WO2012018235A2 - Method for preparing decitabine with improved yield and purity - Google Patents

Abstract

The present invention relates to a method for preparing decitabine with improved yield and purity, and more particularly, to a method for preparing decitabine with improved yield and purity that comprises a step (step 1) of enabling 1,3,5-triacetyl-2-deocyribose, and 5-azacytosine in which a silyl group is introduced, to react in a methylene chloride or EDC solvent in the presence of a TMSO triflate Lewis acid; a step (step 2) of obtaining an intermediate product by crystallizing the reaction product obtained in step 1 using ethyl acetate as a recrystallization solvent; and a step (step 3) of obtaining, from the crystallized intermediate product obtained in step 2, decitabine as an end product in which an acetyl group is deprotected. According to the present invention, the formation of isomers may be minimized by using a novel starting material and a method for synthesizing same, and the purity of a final product may be improved to 99.5% or higher by means og a novel precursor which is crystallized into the form of a free amine instead of a protected amine. Therefore, the method of the present invention may be effectively utilized in preparing decitabine with high purity and high yield.

Description

Method for preparing decitabine with improved yield and purity

The present invention relates to a process for preparing decitabine with improved yield and purity.

Decitabine is a drug for myelodysplastic syndromes (MDS), a type of bone marrow cancer. It is a DNA methylation inhibitor that has a therapeutic effect by inhibiting DNA methylation and has a therapeutic response rate three times higher than that of azacytidine, which has been used before, and all myelodysplastic syndrome regardless of the type of myelodysplastic syndrome in the United States. The drug is being used to treat the syndrome.

DNA methylation is the process by which methyl groups are added to DNA and as a result abnormal methylation, which inactivates genes important for the regulation of cell differentiation and proliferation, is known to cause various types of tumors.

Unlike other hypomethylating agents, such as azacytidine, which acts primarily on RNA, decitabine acts directly on DNA, thereby inhibiting DNA methylation, which causes myelodysplastic syndrome. Decitabine has a dual mechanism of action, including hypomethylation and tumor suppressor gene activation, along with direct and indirect cytotoxic effects of cancer cell suicide. Decitabine also prevents patients with bone marrow dysplasia from receiving blood transfusions, saving patients money and time, as well as avoiding complications related to blood transfusions.

Decitabine is represented by the following formula (1).

 [Formula 1]

Many studies have been reported for preparing decitabine. Hereinafter, this will be described in detail.

According to Czechoslovakia Patent Application No. NL 6414959, forming a triazine ring using isothiobiuret (step 1), as shown in the following scheme; There is disclosed a method for producing decitabine, which comprises a step (step 2) of synthesizing decitabine by removing an acetyl group as a protecting group using ammonia.

Synthetic method as described above has a low synthesis yield of 33%, there is a problem in the storage and handling of the isocyanate compound which is the starting material of the reaction, there is a problem that is difficult to apply to the mass production process because benzene is used as a carcinogenic solvent.

In 1970, M.W. As reported by Winkley et al., A step of preparing a halogen-substituted sugar as shown in the following scheme (step 1); There is disclosed a step (step 2) of preparing decitabine through a substitution reaction with 5-azacytosine in which a silyl group is introduced (J. Org. Chem, 1970, 35, 491).

The synthesis method as described above has a storage problem because dangerous hydrochloric acid gas is required for the synthesis of halogen-substituted sugar (hereinafter referred to as "halosugar") and halosch lacks its own stability. In addition, the time required for the deprotection process is about 3-7 days, so the overall yield is very low, about 7%. In addition, a high pressure reactor is required in the deprotection process with ammonia (step 2), which is more inappropriate for commercial production.

 In addition, German patent application DE 2012888 discloses 5-azacytosine in which protected nucleosides and silyl groups are introduced in excess of tin catalyst and EDC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide) Mention is made of a process for preparing decitabine using acetonitrile as a solvent.

