JP2008508261A - 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative and method for producing the same - Google Patents

Abstract

A 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative useful as an intermediate for the production of gemcitabine and a method for producing the same are provided. Novel 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivatives in solid form and suitable for purification and mass production using simple purification steps such as recrystallization and the like Is produced in a high purity and a high yield while being stereoselective.

Description

The present invention relates to a novel halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative useful as an intermediate for the production of gemcitabine and a method for producing the same.

Gemcitabine of formula (A) is a drug for treating non-small cell lung cancer (NSCLC) and is stereochemically composed of a cytosine nucleobase at the C-1 position of ribofuranose. It is a synthetic nucleoside analogue with a β-oriented structure.

前記式中、Ｐ^１はヒドロキシ保護基であり、Ｌは離脱基である。 Gemcitabine can be prepared by converting a lactol compound into an active ribofuranose intermediate having a reactive leaving group, as shown in Reaction Scheme 1 below.

wherein P ¹ is a hydroxy protecting group and L is a leaving group.

Specifically, gemcitabine can be obtained by: 1a) introducing a reactive leaving group (L) into the C-1 position of the ribofuranose ring of the lactol compound (B) to produce an active ribofuranose intermediate (C); Compounds of (C) may be prepared by glycosylation with cytosine to form an N-glycosidic bond.

In Scheme 1, glycosylation step 1b) proceeds by a bimolecular nucleophilic substitution reaction (S _N 2) mechanism, so that the α - It is important to obtain the anomer in high purity. Accordingly, methods for stereoselectively introducing a leaving group (L) to the C-1 position of the ribofuranose ring of the lactol compound (B) have been investigated.

For example, U.S. Pat. Nos. 4,526,988 and 5,453,499 disclose active ribofuranoses such as 1-α-halo-ribofuranose with a halo leaving group introduced at the C-1 position of the ribofuranose ring. Furanose intermediates are disclosed. Specifically, U.S. Pat. No. 4,526,988 discloses that 2a) the 1-hydroxy group of the lactol compound of formula (D) is reacted with an acetylating agent such as acetic anhydride, as shown in Reaction Scheme 2 below. 2b) reacting the 1-acetate derivative of formula (E) with HBr or HCl gas to produce a 1-haloribofuranose of formula (F); A method for producing 1-α-haloribofuranose derivatives is described.

前記反応式で、Ｒ’はヒドロキシ保護基であり、Ａｃはアセチルであり、ＸはＢｒまたはＣｌである。 Reaction formula 2

In the above scheme, R' is a hydroxy protecting group, Ac is acetyl, and X is Br or Cl.

However, this method suffers from low stereoselectivity and low yields of the desired α-haloanomer.

U.S. Pat. No. 5,453,499 discloses reacting a β-sulfonate compound of formula (G) with a halogenating agent in an inert solvent to give an α:β ratio of 9:1, as shown in Scheme 3. A process is described for preparing 1-haloribofuranose compounds enriched in the α-anomer of formula (H) with a ratio of 1 to 10:1.

前記反応式で、Ｐ”はベンゾイルなどのようなヒドロキシ保護基であり、Ｒ”はスルホンニルであり、Ｙはハロゲンである。 Reaction formula 3

In the above scheme, P″ is a hydroxy protecting group such as benzoyl, R″ is sulfonyl, and Y is halogen.

However, in this process the starting 1-sulfonate compound of formula (G) is prepared from a lactol compound by the method described in U.S. Pat. , the overall α:β selectivity for 1-haloanomers is only 3:1.

Also, for example, 1-α-halo-furanoses with benzoyl-protected 3- and 5-hydroxy groups are in an oil state at room temperature, which is only more difficult to handle and store than solids. Rather, an expensive column chromatography step is required to separate and purify from the mixture of α- and β-anomers. Therefore, there is a need to develop improved methods for producing gemcitabine using α-halo-furanoses.
U.S. Pat. No. 4,526,988 U.S. Pat. No. 5,453,499 U.S. Pat. No. 5,401,861

It is therefore an object of the present invention to provide novel 1-α-halo-D-ribofuranose derivatives in solid form suitable for purification and mass production using simple purification steps such as recrystallization. .

