KR20120051328A - Novel derivatives of nucleosides - Google Patents

Abstract

PURPOSE: A novel nucleoside derivative and a method for synthesizing the same are provided to ensure excellent bioavailability and to enable oral administration. CONSTITUTION: A novel nucleoside derivative is a compound of chemical formula 2. A method for preparing the compound of chemical formula 2 comprise a step of adding NaOMe or hydrogen ion to a compound of chemical formula 10. The compound of chemical formula 10 is prepared by adding LiN_3 to a compound of chemical formula 9.

Description

Novel derivatives of nucleosides

The present invention relates to novel nucleoside derivatives and their synthesis.

There is a need for novel nucleoside derivatives as therapeutic molecules for treating diseases such as cancer. There is also a need for methods of synthesizing novel nucleoside derivatives for the treatment of certain diseases.

It is an object of the present invention to provide a compound of formula 1 or 2, a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the compound of formula (2).

The term "nucleoside derivative" means that some functional groups of the nucleoside are substituted, but is not limited thereto, and examples thereof include compounds of formula 1 or formula 2 defined below.

One embodiment of the present invention includes a nucleoside of the formula (1).

<Formula 1>

One embodiment of the present invention also includes a nucleoside of formula (2).

<Formula 2>

Where

R ₁ and R ₂ are independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted acyloxyalkylcarbonyl, substituted or unsubstituted oxycarbonyl and

로 구성된 군에서 선택된 어느 하나이고;

Any one selected from the group consisting of;

n is independently an integer from 1 to 3;

R ₃ and R ₄ are independently composed of hydrogen, substituted or unsubstituted C ₁ -C ₂₂ alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acyloxyalkylcarbonyl and substituted or unsubstituted oxycarbonyl Any one selected from the group;

R ₅ is independently one selected from the group consisting of hydrogen and substituted or unsubstituted C ₁ -C ₂₂ alkyl;

The substituted C ₁ -C ₂₂ alkyl, substituted acyl, substituted acyloxyalkylcarbonyl and substituted oxycarbonyl are C ₁ -C ₂₂ alkyl, C ₅ -C ₂₂ cycloalkyl, C ₆ -C ₂₂ aryl It may be substituted with one or more substituents selected from the group consisting of.

In one embodiment of the invention the compound may be any one selected from the group consisting of R ₁ and R ₂ are independently hydrogen and substituted or unsubstituted acyl.

이고, n은 1 일 수 있다.In one embodiment the compound of the invention is R ₁

And n may be 1.

The compound of the present invention may be any one selected from the group consisting of the following compounds, but is not limited thereto:

4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (hydroxymethyl) furan-2-yl) pyrimidine-2 ( 1H) -one (4-Azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (hydroxymethyl) furan-2-yl) pyrimidine-2 (1H)- one);

4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (L-isoleucineyloxymethyl) furan-2-yl) Pyrimidin-2 (1H) -one (4-Azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (L-isolucinyloxymethyl) furan-2-yl) pyrimidine-2 (1H) -one);

4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (L-valinyloxymethyl) furan-2-yl) pyrimidine -2 (1H) -one (4-Azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (L-valinyloxymethyl) furan-2-yl) pyrimidine- 2 (1H) -one);

4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (L-phenylalaninyloxymethyl) furan-2-yl) pyrimidine -2 (1H) -one (4-Azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (L-phenylalaninyloxymethyl) furan-2-yl) pyrimidine- 2 (1H) -one); And

4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (elidoyl) furan-2-yl) pyrimidine-2 ( 1H) -one (4-Azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (elaidoyl) furan-2-yl) pyrimidine-2 (1H)- one).

Furthermore, in one embodiment of the present invention, the compound of Formula 2 may be a compound of Formula 1.

<Formula 1>

Further, according to one embodiment of the present invention, a method of preparing a compound of formula 2 by adding NaOMe or hydrogen ions to the compound of formula (10).

<Formula 10>

Where

R` is phenyl or methyl.

In the above method, the compound of Formula 10 may be prepared by adding LiN ₃ to the compound of Formula 9, the compound of Formula 9 may be prepared by adding triazole to the compound of Formula 8, the compound of Formula 8 May be prepared by reacting a compound of Formula 7 with R′COCl, and the compound of Formula 7 may be prepared from a compound of Formula 11 below.

<Formula 7>

(8)

<Formula 9>

<Formula 11>

In Formulas 7 to 9, R ′ is as defined above.

