MX2007000959A - 1- -halo-2,2-difluoro-2-deoxy-d-ribofuranose derivatives and process for the preparation thereof. - Google Patents

Abstract

1- -halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of formula (I) having the 3-hydroxy group protected with a biphenylcarbonyl group is a solid which can be easily purified by a simple procedure such as recrystallization, and therefore, it can be advantageously used as an intermediate in the preparation of gemcitabine in a large scale. Further, the 1- -halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of formula (I) can be prepared with high stereoselectivity using the compound of formula (V) as an intermediate.

Description

DERIVATIVES OF l-oc-HALO-2, 2-DIFLUORO-2-DESOXI-D-RIBOFURANOSA AND PROCESS FOR THE PREPARATION OF THE SAME FIELD OF THE INVENTION The present invention relates to a new derivative of la-halo-2, 2-difluoro-2-deoxy-D-ribofuranose, and to a process for the preparation thereof which is useful as an intermediate in the production of gemcitabine. BACKGROUND OF THE INVENTION Gemcitabine of formula (A), a medicament for the treatment of non-small cell lung cancer (NSCLC), is a synthetic nucleoside analog having a cytosine nucleobase stereochemically oriented upstream to the β direction in C-I of the ribofuranose backbone.

Gemcitabine can be prepared conventionally from a lactol compound as shown in Reaction Scheme 1 via an activated ribofuranose intermediate having a leaving reactive group: Reaction Scheme 1 (ñ) (C) Where P1 is a hydroxy protecting group, and L is a leaving group. Specifically, gemcitabine can be prepared by introducing a salient (L) reactive group in Cl of the ribofuranose ring of a compound (B) lactol to obtain an intermediate (C) of activated ribofuranose, and Ib) glycosylation of the compound of formula (C) C) with cytosine to form an N-glycosidic bond. In Reaction Scheme 1, the glycosylation step Ib) is experienced via a bimolecular mechanism (SN2) of nucleophilic substitution, and thus, it is important in the preparation of gemcitabine to obtain a high purity α-anomer of the compound (C) which has the outgoing group (L) oriented downwards. Accordingly, many attempts have been made to develop a process for stereoselectively introducing a leaving group (L) into C-1 of the ribofuranose ring of compound (B) lactol.

For example, U.S. Patent Nos. 4,526,988 and 5,453,499 describe an activated ribofuranose intermediate such as 1-a-halo-ribofuranose having a halo leaving group introduced in C-1 of the ribofuranose ring. Specifically, U.S. Patent No. 4,526,988 describes a method for preparing a 1-a-halo ribofuranose derivative of formula (F) by 2a) reacting the 1-hydroxy group of a lactol compound of formula (D) with a source of acetyl such as acetic anhydride to obtain a 1-acetate derivative of formula (E), and 2b) react the 1-acetate derivative of formula (E) with HBr or gaseous HCl to obtain a 1-halo ribofuranose, as shown in Reaction Scheme 2: Reaction Scheme 2 wherein, R 'is a hydroxy protecting group, Ac is acetyl, and X is Br or Cl. However, this process provides a low yield of the desired a-halo anomer due to its low stereoselectivity.