Another object of the present invention is to provide a process for producing said compounds with high purity, high yield and high stereoselectivity.

Yet another object of the present invention is to provide novel compounds to be used as intermediates in said process.

前記式中、
Ｒ^１はベンゾイルまたは

であり；
Ｒ^２は水素、シアノ、ハロゲン、カルボアルコキシ、ニトロ、Ｃ_１−２アルコキシ、Ｃ_１−２アルキルまたはジアルキルアミノであり；
ＸはＣｌ、ＢｒまたはＩである。 To achieve the above objects, the present invention provides 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivatives of formula (I) below in solid form:

In the above formula,
R ¹ is benzoyl or

is;
^R2 is hydrogen, cyano, halogen, carboalkoxy, nitro, _C1-2alkoxy , _C1-2alkyl or dialkylamino;
X is Cl, Br or I;

前記式中、Ｒ^１、Ｒ^２及びＸは前記で定義された通りであり、Ｒ^３はメチル、エチルまたはフェニル、好ましくはフェニルである。 In order to achieve the other object, the present invention provides (i) a step of reducing a 1-oxoribose compound of formula (II) to obtain a lactol compound of formula (III);
(ii) reacting the compound of formula (III) with a halophosphoric acid compound of formula (IV) in the presence of a base to obtain a 1-phosphate furanose derivative of formula (V); and (iii) the formula (V). ) with a halogenating agent, the resulting product is recrystallized to give the 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of formula (I) the step of obtaining
There is provided a process for preparing the 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of formula (I) above, characterized in that it comprises:

wherein R ¹ , R ² and X are as defined above and R ³ is methyl, ethyl or phenyl, preferably phenyl.

前記式中、Ｒ^１、Ｒ^２及びＲ^３は前記で定義された通りである。 To achieve the above and other objects, a novel 1-phosphate of formula (V) useful as an intermediate in the preparation of 1-α-halo-D-ribofuranose derivatives of formula (I) Providing Furanose Derivatives:

wherein R ¹ , R ² and R ³ are as defined above.

The 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivatives of the present invention are obtained in solid form and can be easily purified by simple methods such as recrystallization, It is useful as an intermediate for producing gemcitabine. In addition, the 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative according to the present invention is a compound of the formula (I) with high stereoselectivity, high purity and high yield compared to the conventional precursors. ) can be obtained.

As used herein, the term "anomer-enriched" refers to an anomeric mixture having a specific anomer content greater than 50%, preferably an anomeric mixture having substantially high purity α-anomer.

Preferably, in the compounds of formula (I) of the present invention, ^R2 is hydrogen.

The ribofuranose derivative of formula (I) of the present invention is characterized by having a 3-hydroxy group protected by a biphenylcarbonyl group. The derivatives of the invention can also have a biphenylcarbonyl group as a 5-hydroxy protecting group.

Therefore, since the 1-α-haloribofuranose derivative of the present invention is obtained in a solid form, it can be easily purified to a high purity of 99.5% or more by a simple purification process such as recrystallization.
Also, the 1-α-halo-ribofuranose derivative of formula (I) of the present invention was combined with cytosine by a conventional glycosylation reaction so that the cytosine residue was oriented upwards at the C-1 position of the ribofuranose ring (β -sequence) Gemcitabine can be produced.

Purity of the α-haloanomer is a critical factor in the production of gemcitabine via a glycosylation reaction with a 1-haloribofuranose derivative. For example, as the content of β-haloanomers increases, the stereoselectivity of the glycosylation reaction decreases significantly, resulting in lower yields of the desired β-nucleoside gemcitabine.

Thus, glycosylation using the α-halo compounds of the present invention significantly improved the β-/α-anomers compared to conventional methods (β-/α-anomers 2-3 fold)4-14. Enables twice the gemcitabine production effect

前記式中、Ｒ^１、Ｒ^２、Ｒ^３及びＸは前記で定義された通りである。 A method for producing the 1-α-halofuranose derivative of formula (I) is shown in Reaction Scheme 4 below.
Reaction formula 4

wherein R ¹ , R ² , R ³ and X are as defined above.