Hereinafter, the present invention will be described in detail. In the following description of the present invention, a detailed description of related known functions or configurations will be omitted in order not to obscure the subject matter of the present invention.

As used herein, the terms “about”, “substantially”, and the like, are used in the vicinity of the numerical values when a manufacturing and material tolerance inherent in the meanings mentioned are used, and are used to aid the understanding of the present invention. Absolute figures are used to prevent unfair use by unscrupulous infringers.

Compounds of the present invention can generally be prepared according to Scheme 1 below.

<Scheme 1>

4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (hydroxymethyl) represented by Formula 1) in Scheme 1) Furan-2-yl) pyrimidin-2 (1H) -one is prepared by converting the N4-amino group at position 4 into an azide group using formula 11) as a starting material. In addition, the derivative represented by the formula (2) is prepared using the formula (1) as a starting material.

In the preparation of Chemical Formula 1) in Scheme 1), there are several methods for introducing an azide group by deaminoating the amino group at position 4 of Chemical Formula 11), as described in Scheme 2) below.

<Reaction Scheme 2>

In Scheme 2), R is a Na or t-Bu0 group, X is a halogen atom or an anion, and M represents Na or K metal.

In order to prepare the formula 1) in the reaction scheme 2), there are two methods via the intermediate 1) and the intermediate 2) using the formula 11) as a starting material, but the preparation method is a universal method known to those skilled in the art.

<Scheme 3>

As another method for preparing Formula 1, as shown in Scheme 3), the reaction may proceed through a reaction of Steps (Formula 7), (Formula 8a, 8b), (Formula 9a, 9b), and (Formula 10a, 10b). .

Phthalamination for the preparation of formula (7) takes place in an aqueous solution of pH below 6.0 at 95 ° C. or in a high concentration of acidic aqueous solution at room temperature. Acids used herein are Bronsted acids which give protons in water or solvents, such as hydrochloric acid, sulfuric acid, acetic acid and citric acid.

In order to prepare the chemical formula 8) after deamination, typical protecting groups and preparation methods are well known, in addition to the benzoyl group or the acetyl group shown in the scheme.

To prepare formula (9), suitable leaving groups such as 1,2,4-triazole, 3-nitro-1,2,4-triazole, 1 H -tetrazole are introduced instead of the carbonyl group at position 4.

Formula 9) generated during the reaction is difficult to separate because it is unstable to moisture. So it is good to proceed to the next reaction as soon as possible.

To prepare the formula (10) is reacted at 60 ℃ temperature conditions in an unreacted polar solvent such as N, N- dimethylformamide with a material that provides an azide, such as azide lithium or azide sodium, Azide derivatives can be obtained.

When the target compound of formula (1) is deprotected under conditions suitable for each protecting group, a compound similar to the formula (1) can be obtained.

Each reaction was confirmed using thin layer chromatography (TLC) and an appropriate solvent system. When the reaction was terminated by TLC, the product was extracted using an organic solvent, and then chromatographed using an appropriate solvent system. It can be purified by law.

4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (hydroxymethyl) represented by Chemical Formula 2) in Scheme 1) In order to synthesize a derivative of furan-2-yl) pyrimidin-2 (1H) -one, it is prepared using Formula 1) as a starting material.

The derivative of the compound obtained as above may be represented by the formula (2).

<Formula 2>

Where

R ₁ and R ₂ are independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted acyloxyalkylcarbonyl, substituted or unsubstituted oxycarbonyl and

로 구성된 군에서 선택된 어느 하나이고;

Any one selected from the group consisting of;

n is independently an integer from 1 to 3;

R ₃ and R ₄ are independently composed of hydrogen, substituted or unsubstituted C ₁ -C ₂₂ alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acyloxyalkylcarbonyl and substituted or unsubstituted oxycarbonyl Any one selected from the group;

R ₅ is independently one selected from the group consisting of hydrogen and substituted or unsubstituted C ₁ -C ₂₂ alkyl;

The substituted C ₁ -C ₂₂ alkyl, substituted acyl, substituted acyloxyalkylcarbonyl and substituted oxycarbonyl are C ₁ -C ₂₂ alkyl, C ₅ -C ₂₂ cycloalkyl, C ₆ -C ₂₂ aryl It may be substituted with one or more substituents selected from the group consisting of.

Generally monosubstituted 4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (hydroxymethyl) furan-2-yl) The amino acid ester derivative of pyrimidin-2 (1H) -one can be synthesized according to Scheme 4).

