), dichloroethane (DCE), methylisobutylketone (MIBK), or the like, but the polar solvent such as AN or MIBK is preferable in view of solubility of starting material, compound (4).

The ratio of compound (4): R3SO2X : K2CO3 or a tertiary amine is 1: (1 ~ 10) : (1 ~ 10), preferably, 1 : (1-4) : (1#4).

After mixing compound (4), R3SO2X and K2CO3 or a tertiary amine in the organic solvent, the reaction mixture is stirred at 0"-150°C for 0.5 ~ 10 hours. Then, compound (5) having an organic sulfonyl group at 4-C is obtained by the reaction of carbonyl group with a sulfonylation reagent. OS02R3 pi R3S02X N I N H NI O N_'O Base Basé ! 0 0 Compound (4) Compound (5) [Rl = H, lower alkyl, F, Cl, I, CF3: R3 = alkyl, aryl] (4) Amination The organic sulfonyl group at 4-C is transformed to an amine group by the reaction of compound (5) with ammonia, a primary, or a secondary amine in an organic solvent. Methylamine, ethylamine, benzylamine or the like can be used as a primary amine and dimethylamine, diisopropylamine, methylethylamine, methylbenzylamine or

the like can be used as a secondary amine. R4 and R5 in compound (6) can be identical or different with each other and each represent H, alkyl or aryl.

Any kind of organic solvent such as AN, DCE, MIBK, etc. can be used in this step. Ammonia gas or its solution in a solvent can either be used, and a primary or a secondary amine also can be used in a solution in a solvent.

Ammonia, a primary, or a secondary amine is added to the 4-C-activated reaction mixture at 0~ 150°C and then the reaction mixture is stirred for 0.5-3 hours.

After the reaction is completed, the reaction mixture is filtered at 0 w 100 C, to obtain compound (6) whose amine group is transformed from 4-C sulfonyl group of compound (5). OS02R3 NR4R5 ---N N ! or amine I I O O O O

Compound (5) Compound (6) [R1 = H, lower alkyl, F, Cl, I, CF3 : R4 = H, alkyl, aryl : R5= H, alkyl, aryl] (5) Double-Bond Formation In this step, the final product of the present invention, i. e. DDC derivatives are obtained by forming a double bond from the oxetane ring in the course of the reaction of compound (6) with an organic or inorganic base in an organic solvent.

For the convenience of processing, such solvent which has its boiling point

below 100°C as isopropyl alcohol, t-butanol, or the like is preferably used for said organic solvent. Potassium t-butoxide, potassium hydroxide, or the like can be used for said organic or inorganic base.

The ratio of compound (6): base is 1: (1-10), preferably, 1: (1 ~4).

After compound (6) is dissolved in a solvent, a base is added, and the refluxing is executed for 4-6 hours, then, the final target of the present invention, compound (1) is produced.

The reaction mixture in which compound (1) has been produced is cooled to 5 ~10C and its pH is adjusted to 6-8. After stirring it for 1~3 hours at room temperature, the reaction mixture is filtered and the filtrate is concentrated at reduced pressure. Finally, decolorization with methanol and the successive recrystallization give compound (1) with high purity. N R4R5 N R4R5 Ri Base <, Basa N''O-N O HOU O O O Compound (6) Compound (1) [Rl = H, lower alkyl, F, Cl, I, CF3: R4 = H, alkyl, aryl: R5= H, alkyl, aryl] The total reaction scheme is as follows: ° ° o R RZSOZX I N Base II NH R3SOzX HO, I"R 02SO 0 Base 0 I ease O OH R2 02SO Compound (2) Compound (3) Compound (4) OSOZR3 NR4R5 NR4R5 i R N NH3 or amine R \ Base N O N O NO HO < O

Compound (5) Compound (6) Compound (1) [Rl =H, lower alkyl, F, Cl, I, CF3 : R2SO2 = organic sulfonyl group: R2 =alkyl, aryl: R3 = alkyl, aryl: R4 = H, alkyl, aryl: R = H, alkyl, aryl] The synthetic process according to the present invention is advantageous in that the intended compound (1) can be obtained not only from the low-cost and easily- available raw materials over the process with no use of toxic materials such as heavy metals but also in short reaction time without pressurizing in the easily-reachable temperature ranges.

Further, the amination is carried out in the last stage of the process in the present invention, which allows even easier reaction and crystallization than the conventional process that has the step of early amination, with the result of easy separation and purification of the intermediate or product in each step, whereby the large-scale synthesis is made possible. Still further, the process according to the present invention has another advantage of simple recrystallizing purification of compound (1) in comparison with the previous chromatographic separation.

EXAMPLES To assist in understanding the present invention more clearly, the following examples are appended. The examples should not, of course, be construed to limit or alter the scope of the present invention. Further, the variations or modifications of the present invention which do not depart from the spirit of the present invention can easily be made by one of ordinary skill in the art and are considered to fall within the scope of the present invention.

Example 1 (1) Synthesis of 2'-deoxy-3'5'-dimethanesulfonyluridine To 50g of 2'-deoxyuridine were added pyridine of 60mL and dichloromethane of 40mL and then the reaction mixture was cooled to 5°C. 39mL of Methanesulfonyl chloride was added dropwise while stirring at room temperature. 50mL of water was added to remove the additionally-produced dichloromethane by evaporation. Then, the cake was filtered and 78.3g (93%) of 2'-deoxy-3', 5'-dimethanesulfonyluridine was obtained.