U.S. Patent No. 5,453,499 discloses a process for preparing an α-enriched 1-halo ribofuranose of formula (H) having an a: β ratio of 9: 1 to 10: 1 by reacting a β-sulfonate compound of formula (G) with a halide source in an inert solvent, as shown in Reaction Scheme 3: Reaction Scheme 3 wherein, P "is a hydroxy protecting group such as benzoyl, R" is sulfonate, and Y is halogen. However, the 1-sulfonate compound of formula (G) used as a starting material in this process, prepared via a lactol compound by the method described in US Patent No. 5,401,861, has a ratio: β of about 1: 4 , and consequently, the ratio (a: ß) of global stereoselectivity for the 1-halo anomer is only about 3: 1. In addition, the above 1-a-halo-furanoses having the 3- and 5-hydroxy groups protected, for example, by benzoyl groups, exist in an oily state which is more difficult to handle and store than a solid form, in addition from the fact that an inexpensive column chromatography process is required for its isolation from a mixture of -and β-anomers. Therefore, there has been a need to develop an improved process for preparing gemcitabine using an a-halo-furanose as an intermediate. BRIEF DESCRIPTION OF THE INVENTION Accordingly, it is a primary object of the present invention to provide a novel 1-a-halo-D-ribofuranose derivative in a solid form, which can be purified using a simple purification procedure such as recrystallization suitable for mass production. It is another object of the present invention to provide a highly stereoselective method for preparing said compound with high purity and yield. It is still another object of the present invention to provide a compound that can be used as an intermediate in said method. In accordance with one aspect of the present invention, there is provided a l-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of formula (I) in a solid form: wherein, R1 is benzoyl or R2 is hydrogen, cyano, halogen, carboalkoxy, nitro, C? _2 alkoxy, C? _2 alkyl or dialkylamino; and X is Cl, Br or I. In accordance with another aspect of the present invention, there is provided a method for preparing the 1-a-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of formula I), comprising the steps of (i) reducing to a 1-oxoribose compound of formula (II) to obtain a lactol compound of formula (III); (ii) reacting the compound of formula (III) with a halophosphate compound of formula (IV) in the presence of a base to obtain a 1-phosphate furanose derivative of formula (V); and (iii) reacting the compound of formula (V) with a halide source, followed by recrystallization of the resulting product to obtain the 2-difluoro-2-deoxy-D-ribofuranose derivative of the formula (I): (DOO OR X-P OR8) 2 (IV) wherein, R1, R2 and X have the same meanings as defined above; and R3 is methyl, ethyl or phenyl, preferably phenyl. According to yet another aspect of the present invention, there is provided a novel 1-phosphate furanose derivative of formula (V) which can be used as an intermediate in the preparation of the 1- halo-D-ribofyran derivative of formula (I): wherein, R1, R2 and R3 have the same meanings as defined above. DETAILED DESCRIPTION OF THE INVENTION The term "enriched anomer" used herein refers to a mixture of anomers, having a specific content of anomers greater than 50%, preferably a substantially pure anomer. Among the compounds of formula (I) of the present invention, those wherein R2 is hydrogen are preferred. The inventive ribofuranose derivative of formula (I) is characterized as having a 3-hydroxy group protected with a biphenylcarbonyl group. Also, the inventive derivative may have a biphenylcarbonyl group as the 5-hydroxy protecting group. Thus, the inventive 1-a-halo-ribofuranose derivative can be obtained as a solid and, accordingly, can be easily purified in a high purity of 99.5% or more by a simple purification procedure such as recrystallization. Also, the inventive 1-a-halo-ribofuranose derivative of formula (I) can be coupled with cytosine by a conventional glycosylation reaction to prepare the gemcitabine having the cytosine radical in Cl of the ribofuranose ring oriented upwards (β-configuration). ). In the preparation of gemcitabine via the glycosylation step using a 1-halo ribofuranose derivative, the purity of the 1-halo anomer is very important. If the content of the ß-halo anomer increases, the stereoselectivity of the glycosylation reaction decreases markedly, leading to a low yield of the desired β-nucleoside, gemcitabine. Accordingly, gemcitabine can be efficiently prepared by performing the glycosylation using the