<Scheme 4>

Protected amino acids are esterified to the 5 ′ position using well known coupling agents. The esterified compound may form a free amino group through a deprotection reaction to obtain a single substituted derivative.

More specifically, as shown in Scheme 5), there may be mentioned a specific amino acid reaction at the 5 'position, but the amino acid groups which can be protected are not limited thereto.

Scheme 5

Each reaction was confirmed using thin layer chromatography (TLC) and an appropriate solvent system. When the reaction was terminated by TLC, the product was extracted using an organic solvent, and then chromatographed using an appropriate solvent system. It can be purified by law.

And 4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (hydroxymethyl) furan-2 monosubstituted at position 5 ′ Acyl derivatives of -yl) pyrimidin-2 (1H) -one can be synthesized according to Scheme 6).

<Scheme 6>

By esterification with an appropriate acyl chloride, a single substituted derivative can be obtained. Each reaction was confirmed using thin layer chromatography (TLC) and an appropriate solvent system. When the reaction was terminated by TLC, the product was extracted using an organic solvent, and then chromatographed using an appropriate solvent system. It can be purified by law.

Examples to be described later to specifically explain the preparation method of the preferred nucleoside derivatives of the present invention to help the understanding of the present invention.

The present invention relates to a novel nucleoside derivative and its synthesis. As a therapeutic molecule for treating a disease such as cancer, the novel nucleoside derivative has excellent bioavailability and increases the half-life of the drug. It reduces the resistance resulting from high-dose administration due to its short half-life, and allows oral administration, which is convenient for taking.

1 is 4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (hydroxymethyl) furan-2-yl) pyrimidine ¹ H NMR spectrum of Formula -2 (1H) -one is shown.
FIG. 2 shows 4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (hydroxymethyl) furan-2-yl) pyrimidine Mass spectrometry (Mass) spectrum of -2 (1H) -one is shown.

Hereinafter, the present invention will be described in detail. However, the following Examples and Experimental Examples are merely illustrative of the present invention, but the content of the present invention is not limited thereto.

Example  1.1-((2R, 4R, 5R) -3,3- Difluoro - Tetrahydro -4- Hydroxy -5- (lower Idroxymethyl ) Furan -2-yl) pyridine-2,4 (1H, 3H) Dion's  Preparation (Formula 7)

After dissolving Formula 11) (5 g, 16.7 mmol, 1.0 equiv) in 2N acetic acid aqueous solution (350 ml), sodium nitrite (16.7 g, 14.5 equiv) was slowly added, and left at room temperature for 48 hours. The mixture was adjusted to pH 6-7 with 2N aqueous sodium hydroxide solution and concentrated under reduced pressure. Methanol / ethyl acetate (1: 5, 360 ml) was added after concentration under reduced pressure, and the insoluble salt was removed. This process was repeated several times to remove all salts and concentrated under reduced pressure to obtain the formula (7) (4.22 g) as a light brown transparent oil in 95% yield.

¹ H-NMR (300 MHz, DMSO-d6) δ 11.5 (s, 1H), 7.79 (d, J = 8 Hz, 1H), 6.39 (br, OH), 6.05 (t, J = 7 Hz, 1H), 5.73 ( d, J = 8 Hz, 1H), 5.35 (m, 1H), 4.19 (m, OH), 3.79 (m, 3H)

Example  2. 1-((2R, 4R, 5R) -3,3- Difluoro - Tetrahydro -4- Acetoxy -5- ( Acetoxymethyl ) Furan -2-yl) pyridine-2, Of 4 (1H, 3H) dione  Preparation (Formula 8a)

Formula 7) (0.61 g, 2.31 mmol, 1 equivalent), 4-dimethylaminopyridine (0.14 g, 0.5 equivalent), 4-methylmorpholine (1.78 ml, 7 equivalents) was dissolved in tetrahydrofuran (12 ml), and then 0. Cool to C. Then, benzoyl chloride (0.67 ml, 2.5 equivalents) was slowly added, followed by stirring at 5 ° C. or lower for 8 hours. After confirming the remaining of the formula (7) by thin layer chromatography, and concentrated under reduced pressure. After diluting with saturated aqueous sodium hydrogen carbonate solution (10 ml), brine (7 ml) and methylene chloride (30 ml), only the organic layer was separated. The separated organic layer was concentrated under reduced pressure after removing water with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was separated by column chromatography (ethyl acetate: hexane = 1: 1) to obtain a white solid compound of formula 8a) (0.79 g) in a yield of 72%.