In Reaction Scheme 4 above, the 1-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of formula (I) is prepared by reacting (i) the 1-oxoribose compound of formula (II) with a conventional method. (ii) reacting the mixture of formula (III) with a halophosphate compound of formula (IV) in the presence of a base; and iii) reacting the compound of formula (V) with a halogenating agent to give a compound of formula (I). By the step of obtaining, it can be produced in a state of a mixture having an α-anomer content of 99.5% or more.

The present invention comprises the use of novel furanose intermediates of formula (V) having a phosphate leaving group to prepare 1-haloribofuranoses of formula (I) containing a high proportion of the α-anomer. Features above.

Thus, in step (ii) of the preparation of the phosphate furanose of formula (V) from the lactol compound of formula (III), the β-phosphate anomer can be obtained with a β/α ratio greater than 10. In addition, it is possible to obtain α-halofuranose of formula (I) having a high ratio of α/β of 10 times or more by performing step (iii) onward without separating the intermediates.
Also according to the present invention, α-halofuranoses are obtained in solid form when biphenylcarbonyl groups are introduced as 3- and/or 5-hydroxy protecting groups on the ribofuranose ring, and this solid form can be easily It can be easily purified to an optical isomer purity of 99.5% or more using a simple purification process, thereby producing the desired β-nucleosides having a high β/α ratio of 4 to 14. Such a high β/α ratio is significantly higher than 2 to 3 times the β/α ratio in conventional methods.

前記式中、Ｒ^２は前記で定義された通りであり、Ｒ^４はメチルまたはエチルであり、Ｒ^５はＣ_１−３アルキルであり、ＭはＮＨ_４、ナトリウムまたはカリウムである。 In step (i) of Reaction Scheme 4, the compound of formula (II) is reduced with a reducing agent according to the methods described in U.S. Pat. Nos. 4,526,988 and 5,464,826 to give the formula The lactol compound (III) can be produced. The 1-oxoribose compound of formula (II) used as a starting material in step (i) can be obtained by protecting the 3-hydroxy group of the compound of formula (VI) below with a biphenylcarbonyl protecting group and then converting the resulting product into It can be prepared by a procedure comprising hydrolysis in the presence of a base to give the 3R-carboxylic acid enantiomer of formula (VII):

wherein ^R2 is as defined above, ^R4 is methyl or ethyl, ^R5 is _C1-3 alkyl and M is _NH4 , sodium or potassium.

Suitable solvents in step (i) include tetrahydrofuran, diethyl ether or dioxane; reducing agents include lithium aluminum hydride, diisobutylaluminum hydride or lithium tri-tert-butoxyaluminum hydride, preferably Lithium tri-tert-butoxyaluminum hydride is used, and the reaction is carried out at -50 to -20°C for 1 to 2 hours after adding a reducing agent.

In said reduction step (i), the lactol compound of formula (III) is obtained as a 1:1 to 2:1 mixture of α- and β-anomers, and each anomer obtained in step (i) is separated or , or the next step (ii) can be performed immediately without a separation step.

In step (ii), a compound of formula (III) is reacted with a haloline agent of formula (IV) in the presence of a base to form a mixture containing high β-isomers of formula (V) with a β/α ratio of 10 or greater. can be obtained. At this stage, the phosphate leaving group is dimethyl phosphate, diethyl phosphate or diphenyl phosphate, preferably diphenyl phosphate.

Step (iii) involves dissolving the desired β-anomer obtained in step (ii) in a solvent such as water, ethanol, propanol, isopropanol, n-butanol, ethyl acetate and mixtures thereof, preferably isopropanol or water-isopropanol mixtures. It can be performed after separation by recrystallization using . This step can also be carried out with the crude product of step (ii) intact without such a separation step.

The halophosphoric acid compound of formula (IV) can be used in an amount of 1.1 to 1.5 molar equivalents relative to the lactol compound of formula (III). Compounds of formula (IV) are commercially available or can be found in the literature [Bioche melting point reps. , 1, 50 (1951)] or [J. Chem. Soc. , 2921 (1949)]. In step (ii), catalysts such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine can be used to facilitate the reaction.