inventive a-halo compound having a high proportion of β- / α-anomer from 4 to 14, which is notably higher relative to conventional methods (the ratio ß- / a-anomer is 2 to 3). The inventive method for preparing the 1-a-halo furanose derivative of formula (I) is described in Reaction Scheme 4. Reaction Scheme 4 wherein, R1, R2, R3 and X have the same meanings as defined above. In Reaction Scheme 4, the l-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of formula (I) can be prepared in a form having a high a-anomer content of 95% or more by (i) reducing the 1-oxoribose compound of formula (II) according to a conventional method to obtain the lactol compound of formula (III), a mixture of cx- and β-anomers; (ii) reacting the compound of formula (III) with a halo phosphate compound of formula (IV) in the presence of a base to obtain the β-enriched furanose phosphate of formula (V) having a β / a ratio of 10 or more; and (iii) reacting the compound of formula (V) with a halide source to obtain the compound of formula (I). The use of the novel furanose intermediates of formula (V) having a phosphate leaving group is the only characteristic of the inventive method for preparing the 1-halo ribofuranose of formula (I) having a high a-anomer content. Thus, in step (ii) to prepare the furanose phosphate of formula (V) from the lactol compound of formula (III), the anomeric β-phosphate can be obtained with a high ratio β / a of greater than 10. Also, the subsequent step (iii) can be carried out continuously without isolating the intermediate to obtain the a-halo furanose of formula (I) with a high a / β ratio of at least 10. In addition, according to the present invention, the a-halo furanose is obtained as a solid when a biphenylcarbonyl group is adopted as the 3- and / or 5-hydroxy protecting groups of the ribofuranose ring, and the solid form can be easily purified to an enantiomer purity of 99.5% or more using a process simple purification, which makes it possible to prepare the desired β-nucleoside having a high ß / a ratio of 4 to 14. Such a high ß / a ratio is markedly higher than the ß / a ratio of 2 to 3 that is made in conventional methods. Specifically, in step (i) of Reaction Scheme 4, the lactol compound of formula (III) can be prepared by reducing the compound of formula (II) with a reducing agent, as described in U.S. Patent Nos. 4,526,988 and 5,464,826. The 1-oxoribose compound of formula (II) used as the starting material in step (i) can be prepared by a method comprising the steps of protecting the 3-hydroxy group of a compound of formula (VI) with a group of biphenylcarbonyl protection, followed by hydrolyzing the resulting product in the presence of a base to obtain a 3R-carboxylate enantiomer of formula (VII): (VD wherein, R2 has the same meanings as defined above, R4 is methyl or ethyl, Rs is alkyl of C? _3, and M is NH, sodium or potassium.) The solvent suitable for use in step (i) is tetrahydrofuran, diethyl ether or dioxane, and the reducing agent can be lithium aluminum hydride, diisobutyl aluminum hydride or lithium tri-butoxyaluminohydride, preferably lithium tri-butoxyaluminohydride, and the reduction can be conducted at room temperature for 1 to 2 hours after the addition of the reducing agent at -50 to -20 ° C. In this step (i) of reduction, the lactol compound of formula (III) is obtained as a 1: 1 to 2: 1 mixture. of a- and β-anomers, and the next step (ii) can be conducted after isolating each anomer obtained in step (i), or directed as it is without such an isolation process. Furanose phosphate of formula (V) can be prepared by reacting the compound of formula (III) with the compound of halofosphate of formula (IV) in the presence of a base to obtain the β-enriched compound of formula (V) having a β / a ratio of 10 or more. In this step, the phosphate leaving group used may be dimethyl phosphate, diethylphosphate, or diphenyl phosphate, preferably diphenyl phosphate.