¹ H-NMR (300MHz, DMSO-d6) δ 11.6 (s, 1H), 8.06 (d, J = 7Hz, 2H), 7.96 (d, J = 7Hz, 2H), 7.74 (t, J = 7Hz, 2H ), 7.63 (m, 4H), 7.49 (m, 2H), 6.37 (m, 1H), 5.82 (1H), 5.74 (m, 1H), 4.80 (m, 1H), 4.73 (m, 1H)

Example  3. 1-((2R, 4R, 5R) -3,3- Difluoro - Tetrahydro -4- Acetoxy -5- ( Acetoxymethyl ) Furan -2-yl) pyridine-2, Of 4 (1H, 3H) dione  Preparation (Formula 8b)

Formula 7) (4.22 g, 15.9 mmol, 1 equivalent) was dissolved in pyridine (63 ml) and cooled to 0 ° C. Acetic anhydride (4.50 ml, 3 equiv) was slowly added, followed by stirring at 5 DEG C or lower for 16 hours. After confirming the remaining compound 7) by thin layer chromatography, it was concentrated under reduced pressure. Dilute with saturated aqueous sodium hydrogen carbonate solution (30ml), brine (30ml), ethyl acetate (60ml), separate organic layer only, remove water with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a dark brown oil (8b) (4.51g). Was obtained in a yield of 81%.

¹ H-NMR (300MHz, DMSO-d6) δ 11.5 (s, 1H), 7.60 (d, J = 8Hz, 1H), 6.27 (t, J = 8Hz, 1H), 5.84 (d, J = 8Hz, 1H ), 5.42 (m, 1H), 4.37 (m, 3H), 2.16 (s, 3H), 2.06 (s, 3H)

Example  4. 4- Azido -1-((2R, 4R, 5R) -3,3- Difluoro - Tetrahydro -4- Benzoyloxy -5- ( Benzoyloxy ) Furan -2-yl) pyridine-2,4 (1H, 3H) Dion's  Preparation (Formula 10a)

Compound 8a) (0.42 g, 0.889 mmol, 1 equiv) and 1,2,4-triazole (0.15 g, 1.5 equiv) were added to acetonitrile (16 ml), followed by slow stirring at room temperature. Triethylamine (1.24 ml, 10 equivalents) was added to the reaction mixture, which was stirred for about 15 minutes at room temperature. Then, the temperature was lowered to 5 ° C. or lower, and phosphoryl chloride (0.83 ml, 10 equivalents) was slowly added for 15 minutes. And it stirred, raising the temperature to room temperature gradually. After 8 hours, thin layer chromatography confirmed that a new material was formed, and 10 equivalents of triethylamine and phosphoryl chloride were added. After 8 hours, 10 equivalents of triethylamine and phosphoryl chloride were further added by thin layer chromatography, and the reaction was performed. After confirming that all the compounds 8a) disappeared by thin layer chromatography, the mixture was concentrated under reduced pressure, diluted with brine (7 ml), saturated sodium bicarbonate (10 ml) and ethyl acetate (30 ml), and only the organic layer was separated. The separated organic layer was concentrated under reduced pressure after removing water with anhydrous sodium sulfate to obtain a mixture of Formula 9a). The mixture of 9a) was dissolved in N, N-dimethylformamide (8 ml), and azide lithium (1.25 ml, 4 equivalents) was added thereto, followed by stirring at 60 ° C. for 6 hours. After confirming the remaining of the formula (9a) by thin layer chromatography, and concentrated under reduced pressure. The concentrated mixture under reduced pressure was separated by column chromatography (ethyl acetate: hexane = 1: 1) to obtain a white solid Formula 10a (0.24 g) in a yield of 54%.

Compound 9a: ¹ H-NMR (DMSO-d6) δ 9.48 (s, 1H), 8.44 (s, 1H), 8.08 (d, J = 7Hz, 2H), 7.97 (m, 3H), 7.75 (m, 1H ), 7.61 (m, 3H), 7.48 (t, J = 7 Hz, 2H), 7.10 (d, J = 7 Hz, 1H), 6.57 (t, J = 8 Hz, 1H), 5.87 (m, 1H), 4.94 (m, 1 H), 4.80 (m, 2 H);

Compound 10a: ¹ H-NMR (DMSO-d6) δ 8.10 (d, J = 7 Hz, 2H), 7.99 (m, 3H), 7.75 (m, 1H), 7.62 (m, 3H), 7.50 (m, 2H ), 6.75 (t, J = 8 Hz, 1H), 5.89 (m, 1H), 4.96 (m, 1H), 4.81 (m, 2H)