Also, the base used to neutralize the acid produced in step (ii) is selected from the group consisting of pyridine, triethylamine, tributylamine, diisopropylethylamine, methylpiperidine, preferably triethylamine, , the base is used in an amount of 1.2 to 2.0 molar equivalents relative to the lactol compound of formula (III), and the solvent used in step (ii) includes benzene, toluene, acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, Chloroform, preferably toluene, is used and the reaction can be carried out at -25 to 50°C for 2 to 10 hours.

In step (iii), the 1-phosphate furanose of formula (V) is reacted with a halogenating agent, and the resulting product is recrystallized to obtain a highly pure α-anomer (99.5% or more). β-anomer content less than 0.5%) can be obtained.

Halogenating agents that can be used in step (iii) include HCl/acetic acid, HBr/acetic acid, HBr/propionic acid, trialkylsilyl halides, lithium halides, sodium halides, cesium halides, potassium halides, halogen tetraalkylammonium chloride and mixtures thereof, especially 30%-HBr/acetic acid, 30%-HBr/propionic acid, tetrabutylammonium iodide, tetrabutylammonium bromide, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride and a trimethylsilyl chloride-lithium bromide mixture. Such halogenating agents are used in 5 to 30 molar equivalents, preferably 10 to 20 molar equivalents, relative to the compound of formula (V).

When using 1.0 M HCl/acetic acid, 30%-HBr/acetic acid or 30%-HBr/propionic acid as the halogenating agent, it is used neat, and the other halogenating agents are dichloromethane, dibromoethane, dichloroethane. , chloroform, THF, 1,4-dioxane, acetonitrile, N,N-dimethylformamide or N,N-dimethylacetamide.

Step (iii) can be carried out in a solvent such as dichloromethane, dibromoethane, dichloroethane or chloroform at a temperature of 0 to 50°C, preferably 10 to 30°C for 30 minutes to 24 hours.

The 1-haloribofuranose produced is a mixture of α- and β-anomers with an α/β ratio of 10 or greater; Separation by recrystallization using a solvent such as a mixture of these, preferably isopropanol or an isopropanol-water mixture to obtain a product containing 1-α-haloribofuranose with a high purity of 99.5% or more. can be done.

The overall yield of the process for preparing 1-α-halofuranoses of formula (I) using the 1-phosphate furanoses of formula (V) of the present invention as intermediates is 65 to 75%, which is The overall yield of product (approximately 45% overall yield) is significantly higher than that achievable by conventional methods.

を意味する。 EXAMPLES The present invention will now be described in more detail with reference to Production Examples and Examples. However, the following examples are only for illustrating the present invention, and do not limit the scope of the present invention.
In the Preparations and Examples below, the term "-OCOBiPh" or "BiPhOCO-"

means

HPLC analysis for compounds of formula (V) was carried out using a YMC pack pro C18 RS (4.6x150 mm, 5 µm) using a mixture of buffer solution and methanol (17:83, v/v) as eluent; Compound (I) was run using a Capcellpak MG C18 RS (4.6×150 mm, 5 μm) column with a mixture of buffer solution and methanol (1:4, v/v) as the free solution. The buffer solution was prepared by mixing 13.8 g of _NaH2PO4 and 1 L of distilled water, to which _H3PO4 was added until the _{pH was} 2.5.

Production example 1
Preparation of D-erythro-2-deoxy-2,2-difluoro-pentofuranose-1-ulose-5-benzoyl-3-(4-phenyl)benzoate (compound of formula (II))

15 g of D-erythro-2-deoxy-2,2-difluoro-pentofuranose-1-ylose-3-(4-phenyl)benzoate was dissolved in 150 ml of dichloromethane and 6.9 ml of pyridine was added dropwise while stirring. . 7.4 ml of benzoyl chloride dissolved in 40 ml of dichloromethane was gradually added to the reaction mixture while maintaining the temperature of 5 to 10° C. and stirred at room temperature for 7 hours. The product mixture was neutralized with 1N-hydrochloric acid (105 ml), and water was added thereto. The organic layer was separated, washed successively with 100 ml saturated sodium bicarbonate and 100 ml saline, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was recrystallized from diethyl ether/hexane (5:1, v/v) to give 16.8 g (yield: 86%) of the title compound as a white solid.
¹ H-NMR (300 MHz, CDCl ₃ ): 4.90-4.75 (ddd, 2H), 5.10 (dd, 1H), 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)
Melting point: 130-131°C