Step (iii) can be conducted after isolating the desired β-anomer obtained in step (ii) by recrystallization using a solvent such as water, ethanol, propanol, isopropanol, n-butanol, ethyl acetate and a mixture thereof , preferably isopropanol or a mixture of water-isopropanol. This step can also be conducted with the crude product of step (ii) without such isolation process. The halophosphate compound of formula (IV) can be used in an amount ranging from 1.1 to 1.5 molar equivalents based on the lactol compound of formula (III). The compound of formula (IV) is commercially available or can be easily prepared according to the conventional procedures described in Biochem. Preps. , 1, 50 (1951) or J. Chem. Soc, 2921 (1949). Step (ii) can be facilitated by the addition of a catalyst such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine. Also, the base used to neutralize the acid produced in step (ii) can be selected from the group consisting of pyridine, triethylamine, tributylamine, diisopropylethylamine and methylpiperidine, preferably triethylamine, which can be used in an amount ranging from 1.2 to 2.0 equivalents molars based on the lactol compound of formula (III). The solvent used in step (ii) may be benzene, toluene, acetonitrile, tetrahydrofuran, ethyl acetate, methylene chloride or chloroform, preferably toluene, and which is carried out at -25 to 50 ° C for 2 to 10 hours. Further, in step (iii), the highly pure a-anomer of formula (I) of 99.5% or more (ie, the β-anomer content of less than 0.5%) can be obtained by reacting the 1-phosphate furanose of formula (V) with a halide source, followed by recrystallization of the resulting product. The halide source that may be used in step (iii) includes HCl / acetic acid, HBr / acetic acid, HBr / propionic acid, a trialkylsilyl halide, a lithium halide, a sodium halide, a cesium halide, a potassium halide, tetraalkylammonium halide and a mixture thereof; among which HBr / 30% acetic acid, HBr / 30% propionic acid, tetrabutylammonium iodide, tetrabutylammonium bromide, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride and a mixture of trimethylsilyl chloride-bromide are preferred. lithium. Such a halide source is used in an amount ranging from 5 to 30 molar equivalents, preferably from 10 to 20 molar equivalents, based on the compound of formula (V). In case of using HCl / 1.0 M acetic acid, HBr / 30% acetic acid or HBr / 30% propionic acid as the halide source, it is used as a net state, while the other halide sources can be used in a dilute form with a solvent such as methylene chloride, dibromoethane, dichloroethane, chloroform, THF, 1,4-dioxane, acetonitrile, N, N-dimethylformamide or N, N-dimethylacetamide. . Step (iii) can be conducted in a solvent such as methylene chloride, dibromoethane, dichloroethane or chloroform at a temperature in the range of 0 to 50 ° C, preferably 10 to 30 ° C for 30 minutes to 24 hours. The resulting 1-halo ribofuranose is a mixture of α- and β-anomers having an α / β ratio of at least 10 and the desired α-halo anomer can be isolated from the mixture by recrystallization using a solvent such as metalol, ethanol, isopropanol, acetonitrile, water or a mixture thereof, preferably isopropanol or a mixture of isopropanol-water, to obtain the 1-a-halo ribofuranose in a high purity of 99.5% or more. The inventive method for preparing the 1-a-halo furanose of formula (I) using the 1-phosphate furanose of formula (V) as an intermediate provides a total yield of 65 to 75%, which is markedly greater than that which is achieved by the conventional method (total yield of approximately 45%) • The following Preparations and Examples are provided for the sole purpose of illustration and are not intended to limit the scope of the invention. In the following Preparation Examples and Examples, the term "-OCOBiPh" or "BiPhOCO-" refers to HPLC analysis for the compound of formula (V) with a packed column YMC pro C18 RS (4.6x150 mm, 5 μm) using a mixture of buffer and methanol (17 : 83, v / v) as an eluent; and the compound of formula (I), with a Capcellpak MG C18 RS column (4.6x150 mm, 5 μm) using a mixture of a buffer and methanol (1: 4, v / v) as an eluent. The buffer is prepared by mixing 13.8 g of NaH2P0 and 1 L of distilled water, and adding H3P0 thereto to a pH of 2.5. Preparation Example 1: Preparation of D-erythro-2-deoxy-2,2-difluoro-pentofurans-l-ulose-5-benzoyl-3- (4-phenyl) -benzoate (compound of formula (II)). 15 g of D-erythro-2-deoxy-2,2-difluoro-pentofurans-l-ylose-3- (4-phenyl) benzoate are dissolved in 150 ml of methylene chloride, and 6.9 ml of pyridine are added dropwise. while stirring. 7.4 ml of benzoyl chloride dissolved in 40 ml of methylene chloride are slowly added while maintaining the temperature at 5 to 10 ° C, followed by stirring for 7 hrs at room temperature. The resulting mixture is neutralized with 105 ml 1N HCl, and water is added. The organic layer is separated, washed successively with 100 ml of saturated sodium bicarbonate and 100 ml of saline, dried over anhydrous MgSO 4, filtered, and concentrated under reduced pressure. The resulting residue is recrystallized from diethyl ether / hexane (5: 1, v / v), to obtain 16.8 g of the titled compound as a white solid (yield: 86%).