The synthesis method is very difficult to filter tin compounds, such as insoluble tin salts, so that the tin compound remains in decitabine, which is a final material, has a fatal defect in commercially preparing API. In addition, there is a disadvantage that the synthetic yield is as low as 21-41%.

Accordingly, the present inventors have completed the present invention by improving the yield of decitabine and the purity of decitabine itself, and finding an improved manufacturing method of decitabine excellent in both purity and yield.

It is an object of the present invention to provide a process for preparing decitabine with improved yield and purity.

In order to achieve the above object, the present invention as shown in Scheme 1,

5-Azacytosine having 1,3,5-triacetyl-2-dioxyribose of formula 2 and silyl group of formula 3 introduced with trimethylsilyltrifluoromethanesulfonate (hereinafter referred to as "TMSOTf") Lewis acid Reacting in a methylene chloride or ethylene dichloride (hereinafter referred to as "EDC") solvent in the presence of to obtain a compound of formula 4 (step 1);

Obtaining the compound of formula 5 using ethyl acetate as a recrystallization solvent from the compound of formula 4 obtained in step 1 (step 2); And

It provides a method for producing a decitabine with improved yield and purity comprising the step (step 3) of obtaining a decitabine of the formula (1) in which the acetyl group is deprotected from the compound of formula (5) obtained in step 2.

[Formula 1]

Scheme 1

.

.

According to the present invention, not only the conventionally mentioned starting material and its synthesis method can be used to selectively produce intermediates having a specific arrangement, but also the intermediates are free amines in which the amine group is not protected by a protecting group. It can be obtained in the form, and by crystallization it can be obtained decitabine with improved purity to 99.5% or more.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

As the present invention is shown in Scheme 1,

5-Azacytosine having 1,3,5-triacetyl-2-dioxyribose of formula 2 and silyl group of formula 3 introduced with trimethylsilyltrifluoromethanesulfonate (hereinafter referred to as "TMSOTf") Lewis acid Reacting in methylene chloride or EDC solvent in the presence of to obtain a compound of formula 4 (step 1);

 Obtaining the compound of formula 5 using ethyl acetate as a recrystallization solvent from the compound of formula 4 obtained in step 1 (step 2); And

It provides a method for producing a decitabine with improved yield and purity comprising the step (step 3) of obtaining a decitabine of the formula (1) in which the acetyl group is deprotected from the compound of formula (5) obtained in step 2.

Scheme 1

.

.

Hereinafter, the method for preparing decitabine according to the present invention will be described in more detail step by step.

First, step 1 is a step of coupling-reacting 5-azacytosine to which the silyl group of Formula 3 is introduced with 1,3,5-triacetyl-2-deoxyribose of Formula 2.

In step 1, methylene chloride or EDC may be used as the reaction solvent. It is more preferable to use methylene chloride from the viewpoint of facilitating work up after the reaction and increasing the yield.

In addition, the reaction of Step 1 may use Lewis acid as a catalyst. There is no particular limitation on the Lewis acid that can be used, and for example, TMSOTf or the like is preferably used.

Furthermore, step 1 is preferably carried out for 12-24 hours at low temperature reaction conditions of 0-5 ℃. The reaction product obtained in step 1 has a problem in that the yield is lowered due to structural instability accompanied by heat generation during high temperature conditions or work-up. On the other hand, there exists a problem that reaction rate falls at low temperature below 0 degreeC.

Next, step 2 according to the present invention is a step of recrystallization of the reaction product of step 1.

Recrystallization of step 2 is preferably carried out using ethyl acetate as the recrystallization solvent. The reaction product represented by the formula (4) obtained as a result of the step 1 is not only an oily product (Oily product) that is not easy to handle, but also isomers of α and β forms around the carbon 1 of the furanose ring. Or a mixture of β-anomers, hereinafter referred to as "α-anomers" or "β-anomers."