(2) Synthesis of 3'5'-anhydro-2'-deoxyuridine 27g of NaOH was dissolved in 160mL of water and to this solution was added 2 '-deoxy-3', 5'-dimethanesulfonyluridine (71g) divided by 3 portions with the time interval of 30 minutes. After stirring it for 2-3 hours at 35 °C to complete the reaction, it was cooled and its pH was adjusted to 6.7 using AcOH. Then, the reaction mixture

was stirred for 3~5 hours at 5 C and then filtered. The dried cake weighed 33.5g (86%) and was found to be 3', 5'-anhydro-2'-deoxyuridine.

(3) Synthesis of 3'5'-anhydro-2'-deoxy-4-0- (p-toluene- sulfonyl) uridine To 3', 5'-anhydro-2'-deoxyuridine (18g) were added p-toluenesulfonyl chloride (32g), K2CO3 (34g) and acetonitrile (180mL) and the reaction mixture was stirred for reflux for 4#5 hours. After the reaction was completed, 3', 5'-anhydro-2'- deoxy-4-O- (p-toluenesulfonyl) uridine was formed for use as a solution in the next step of reaction.

(4) Synthesis of 3'5'-anhydro-2'-deoxycytidine Insoluble materials in the above solution were filtered off and NH3 gas was added to the filtrate. The filtrate was stirred for 1 hour while maintaining the temperature at 70 C. Then, the reaction solution was concentrated. After adding 600mL of acetone thereto, it was stirred for 1 hour. Then, the reaction mixture was cooled, filtered, and dried, to obtain the cake of 3', 5'-anhydro-2'-deoxycytidine, which was used in the next step without purification.

(5) Synthesis of 2',3'-didehydro-2',3'-dideoxycytidine To 350mL of isopropyl alcohol were added potassium t-butoxide (11. 6g) and the above cake of 3', 5'-anhydro-2'-deoxycytidine, and then the reaction mixture was refluxed for 5 hours. After cooling, pH of the reaction mixture was adjusted to 7.0 using 2N methanolic HC1. After stirring it for 2 hours at room temperature, the reaction mixture was filtered and the filtrate was concentrated at reduced pressure. To the concentration residue, 35mL of methanol was added and the mixture was cooled to 4 °C.

The solid so formed was filtered and decolorized from methanol. The final recrystallization from methanol provided 2', 3'-didehydro-2', 3'-dideoxycytidine (8g, 44%).

Example 2 (1) Synthesis of 2'-deoxy-3', 5'-dimethanesulfonyl-5-fluoro-uridine To lOOg of 2'-deoxy-5-fluorouridine were added pyridine (125mL) and dichloromethane (25mL), and then the reaction mixture was cooled to 3 C. 75mL of Methanesulfonyl chloride was added dropwise and the reaction mixture was stirred for 4 hours at room temperature. Subsequently, water (350mL) was added to remove dichloromethane by evaporation. The cake so formed was filtered and 236g of wet cake of 2'-deoxy-3', 5'-dimethanesulfonyl-5-fluorouridine was obtained, which was used in the next step without drying or purification.

(2) Synthesis of 3'5'-anhydro-2'-deoxy-5-fluorouridine 50g of NaOH was dissolved in 56mL of water. To 86mL of water was added 4mL of NaOH solution and then the solution was warmed to 50°C. Wet cake of 2'- deoxy-3', 5'-dimethanesulfonyl-5-fluorouridine (23.7g) was added thereto and the reaction mixture was stirred at 50 C for 30 minutes. Addition of NaOH solution (4mL) and wet cake of 2'-deoxy-3', 5'-dimethanesulfonyl-5-fluorouridine (23.7g) was repeated by 9 times with the time interval of 30 minutes. After stirring it for 30 minutes at 50 C, the remainder of NaOH solution was all added up thereto and the reaction mixture was additionally stirred for 1 hour. The reaction mixture was then cooled and its pH was adjusted to 6.7 using AcOH. The reaction mixture was stirred for 2 hours at

5 C and then filtered. The dried cake was recrystallized from methanol, to obtain 3', 5 '-anhydro-2'-deoxy-5-fluorouridine (79g, 85%).

(3) Synthesis of 2', 3'-didehydro-2', 3'-dideoxy-5-fluorocytidine To 3', 5'-anhydro-2'-deoxy-5-fluorouridine (40g) were added p- toluenesulfonyl chloride (71g), K2CO3 (37g) and acetonitrile (475mL) and then the reaction mixture was stirred for reflux for 2 hours, to obtain 3', 5'-anhydro-2'-deoxy-5- fluoro-4-O-p-toluenesulfonyluridine solution. NH3 gas was added thereto at 60 C and then the solution was stirred for 2 hours to generate 3', 5'-anhydro-2'-deoxy-5- fluorocytidine. After cooling it to room temperature, the reaction mixture was filtered.

The filtrate was concentrated and 400mL of isopropyl alcohol and 38.8g of potassium t- butoxide were added to the concentration residue. After refluxing for 6 hours, the reaction mixture was cooled and its pH was adjusted to 7.0 using 2N methanolic HC1.

After stirring it at room temperature, the reaction mixture was filtered and the filtrate was concentrated at reduced pressure. To the concentration residue, 100mL of methanol was added and the reaction mixture was cooled to 4 OC. The solid so formed was filtered and decolorized with methanol. The final recrystallization from methanol provided 2', 3'-didehydro-2', 3'-dideoxy-5-fluorocytidine (15g, 38%).

INDUSTRIAL APPLICABILITY The present invention relates to the synthetic process of compound (1), which does not only allow the large-scale synthesis with high yield due to easy reaction and purification, but also can provide the lower-priced medications against Hepatitis B virus and AIDS since the present invention is superior to and more economical than the conventional processes in terms of the costs for equipments, law-materials, and processing by using the low-cost and non-toxic reagents starting from uracil derivatives which are cheaper than cytosine derivatives.