Example  5. 4- Azido -1-((2R, 4R, 5R) -3,3- Difluoro - Tetrahydro -4- Hydroxy -5- ( Hydroxymethyl ) Furan Preparation of 2-yl) pyrimidin-2 (1H) -one (Formula 1)

(104 g, 0.482 mmol, 1 equivalent) was dissolved in methyl alcohol (4 ml), and sodium methoxide (0.10 g, 4 equivalents) was added thereto, followed by stirring at room temperature for 16 hours. After confirming the remaining compound 4 by thin layer chromatography, it was adjusted to pH 4 or less with 2N acetic acid, and concentrated by concentration. The mixture obtained by concentration was separated by column chromatography (ethyl acetate = 1) to obtain a white solid Formula 1) (0.10 g) in a yield of 75% (see FIGS. 1 and 2).

¹ H-NMR (DMSO-d6) δ 8.20 (d, J = 7 Hz, 1H), 7.27 (d, J = 7 Hz, 1H), 6.31 (m, 1H), 4.87 (m, OH), 4.35 (m, 1H), 3.97 (m, OH), 3.81 (m, 1H), 3.73 (m, 2H)

MS (EI): m / z 289 = [M] ⁺

Example  6. 4- Azido -1-((2R, 4R, 5R) -3,3- Difluoro - Tetrahydro -4- Hydroxy -5- (L- Isoleucinyloxymethyl ) Furan 2-yl) pyrimidin-2 (1H) -one preparation (Formula 3)

Formula 1) (0.13 g, 0.450 mmol, 1 equiv) was dissolved in N, N-dimethylformamide (5 ml), dimethylaminopyridine (5.5 mg, 0.1 equiv) and dicyclohexylcarbodiimide (0.20 g, 2.2 equiv) ), L-isoleucine (0.23 g, 2.2 equiv) with protecting group was added. After stirring for 9 hours at room temperature, the resulting solids were filtered off and concentrated under reduced pressure. After concentration under reduced pressure, the residue was separated by column chromatography (ethyl acetate = 1) to obtain a white solid compound of formula 3a) (66 mg) in a yield of 37%. The obtained Formula 3a) was added to a mixed solvent of trifluoroacetic acid and methyl alcohol (1: 1, 4 ml), stirred for 3 hours, and then concentrated under reduced pressure. The oily mixture was separated by column chromatography (ethyl acetate = 1) to give a white solid Formula 3) (20 mg) in 37% yield.

¹ H-NMR (MeOD- d ₄ ) δ 8.20 (d, J = 7 Hz, 1H), 7.05 (d, J = 7 Hz, 1H), 6.42 (m, 1H), 4.41 (m, 1H), 4.02 (m , 2H), 3.82 (m, 2H), 2.03 (m, 1H), 1.76 (m, 1H), 1.43 (m, 1H), 0.96 (m, 3H), 0.87 (m, 3H)

Example 7. 4- azido- 1-((2R, 4R, 5R) -3,3 -difluoro - tetrahydro- 4 -hydroxy -5- (L -valinyloxymethyl ) furan -2- I) Preparation of pyrimidin-2 (1H) -one (Formula 4 )

Formula 4) was obtained in the same manner as in Example 6, except that L-valine (0.16 g, 2.2 equivalent) having a protecting group was used.

¹ H-NMR (MeOD- d ₄ ) δ 8.20 (d, J = 7 Hz, 1H), 7.05 (d, J = 7 Hz, 1H), 6.42 (m, 1H), 5.62 (m, 1H), 4.41 (m , 1H), 4.16 (m, 1H), 4.02 (m, 1H), 3.82 (m, 1H), 2.37 (m, 1H), 1.19 (d, J = 7 Hz, 6H)

Example  8. 4- Azido -1-((2R, 4R, 5R) -3,3- Difluoro - Tetrahydro -4- Hydroxy -5- (L- Phenylalaninyloxymethyl ) Furan 2-yl) pyrimidin-2 (1H) -one preparation (Formula 5)

Formula 5) was obtained in the same manner as in Example 6, except that L-phenylalanine (0.20 g, 2.2 equivalent) having a protecting group was used.