Production example 2
Preparation of D-erythro-2-deoxy-2,2-difluoro-pentofuranose-1-ylose-3,5-di-(4-phenyl)benzoate (compound of formula (II))

20 g of D-erythro-2-deoxy-2,2-difluoro-pentofuranose-1-ylose-3-(4-phenyl)benzoate was dissolved in 300 ml of chloroform, and 9.5 ml of pyridine was added dropwise with stirring. added. After gradually adding 10.1 ml of benzoyl chloride dissolved in 55 ml of chloroform to the reaction mixture, the mixture was reacted at room temperature for 6 hours. The product mixture was neutralized with 140 ml of 1N HCl and washed sequentially with 150 ml of water, 150 ml of saturated sodium bicarbonate, and 150 ml of saline. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate/hexane (3:1, v/v) to give 21.8 g (yield: 72%) of a white solid.
^<1> H-NMR (300 MHz, _CDCl3 ): 4.72-4.79 (m, 2H), 5.03 (q, 1H), 5.84-5.76 (m, 1H), 7.48- 7.44 (m, 6H), 7.72-7.60 (m, 8H), 8.15-8.07 (m, 4H)
Melting point: 137-139°C

Example 1
1-α-bromo-2-deoxy-2,2-difluoro-D-ribofuranosyl-3-benzoyl-5-(4-phenyl)benzoate (compound of formula (I); R ¹ = benzoyl, R ² = 4-phenyl) production
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-butoxyaluminum hydride was dissolved in 160 ml of THF, stirred at room temperature for 30 minutes, and cooled to -40°C. A solution obtained by dissolving the compound obtained in Production Example 1 in 80 ml of THF was added to the reaction mixture, the temperature was gradually raised to normal temperature, and the reaction was carried out at that temperature for 2 hours. After the reaction was over, 220 ml of 1N HCl was added dropwise to the reaction mixture to decompose excess lithium tri-tert-butoxyaluminum hydride. An organic layer (THF) and an aqueous layer were separated, and the aqueous layer was extracted with 220 ml of diethyl ether. The ether extract was combined with the THF layer and washed sequentially with 220 ml water, 220 ml saturated sodium bicarbonate and 220 ml saline. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain 18.3 g (yield: 91%) of the title compound as a pale yellow syrup.
^<1> H-NMR (300 MHz, _CDCl3 ): 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-1β-diphenyl phosphate (compound of formula (V))

18.3 g of the compound obtained in step 1 was dissolved in 146 ml of toluene and 6.7 ml of triethylamine was added thereto. 12.4 ml of diphenyl chlorophosphate dissolved in 37 ml of toluene was added dropwise to the mixture, and the mixture was stirred at room temperature for 4 hours. After the reaction was over, 48 ml of 1N HCl was added to neutralize the remaining triethylamine, the toluene and aqueous layers were separated, and the aqueous layer was extracted with 48 ml of diethyl ether. The ether extract was combined with the toluene layer and washed sequentially with water, saturated sodium bicarbonate and saline. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of solid α- and β-phosphates. This mixture was analyzed by ¹ H-NMR to confirm that the ratio of α-phosphate:β-phosphate was 1:10.6. Selective recrystallization of the β-phosphate from isopropanol-water (3:1, v/v) afforded 26.5 g (yield: 87%) of the title compound as a white solid.
¹ H-NMR (300 MHz, _CDCl3 ): 4.56-4.25 (m, 3H), 5.80 (m, 1H), 5.95 (t, 1H), 7.44-6.98 ( m, 16H), 7.51 (d, 2H), 7.57 (d, 2H), 7.89 (d, 2H), 8.01 (d, 2H)
Melting point: 101-103°C
Purity by HPLC (area %): 1.76% α-phosphate anomer, 98.24% β-phosphate anomer

step 3)
Preparation of 1-α-bromo-2-deoxy-2,2-difluoro-D-ribofuranosyl-3-benzoyl-5-(4-phenyl)benzoate (compound of formula (I))