XH-NMR (300MHz, CDC13): 4.90-4.75 (ddd, 2H), 5.10 (dd, ÍH), 5.87 (ddd, 1H), 7.65 ~ 7.50 (m, 5H), 7.78-7.67 (m, 3H), 7.81 (d, 2H), 8.13 (d, 2H), 8.23 (d, 2H) pf : 130-131 ° C Preparation Example 2: Preparation of D-erythro-2-deoxy-2, 2-difluoro-pentofurans-l-ylose-3,5-di- (4-phenyl) benzoate (compound of formula II)) 20 g of D-erythro-2-deoxy-2,2-difluoro-pentofuranos-l-ylose-3- (4-phenyl) benzoate are dissolved in 300 ml of chloroform, and 9.5 ml of pyridine are added dropwise while shake 10.1 ml of benzoyl chloride dissolved in 55 ml of chloroform are slowly added, followed by stirring 6 hours at room temperature. The resulting mixture is neutralized with 140 ml of 1N HCl, washed successively with 150 ml of water, 150 ml of saturated sodium bicarbonate and 150 ml of saline. The organic layer is separated, dried over anhydrous MgSO 4, and concentrated under reduced pressure. The resulting residue is recrystallized from ethyl acetate / hexane (3: 1, v / v), to obtain 21.8 g of the compound titled as a white solid (yield: 72%). ^ -R (300MHz, CDCl3): 4.72-4.79 (m, 2H), 5.03 (q, ÍH), 5.84 ~ 5.76 (m, IH), 7.48 ~ 7.44 (m, 6H), 7.72 ~ 7.60 (m, 8H ), 8.15-8.07 (m, 4H) pf : 137-139 ° C Example 1: Preparation of la-bromo-2-deoxy-2, 2-difluoro-D- 'ribofuranosyl-5-benzoyl-3- (4-phenyl) benzoate (compound of formula (I) R1 = benzoyl and R2 = 4-phenyl) Step 1) Preparation of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3-benzoyl-5- (4-phenyl) benzoate (compound of formula (III)) 13.5 g of lithium tri-tert-butoxyaluminohydride are dissolved in 160 ml of THF and stirred for 30 minutes at room temperature, followed by cooling to -40 ° C. The compound obtained in Preparation Example 1 dissolved in 80 ml of THF is added, the mixture is heated slowly to room temperature, and it is allowed to react at that temperature for 2 hrs. At the end of the reaction, 220 ml of 1N HCl are added dropwise to the reaction mixture to decompose the excess of tri-tert-butoxyaliumphihydride. The organic (THF) and aqueous layers are separated and the aqueous layer is extracted with 220 ml of diethyl ether. The ether extract is combined with the THF layer and washed successively with 220 ml of water, 220 ml of saturated sodium bicarbonate and 220 ml of saturated saline. The organic layer is separated, dried over anhydrous MgSO, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography to obtain 18.3 g of the compound titled as a pale yellow syrup (yield: 91%).

XH-NMR (300MHz, CDC13): 3.89 ~ 3.91 (d, 1H), 4.61-4.81 (m, 2H), 5.31 ~ 5.92 (m, 2H), 7.26 ~ 7.70 (m, 10H), 8.05 ~ 8.16 (m , 4H) Step 2) Preparation of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3-benzoyl-5- (4-phenyl) benzoyl-lβ-diphenylphosphate (compound of formula (V)) 18.3 g of the compound obtained in Step 1 are dissolved in 146 ml of toluene, and 6.7 ml of triethylamine are added. 12.4 ml of diphenylchlorophosphate dissolved in 37 ml of toluene are added dropwise to the mixture, followed by stirring for 4 hours at room temperature. At the end of the reaction, the residual triethylamine is neutralized by adding 48 ml of 1N HCl, the toluene and the aqueous layers are separated and the aqueous layer is extracted with 48 ml of diethyl ether. The ether extract is combined with the toluene layer and washed successively with water, saturated sodium bicarbonate and saturated saline. The organic layer is separated, dried over anhydrous MgSO 4, and concentrated under reduced pressure to obtain a mixture of α- and β-phosphate as a solid. The mixture was examined by 1 H-NMR and the a-phosphate: β-phosphate ratio was found to be 1: 10.6. The β-phosphate isopropanol / water (3: 1, v / v) is selectively recrystallized to obtain 26.5 g of the titled compound as a white solid (yield: 87%). 