The α- and β-anomers present in the form of a mixture are subjected to the recrystallization according to step 2 of the present invention to obtain the non-oil-like formula (4) in the form of a free amine in which trimethylsilyl group (TMS) has been removed. In addition to obtaining non-oily compounds, β-anomers are obtained with high purity of 90% or more.

In addition, the pyranose ring compound which is present in the final product (decitabine), which has been presented as a conventional problem, affecting the purity of the product, is removed in the reaction process of step 2, thereby improving the purity of the intermediate and the final product. Can be.

Furthermore, step 2 of the present invention preferably performs recrystallization for 1-3 hours. If the recrystallization time is short, proper crystallization of the product does not proceed, and if the recrystallization time is long, product loss due to solubility may occur.

Next, step 3 according to the present invention is a step of deprotecting the acetyl group from the decitabine intermediate of the formula (4).

In the deprotection process of step 3, sodium methoxide, ammonia, sodium ethoxide, potassium carbonate, etc. may be used as a base in methanol or ethanol solvent. The bases have low solubility in solvents, especially methanol, so that they are easy to remove after the reaction. It is preferable to use sodium methoxide in methanol solvent from the viewpoint of yield, reaction time shortening, minimization of impurities, etc., wherein the sodium methoxide is more preferably used at 28% concentration:

In addition, the present invention may further comprise the step (step 4) of purifying the decitabine product obtained by performing step 3.

The purification step may be carried out by including a purification step (step 4) consisting of dissolving and refluxing the decitabine of the formula (1) in a methanol solvent, concentrated under reduced pressure and stirred at room temperature to recrystallize.

 Furthermore, the present invention provides a process for preparing 1,3,5-triacetyl-deoxyribose of formula (II) comprising steps A, B and C, as shown in Scheme 2:

Reacting 2-dioxy-D-ribose of Formula 6 with 20-25 ° C. in a methanol solvent in the presence of hydrochloric acid to obtain 2-dioxyribose methylglycoside of Formula 7 (step A);

2-dioxyribose methylglycoside of Formula 7 obtained in step A was dissolved in 20-25 ° C. ethyl acetate solvent, acetic anhydride and pyridine were added, and warmed to 70-80 ° C. to protect with acetyl group. Obtaining 3,5, -diacetyl-2-deoxyribose methylglucoside of (step B); And

Dissolving 3,5, -diacetyl-2-dioxyribose methylglucoside of Formula 8 obtained in step B in an acetic acid solvent at 20-25 ° C., followed by addition of acetic anhydride and sulfuric acid to react (step C) :

Scheme 2

Hereinafter, the method for preparing the starting material will be described in more detail step by step.

First, step A according to the present invention is a step of protecting the 2-dioxy-D-ribose of formula 6 with a hydroxy group of carbon number 1 as a methoxy group.

Step A may be carried out at a reaction temperature of 20-25 ° C. in a methanol solvent in the presence of hydrochloric acid. The reaction of step A is preferably carried out for 0.5-4 hours. If the reaction time is performed for more than 4 hours, there is a problem in that impurities in the form of pyranose rings, which are structural isomers of the furanose ring, are generated, and if the reaction time is performed in less than 0.5 hours, there is a problem that the yield is lowered. In addition, from the viewpoint of suppressing the generation of impurities, the hydrochloric acid catalyst used in the step A is preferably neutralized after the reaction is completed.

Next, step B according to the present invention is a step of protecting the remaining hydroxy group of the reaction product of step A protected with a methoxy group with an acetyl group. Step B may be carried out by reacting acetic anhydride in the presence of a pyridine base.

Ethyl acetate may be used as the reaction solvent. When the reaction temperature of methylglycoside of formula (7) is dissolved in ethyl acetate, the solution is added acetic anhydride and pyridine and then warmed to 70-80 ° C. to protect hydroxy groups of carbon 3 and 5 of the compound of formula (7) with acetyl. Let's do it. In this case, the protection reaction is preferably carried out for 12-24 hours.