22.8 g of the compound obtained in step 2 was added to 80.5 ml of 30%-HBr/acetic acid and stirred at room temperature for 6 hours. After the reaction was over, the product mixture was diluted with 400 ml of dichloromethane and the diluted solution was poured into 500 ml of ice water. The organic layer was separated, washed successively with ice water, sodium bicarbonate and saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a solid mixture of α- and β-bromo anomers. The mixture was analyzed by ¹ H-NMR and confirmed to have a ratio of α-bromo:β-bromo of 10.7:1. The α-bromo mixture was selectively recrystallized from isopropanol to give 17.0 g (yield: 82%) of the title compound as a white solid.
¹ H-NMR (300 MHz, CDCl ₃ ): 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, 1H), 5.60 (dd. 1H)
Melting point: 111-112°C
HPLC purity (area %): α-bromo anomer 99.74%, β-bromo anomer 0.26%

Example 2
1-α-bromo-2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-di-(4-phenyl)benzoate (compound of formula (I); R ¹ = 4-biphenylcarbonyl, R ² = 4-phenyl) production
step 1)
Preparation of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-di-(4-phenyl)benzoate (compound of formula (III))

8.66 g of lithium tri-tert-butoxyaluminum hydride was dissolved in 120 ml of THF, stirred at room temperature for 30 minutes, and then cooled to -40°C. A solution prepared by dissolving the compound obtained in Production Example 2 in 100 ml of THF was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After the reaction is over, 142ml of 1N-HCl is slowly added dropwise to the reaction mixture to decompose excess lithium tri-tert-butoxyaluminum hydride, the THF layer and the aqueous layer are separated, and the aqueous layer is dissolved in 150ml of diethyl ether. extracted with The ether extract was combined with the THF layer and washed sequentially with water, saturated sodium bicarbonate and saline. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from toluene to obtain 13.4 g of the title compound as a white solid (yield: 89%).
^<1> H-NMR (300 MHz, _CDCl3 ): 3.45 (s, 1H), 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)
Melting point: 156-158°C

step 2)
Preparation of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-di-(4-phenyl)benzoyl-1β-diphenyl phosphate (compound of formula (V))

13 g of the compound obtained in step 1 was dissolved in a mixed solvent of 130 ml of toluene and 100 ml of dichloromethane, and 5.1 ml of triethylamine was added thereto. 7.6 ml of diphenyl chlorophosphate was added dropwise to the resulting mixture and stirred at room temperature for 5 hours. After the reaction was completed, the solvent was removed under reduced pressure, the resulting solid was dissolved in 130 ml of dimethylmethane, and 65 ml of 1N HCl was added thereto. The organic layer was separated, washed successively with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a solid α- and β-phosphoric acid mixture. The mixture was analyzed by ¹ H-NMR to confirm that the ratio of α-phosphate:β-phosphate was 1:10.8. Selective recrystallization of the β-phosphate from diisopropanol afforded 15.6 g of the title compound as a white solid (yield: 83%).
¹ H-NMR (300 MHz, CDCl ₃ ): 4.70-4.40 (m, 3H), 5.90 (m, 1H), 6.08 (t, 1H), 7.70-7.08 ( m, 24H), 8.15-8.04 (dd, 4H)
Melting point: 145-147°C
Purity by HPLC (area %): 1.29% α-phosphate anomer, 98.71% β-phosphate anomer

step 3)
Preparation of 1-α-bromo-2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-di-(4-phenyl)benzoate (compound of formula (I))

13 g of the compound obtained in step 2 was dissolved in 83.2 ml of 30%-HBr/acetic acid and stirred at room temperature for 7 hours. 50 ml of ice water was added to the reaction solution, and the produced solid was filtered. This solid was a mixture of α- and β-bromo anomers and ¹ H-NMR analysis indicated a 10.9:1 ratio of α-bromo to β-bromo anomers. The α-bromo compound was selectively recrystallized from ethanol to obtain 8.45 g (yield: 83%) of the title compound as a white solid.
^<1> H-NMR (300 MHz, _CDCl3 ): 4.89-4.2, 2 (m, 3H), 5.62 (dd, 1H), 6.55 (d, 1H), 7.73-7. 42 (m, 14H), 8.63-8.11 (dd, 4H)
Melting point: 151-153°C
HPLC purity (area %): α-bromo anomer 99.67%, β-bromo anomer 0.33%