1H-NMR (300MHz, CDC13): 4.56-4.25 (m, 3H), 5.80 (m, HH), 5.95 (t, HH), 7.44-6.98 (m, 16H), 7.51 (d, 2H), 7.57 ( d, 2H), 7.89 (d, 2H), 8.01 (d, 2H) pf : 101-103 ° C HPLC purity (% area): anomeric phosphate 1.76%, anomeric phosphate 98.24%. Step 3) Preparation of l-a-bromo-2-deoxy-2,2-difluoro-D-ribofuranosyl-3-benzoyl-5- (4-phenyl) benzoate (compound of formula (I)) acét aiccoó 1 esa & KnlIMt 22.8 g of the compound obtained in Step 2 are added to 80.5 ml of HBr / 30% acetic acid followed by stirring for 6 hours at room temperature. At the end of the reaction, the resulting mixture is diluted with 400 ml of methylene chloride and poured into 500 ml of ice / water. The organic layer is separated, washed successively with ice water, saturated sodium bicarbonate and saline, dried over anhydrous MgSO 4, and concentrated under reduced pressure to obtain a mixture of an- and β-bromo anomers as a solid. The mixture was examined by 1 H-NMR and the a-bromine: β-bromine ratio was found to be 10.7: 1. The a-bromine compound is selectively recrystallized from isopropanol to obtain 17.0 g of the titled compound as a white solid (yield: 82%). aH-NMR (300MHz, CDC13): 8.19 (d, 2H), 8.06 (d, 2H), 7.73 (d, 2H), 7.63 (d, 2H), 7.64-7.41 (m, 6H), 6.56 (d, ÍH), 5.60 (dd. 1H) pf : 111-112 ° C Purity HPLC (% area): a-bromine anomer 99.74%, b-bromine anomer 0.26% Example 2: Preparation of la-bromo-2-deoxy-2, 2-difluoro-D-ribofuranosyl- 3, 5-di- (4-phenyl) benzoate (compound of formula (I): R1 = 4-biphenylcarbonyl and R2 = 4-phenyl) Step 1) Preparation of 2-deoxy-2,2-difluoro-D-ribofuranosyl -3,5-di- (4-phenyl) benzoate (compound of formula (IID) 8.66 g of tri-tert-butoxyaluminohydride are dissolved in 120 ml of THF and stirred for 30 minutes at room temperature, followed by cooling to -40 ° C. The compound obtained in Preparation Example 2 dissolved in 100 ml of THF is added and stirred for 1 hour at room temperature. At the end of the reaction, 142 ml of 1N HCl are slowly added dropwise to the reaction mixture to decompose the excess of lithium tri-tert.-butoxyaluminohydride, the THF and aqueous layers are separated, and the aqueous layer is extracted with 150 ml. ml of diethyl ether. The ether extract is combined with the THF layer, and washed successively with water, saturated sodium bicarbonate and saline. The organic layer is separated, dried over anhydrous MgSO, and concentrated under reduced pressure. The residue is recrystallized from toluene to obtain 13.4 g of the titled compound as a white solid (yield: 89%). A-NMR (300MHz, CDC13): 3.45 (s, lH), 3.8 (s), 4.85 ~ 4.50 (m, 3H), 5.8 ~ 5.4 (m, 2H), 7.49 ~ 7.43 (m, 6H), 7.71- 7.61 (m, 8H), 8.18-8.12 (m, 4H) pf : 156-158 ° C Step 2) Preparation of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-di- (4-phenyl) benzoyl-l-diphenylphosphate (compound of formula (V)) 13 g of the compound obtained in Step 1 are dissolved in a mixture of 130 ml of toluene and 100 ml of methylene chloride, and 5.1 ml of triethylamine are added. 7.6 ml of diphenylchlorophosphate are added dropwise to the resulting mixture and stirred for 5 hours at room temperature. At the end of the reaction, the solvent is removed under reduced pressure, the resulting solid is dissolved in 130 ml of methylene chloride, and 65 ml of 1N HCl are added. The organic layer is separated, washed successively with water, saturated sodium bicarbonate and saline, dried over anhydrous MgSO 4, and concentrated under reduced pressure to obtain a mixture of α- and β-phosphate as a solid. The mixture was examined by "" "H-? MR and it was found that the a-phosphate: β-phosphate ratio is 1: 10.8. The isopropanol β-phosphate is selectively recrystallized to obtain 15.6 g of the titled compound as a white solid. (yield: 83%). XH-RM (300MHz, CDC13): 4.70-4.40 (m, 3H), 5.90 (m, 1H), 6.08 (t, ÍH), 7.70 ~ 7.08 (m, 24H), 8.15 -8.04 (dd, 4H) mp: 145-147 ° C HPLC purity (% area): anionic phosphate 1.29%, anomeric phosphate 98.71% Stage 3) Preparation of la-bromo-2-deoxy-2, 2-difluoro-D-ribofuranosyl-3, 5-di- (4-phenyl) benzoate (compound of formula (D) 13 g of the compound obtained in Step 2 are dissolved in 83.2 ml of HBr / 30% acetic acid and stirred for 7 hours at room temperature. 50 ml of ice / water are added and the solid formed is filtered. The filtered solid is a mixture of α- and β-bromo anomers and a 1 H-NMR analysis showed that the a-bromine: β-bromine ratio is 10.9: 1. The a-bromine compound is recrystallized selectively from ethanol to obtain 8.45 g of the title compound as a white solid (yield: 83%). 