¹ H-NMR (MeOD- d ₄ ) δ 8.20 (d, J = 7 Hz, 1H), 7.37 (m, 5H), 7.05 (d, J = 7 Hz, 1H), 6.42 (m, 1H), 6.11 (m , 1H), 5.50 (m, 1H), 4.57 (m, 1H), 4.02 (m, 1H), 3.82 (m, 1H), 3.30 (m, 2H)

Example  9. 4- Azido -1-((2R, 4R, 5R) -3,3- Difluoro - Tetrahydro -4- Hyde Roxy-5- ( Ellaidillo ) Furan -2-yl) pyrimidin-2 (1H) -one (Formula 6)

Formula 1) (0.1 g, 0.346 mmol, 1 equiv) was dissolved in N, N-dimethylformamide (5 ml), and elidoyl chloride (0.11 g, 1.0 equiv) was added to N, N-dimethylformamide (2 ml). Melt and add. Stir at room temperature for 12 hours. After confirming the remaining compound 4 by thin layer chromatography, and concentrated under reduced pressure to remove the solvent. After concentration under reduced pressure, separation by column chromatography (methylene chloride: methanol = 12: 1) yielded a light yellow oil of formula 6) (45 mg) in a yield of 23%.

¹ H-NMR (DMSO- d6 ) δ 8.20 (d, J = 7 Hz, 1H), 7.05 (d, J = 7 Hz, 1H), 6.45 (m, 1H), 6.17 (m, 1H), 5.35 (m, 2H), 4.4 (m, 3H), 3.95 (m, 1H), 2.35 (m, 2H), 1.95 (m, 4H), 1.55 (m, 2H), 1.25 (m, 20H), 0.85 (m, 3H )

Claims (10)

A compound of Formula 2 or a pharmaceutically acceptable salt thereof:
<Formula 2>

Where
R ₁ and R ₂ are independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted acyloxyalkylcarbonyl, substituted or unsubstituted oxycarbonyl and

Any one selected from the group consisting of;
n is independently an integer from 1 to 3;
R ₃ and R ₄ are independently composed of hydrogen, substituted or unsubstituted C ₁ -C ₂₂ alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acyloxyalkylcarbonyl and substituted or unsubstituted oxycarbonyl Any one selected from the group;
R ₅ is independently one selected from the group consisting of hydrogen and substituted or unsubstituted C ₁ -C ₂₂ alkyl;
The substituted C ₁ -C ₂₂ alkyl, substituted acyl, substituted acyloxyalkylcarbonyl and substituted oxycarbonyl are C ₁ -C ₂₂ alkyl, C ₅ -C ₂₂ cycloalkyl, C ₆ -C ₂₂ aryl It may be substituted with one or more substituents selected from the group consisting of.
The method of claim 1,
R ₁ and R ₂ are independently one selected from the group consisting of hydrogen and substituted or unsubstituted acyl;
The substituted acyl is a compound or a pharmaceutically acceptable compound, characterized in that substituted with one or more substituents selected from the group consisting of C ₁ -C ₂₂ alkyl, C ₅ -C ₂₂ cycloalkyl, C ₆ -C ₂₂ aryl. salt.
The method of claim 1,
R ₁ is

And n is 1, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
Compound of formula 2 is 4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (hydroxymethyl) furan-2-yl) Pyrimidin-2 (1H) -one;
4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (L-isoleucineyloxymethyl) furan-2-yl) Pyrimidin-2 (1H) -one;
4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (L-valinyloxymethyl) furan-2-yl) pyrimidine -2 (1H) -one;
4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (L-phenylalaninyloxymethyl) furan-2-yl) pyrimidine -2 (1H) -one; And
4-azido-1-((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (elidoyl) furan-2-yl) pyrimidine-2 ( 1H) -one, or a pharmaceutically acceptable salt thereof, characterized in that any one selected from the group consisting of.
The method of claim 1,
The compound of formula (2) is a compound or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula (1).
<Formula 1>

To prepare a compound of Formula 2 by adding NaOMe or hydrogen ions to the compound of Formula 10:
<Formula 10>

Where
R` is phenyl or methyl.
The method of claim 6,
LiN ₃ is added to the compound of Formula 9 to prepare a compound of Formula 10.
&Lt; Formula 9 >

Where
R` is phenyl or methyl.
The method of claim 7, wherein
A method for preparing a compound of Formula 2, further comprising the step of preparing a compound of Formula 9 by adding triazole to the compound of Formula 8.
(8)

Where
R` is phenyl or methyl.
The method of claim 8,
A method of preparing a compound of Formula 2, further comprising preparing a compound of Formula 8 by reacting a compound of Formula 7 with R′COCl:
(6)

R ′ in R′COCl is phenyl or methyl.
10. The method of claim 9,
The compound of formula (7) is prepared from the compound of formula (11).
<Formula 11>

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