Example 3
Preparation of 1-α-bromo-2-deoxy-2,2-difluoro-D-ribofuranosyl-3-benzoyl-5-(4-phenyl)benzoate

6.5 g of lithium tri-tert-butoxyaluminum hydride was dissolved in 100 ml of THF, stirred at room temperature for 30 minutes, and frozen to -40°C. A solution prepared by dissolving 10 g of the compound obtained in Preparation Example 1 in 50 ml of THF was added dropwise to the reaction mixture and stirred at room temperature for 2 hours. After the reaction was completed, 120 ml of 1N-HCl was added to the reaction mixture to decompose excess lithium tri-tert-butoxyaluminum hydride, the THF layer and aqueous layer were separated, and the aqueous layer was extracted with 150 ml of diethyl ether. The ether extract was combined with the THF layer and washed sequentially with water, saturated sodium bicarbonate and saline. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 10.5 g of syrupy residue.

The obtained residue was dissolved in 100 ml of toluene, and 4.0 ml of triethylamine was added thereto. 6.4 ml of diphenyl chlorophosphate dissolved in 30 ml of toluene was added dropwise to the resulting mixture and stirred at room temperature for 4 hours. After the reaction was finished, 30 ml of 1N HCl was added to the product mixture to neutralize the remaining triethylamine, the toluene layer and the aqueous layer were separated, and the aqueous layer was extracted with 30 ml of diethyl ether. The ether extract was combined with the toluene layer and washed sequentially with water, saturated sodium bicarbonate and saline. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 14.9 g of a mixture of α- and β-phosphates as syrup. The mixture was analyzed by ¹ H-NMR and confirmed to have an α-phosphate:β-phosphate ratio of 1:10.3.

After that, 57.2 ml of 30%-HBr/acetic acid was added to the phosphate mixture and stirred at room temperature for 7 hours. After the reaction was over, the mixture was diluted with 280 ml of dichloromethane, poured into ice water, and the dichloromethane layer was separated. The dichloromethane layer was washed sequentially with ice water, saturated sodium bicarbonate and saline. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a solid mixture of α- and β-isomers. The mixture was analyzed by ¹ H-NMR and confirmed to have an α-bromo:β-bromo ratio of 10.5:1. The α-bromo compound was selectively recrystallized from isopropanol to obtain 8.0 g (yield: 70%) of the title compound as a white solid.
¹ H-NMR and melting point. The data were identical to those of the compound according to Step 4 of Example 1 above.
Purity by HPLC (area %): α-bromo anomer 99.51%, β-bromo anomer 0.48%

ジクロロメタン４０ｍｌにヨードトリメチルシラン５．６ｍｌを加え、実施例１の段階２で得た化合物１．８ｇを加え、前記混合物を室温で０．５時間攪拌した。混合物を氷浴で冷却させながら飽和重炭酸ナトリウム１００ｍｌに滴加して０．５時間攪拌した。ジクロロメタン層を分離し、無水硫酸マグネシウムで乾燥し、減圧下で濃縮させて固体のα−及びβ−異性体の混合物を得た。この混合物を^１Ｈ−ＮＭＲで分析し、α−異性体：β−異性体の比率が１４．２：１であることを確認した。α−異性体化合物をイソプロパノールから選択的に再結晶して白色固体の標題化合物１．３６ｇ（収率：９２％）を得た。
^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：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，１Ｈ），５．６０（ｄｄ，１Ｈ），４．８６〜４．６８（ｍ， ３Ｈ）
ＨＰＬＣの純度（面積％）：α−異性体アノマー９９．８１％、β−異性体アノマー ０．１８％ Example 4
Preparation of 1-α-iodo-2-deoxy-2,2-difluoro-D-ribofuranosyl-3-benzoyl-5-(4-phenyl)benzoate