1H-R N (300MHz, CDC13): 4.89-4.22 (m, 3H), 5.62 (dd, IH), 6.55 (d, ÍH), 7.73 ~ 7.42 (m, 14H), 8.63-8.11 (dd, 4H) p.f. : 151-153 ° C Purity HPLC (% area): a-bromine anomer 99.67%, b-bromine anomer 0.33% Example 3: Preparation of la-bromo-2-deoxy-2, 2-difluoro-D-ribofuranosyl -3-benzoyl-5- (4-phenyl) benzoate (Preparation in situ) 6.5 g of lithium tri-tert-butoxyaluminohydride are dissolved in 100 ml of THF and stirred for 30 minutes at room temperature and cooled to -40 ° C. 10 g of the compound obtained in Preparation Example 1 dissolved in 50 ml of THF are added dropwise and stirred for 2 hours at room temperature. At the end of the reaction, 120 ml of 1N HCl is added to the reaction mixture to decompose the excess of lithium tri-tert-butoxyaluminohydride, the THF and aqueous layers are separated, and the aqueous layer is extracted with 150 ml of diethyl ether. ether. The ether extract is combined with the THF layer, and washed successively with water, saturated sodium bicarbonate and saline. The organic layer is separated, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain 10.5 g of a residue in the syrup state. The resulting residue is dissolved in 100 ml of toluene, and 4.0 ml of triethylamine are added. 6.4 ml of diphenylchlorophosphate dissolved in 30 ml of toluene are added dropwise to the resulting mixture, followed by 4 hours of stirring at room temperature. At the end of the reaction, 30 ml of 1N HCl is added to the mixture to neutralize the residual triethylamine, the toluene and aqueous layers are separated, and the aqueous layer is extracted with 30 ml of diethyl ether. The ether extract is combined with the toluene layer, and washed successively with water, saturated sodium bicarbonate and saline. The organic layer is separated, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain 14.9 g of a mixture of α- and β-phosphate as a syrup. The mixture was examined by XH-NMR and the a-phosphate: β-phosphate ratio was found to be 1: 10.3. Subsequently, 57.2 ml of HBr / 30% acetic acid is added to the phosphate mixture and stirred for 7 hours at room temperature. At the end of the reactionThe mixture is diluted with 280 ml of methylene chloride, poured onto ice / water, and the methylene chloride layer is separated. The methylene chloride layer is washed successively with ice / water, saturated sodium bicarbonate, and saline. The organic layer is separated, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain a mixture of α- and β-isomers as a solid. The mixture was examined by ^? - NMR and the a-bromine: β-bromine ratio was found to be 10.5: 1. The a-bromo compound of isopropanol is selectively recrystallized to obtain 8.0 g of the titled compound as a white solid (yield: 70%).

The data of -1 H-NMR and p.f. are the same as those found in Step 4 of Example 1. HPLC purity (% area): 99.51% a-bromo anomer, 0.48% b-bromomer anomer Example 4: Preparation of la-iodo-2-deoxy-2, 2-difluoro-D-ribofuranosyl-3-benzoyl-5- (4-phenyl) benzoate 5.6 ml of iodotrimethylsilane are added to 40 ml of methylene chloride, and 1.8 g of the compound obtained in Step 2 of Example 1 are added, and the mixture is stirred for 0.5 hour at room temperature. The mixture is added dropwise to 100 ml of saturated sodium bicarbonate while cooling on an ice bath, and stirred for 0.5 hour. The methylene chloride layer is separated, dried over anhydrous MgSO 4, and concentrated under reduced pressure to obtain a mixture of α- and β-isomers as a solid. The mixture was examined by 1 H-NMR and the a-iodine: ß-iodine ratio was found to be 14.2: 1. The α-iodo compound is selectively recrystallized from isopropanol to obtain 1.36 g of the titled compound as a white solid (yield: 92%). aH-NMR (300MHz, CDC13): 8.24 (d, 2H), 8.06 (d, 2H), 7.74 (d, 2H), 7.66 (d, 2H), 7.64-7.43 (m, 6H), 6.93 (d, ÍH), 5.60 (dd, ÍH), 4.86-4.68 (m, 3H) HPLC purity (% area): 99.81% anomeric iodine, 0.18% anomeric iodine-iodine Comparative Example 1: Preparation of laiodine-2 -deoxy-2, 2-difluoro-D-ribofuranosyl-3, 5-dibenzoate The title compound is prepared according to the method described in US Patent No. 5,453,499 as described below. 80 ml of tetrahydrofuran and 80 ml of tetrabutylammonium iodide are added to 1 g of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-β- (p-bromobenzene) sulfonate, and reflux the mixture for 3.5 hours. The resulting mixture comprises a mixture of α-iodine and β-iodine, and an XH-NMR analysis shows that the a-iodine: β-iodine ratio is 10: 1.