To 40 ml of dichloromethane was added 5.6 ml of iodotrimethylsilane, 1.8 g of the compound obtained in step 2 of Example 1 was added and the mixture was stirred at room temperature for 0.5 hour. The mixture was added dropwise to 100 ml of saturated sodium bicarbonate while cooling in an ice bath and stirred for 0.5 hours. The dichloromethane layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of solid α- and β-isomers. The mixture was analyzed by ¹ H-NMR and confirmed to have a 14.2:1 α-isomer:β-isomer ratio. The α-isomer compound was selectively recrystallized from isopropanol to obtain 1.36 g (yield: 92%) of the title compound as a white solid.
^<1> H-NMR (300 MHz, _CDCl3 ): 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, 1H), 5.60 (dd, 1H), 4.86-4.68 (m, 3H)
Purity by HPLC (area %): α-isomer anomer 99.81%, β-isomer anomer 0.18%

Comparative example 1
Preparation of 1-α-iodo-2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoate The title compound is prepared as follows by the method described in U.S. Pat. No. 5,453,499. bottom.

80 ml of tetrahydrofuran and 80 ml of tetrabutylammonium iodide were added to 1 g of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-β-(p-bromobenzene)sulfonate and the mixture was refluxed for 3.5 hours. The product mixture contained a mixture of α-iodine and β-iodine, and ¹ H-NMR analysis indicated a 10:1 ratio of α-iodine:β-iodine.

The mixture was allowed to cool and diluted with dichloromethane and water to separate the α-iodo compound. The organic layer was separated, washed successively with 1N HCl, sodium carbonate, saturated saline and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a syrupy residue. The resulting residue was purified by silica gel flash chromatography (toluene/hexane (2:1, v/v)) to give 302 mg (yield: 45%) of the title compound.
^<1> H-NMR (300 MHz, _CDCl3 ): 8.12 (m, 4H), 7.72-7.4 (m, 6H), 6.92 (d, 1H), 5.60 (dd, 1H) , 4.91-4.62 (m, 3H)

Claims (12)

1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative in solid form of the following formula (I):

In the above formula,
R ¹ is benzoyl or

Is;
R ² is hydrogen, cyano, halogen, carboalkoxy, nitro, C _1-2 alkoxy, C _1-2 alkyl or dialkylamino;
X is Cl, Br or I. The derivative according to claim 1, wherein R ² is hydrogen.   The derivative according to claim 1, wherein the β-anomer content of the formula (I) is 0.5% or less. (I) reducing the 1-oxoribose compound of formula (II) to obtain a lactol compound of formula (III);
(Ii) reacting the lactol 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) said formula (V ) And a halogenating agent, and then the resulting product is recrystallized to give a 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of the above formula (I) Getting the stage,
A method for producing a 1-α-halo-2,2-difluoro-2-deoxy-D-ribofuranose derivative of the above formula (I), which comprises:

In the above formula,
R ¹ , R ² and X are as defined in section 1 and R ³ is methyl, ethyl or phenyl.   The method according to claim 4, wherein the base used in step (ii) is selected from the group consisting of pyridine, triethylamine, tributylamine, diisopropylethylamine and methylpiperidine.   6. The method according to claim 5, wherein the base used in step (ii) is triethylamine.   The halogenating agent used in the step (iii) is HCl / acetic acid, HBr / acetic acid, HBr / propionic acid, trialkylsilyl halide, lithium halide, sodium halide, cesium halide, potassium halide, tetrahalide. 5. The method of claim 4, wherein the method is selected from the group consisting of alkyl ammonium and mixtures thereof.   The halogenating agent used in the step (iii) is 30% -HBr / acetic acid, 30% -HBr / propionic acid, tetrabutylammonium iodide, tetrabutylammonium bromide, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride and 8. The method of claim 7, wherein the method is selected from the group consisting of a trimethylsilyl chloride-lithium bromide mixture.   The method according to claim 4, wherein the recrystallization in the step (iii) is performed using a solvent selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, water, and a mixed solvent thereof.   The method according to claim 9, wherein the recrystallization in the step (iii) is performed using isopropanol or an isopropanol-water mixed solvent.   Process according to claim 4, characterized in that the derivative of formula (I) 1 is obtained with a purity of 99.5% or more. 1-phosphate furanose derivative of the following formula (V):

In the above formula,
R ¹ is benzoyl or

Is;
R ² is hydrogen, cyano, halogen, carboalkoxy, nitro, C _1-2 alkoxy, C _1-2 alkyl or dialkylamino;
R ³ is methyl, ethyl or phenyl.