In order to isolate the α-iodo compound, the mixture is cooled and diluted with dichloromethane and water. The organic layer is separated, washed successively with 1 N HCl, sodium carbonate, saturated saline and water, dried over anhydrous MgSO 4, and concentrated under reduced pressure to obtain a residue in a syrup state. The resulting residue is purified by flash chromatography on silica gel (toluene / hexane (2: 1, v / v)) to obtain 302 mg of the title compound (yield: 45%). XH-RM? (300MHz, CDC13): 8.12 (m, 4H), 7.72 -7.4 (m, 6H), 6.92 (d, ÍH), 5.60 (dd, ÍH), 4.91 -4.62 (m, 3H) While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes to the invention may be made by those skilled in the art that also fall within the scope of the invention as defined by the appended claims.

Claims (1)

1. CLAIMS 1. A derivative of l-a-halo-2, 2-difluoro-2-deoxy-D-ribofuranose of formula (I) in a solid form: characterized because olí R is benzoyl or R2 is hydrogen, cyano, halogen, carboalkoxy, nitro, C? _2 alkoxy, C? _2 alkyl or dialkylamino; and X is Cl, Br or I. The derivative of claim 1, characterized in that R2 is hydrogen. 3. The derivative of claim 1, characterized in that the content of β-anomer is 0.5% or less. 4. A method for preparing the halo-2, 2-difluoro-2-deoxy-D-ribofuranose derivative of the formula (I), characterized in that it comprises the steps of (i) reducing a 1-oxoribose compound of the formula (II) to obtain a lactol compound of formula (III); (ii) reacting the compound of formula (III) with a halophosphate compound of formula (IV) in the presence of a base to obtain a 1-phosphate furanose derivative of formula (V); and (iii) reacting the compound of formula (V) with a halide source, followed by recrystallization of the resulting product to obtain the 2-difluoro-2-deoxy-D-ribofuranose derivative of the formula (I): ata wherein, R1, R2 and X have the same meanings as defined in claim 1; and R3 is methyl, ethyl or phenyl. The method of claim 4, characterized in that the base used in step (ii) is selected from the group consisting of pyridine, triethylamine, tributylamine, diisopropylethylamine and methylpiperidine. 6. The method of claim 5, characterized in that the base used in step (ii) is triethylamine. The method of claim 4, characterized in that the halide source used in step (iii) is selected from the group consisting of HCl / acetic acid, HBr / acetic acid, HBr / propionic acid, a trialkylsilyl halide, a lithium halide, a sodium halide, a cesium halide, a potassium halide, tetraalkylammonium halide and a mixture thereof. The method of claim 7, characterized in that the halide source used in step (iii) is selected from the group consisting of HBr / 30% acetic acid, HBr / 30% propionic acid, tetrabutylammonium iodide, bromide of tetrabutylammonium, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride and a mixture of tri-ethylsilyl-lithium bromide 9. The method of claim 4, characterized in that the recrystallization in step (iii) is carried out using a solvent selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, water and a mixture thereof. The method of claim 9, characterized in that the recrystallization in step (iii) is carried out using isopropanol or a mixture of isopropanol-water. 11. The method of claim 4, characterized in that the derivative of formula (I) is obtained in a purity of 99. 5% or more. 12. A 1-phosphate furanose derivative of formula (V): characterized in that, R is benzoyl or R2 is hydrogen, cyano, halogen, carboalkoxy, nitro, C? _2 alkoxy, C? _2 alkyl or dialkylamino; and R 4 is methyl, ethyl or phenyl.