Next, step C according to the present invention is a step of changing the methoxy group of carbon number 1 introduced as a result of performing step A to an acetyl group. Step C may be carried out by reacting acetic anhydride under a concentrated sulfuric acid catalyst. It is preferable to use acetic acid as a reaction solvent, and it is preferable to carry out by maintaining the reaction temperature at 0-10 ℃.

Further, the reaction of step C is preferably performed within 1 hour and then terminate the reaction quickly. If the reaction is carried out for more than 1 hour, there is a problem in that the entire reaction product is transformed into a polymer mixture, which makes the operation impossible. Due to the rapid termination of the reaction, some compounds of formula (7) which are not completely converted into the compounds of formula (2) which are starting materials of the present invention are present.However, the reaction of step 1 of the decitabine preparation method of the present invention As a result, they can contribute to an increase in overall yield.

The present invention also provides a process for preparing decitabine of Formula 1 from a compound of Formula 2 comprising steps i) to vi), as shown in Scheme 3:

Scheme 3

.

.

In the production method according to the invention step i) to step iii) can be carried out in the same manner as the above-described step A to step C.

In addition, in the manufacturing method, steps iv) to vi) may be performed in the same manner as in the above-described steps 1 to 3.

Such a preparation method according to the present invention can selectively produce only intermediates having a specific arrangement using a starting material and a synthesis method thereof, which are not mentioned in the prior art, and also the intermediates are not preamines in which the amine group is not protected by a protecting group. It can be obtained in the form of (free amine), and by crystallization it can be obtained decitabine with improved purity to more than 99.5%.

Hereinafter, the present invention will be described in more detail with reference to Preparation Examples and Examples. However, the following examples are only for illustrating the present invention, and the contents of the present invention are not limited by the following preparation examples and examples.

Preparation Example 1 Preparation of 5-Azacytosine (Formula 3) Incorporating a Silyl Group

199.5 g of 5-azacytosine, 16.5 g of ammonium sulfate, and 1134.6 g of Hexa Methyl Di Silazane (HMDS) were added thereto, and the reaction was refluxed by heating to 130-140 ° C. After the reaction was continued for 5 hours while maintaining the reaction temperature, the excess HMDS was concentrated under reduced pressure, and 1600 ml of normal hexane was added to crystallize. The solid was collected by filtration and dried under nitrogen to obtain 434 g of 5-azacytosine containing 95% yield of silazyl group as a white solid.

Example 1 Preparation of Decitabine 1

Step 1: Preparation of Decitabine Intermediate (Formula 4)

434 g of 5-azacytosine to which the silyl group prepared in Preparation Example 1 was introduced were added and diluted with 2.8 L of methylene chloride. After the reaction was cooled to 0-5 ° C., 400 g of 1,3,5-triacetyl-2-dioxyribose was dissolved in 1.2 L of methylene chloride, and slowly added to the reaction product, followed by trimethylsilyltrifluoromethanesulfonate 410. g was also added slowly. When the addition is complete, the reaction temperature is maintained at 0-5 ° C. and stirred for 12-24 hours. If the content of 1,3,5-triacetyl-2-dioxyribose is 1% or less, the result is 173.4 g of sodium carbonate and sodium bicarbonate. The reaction was slowly added to a solution of 173.4 g dissolved in 6.1 L of water to terminate the reaction to obtain a compound of formula 4.

¹ H-NMR (DMSO, 300 MHz): 0.0-0.15 (s, TMS), 1.9-2.1 (m, 6H, acetyl CH ₃ ), 2.3-2.75 (m, 2H), 4.1-4.3 (m, 2H), 4.7-5.2 (m, 2H), 6.0 (s, 1H), 7.5 (bs, NH ₂ ), 8.3 (s, 1H, triazine ring)

Step 2: Preparation of Recrystallization Product (Formula 5)

The reaction product of step 1 was separated and the lower organic layer was collected, washed with 3.8 L of water, and concentrated under reduced pressure. 1.2 L of ethyl acetate was added to the obtained product, stirred at room temperature for 1-3 hours, filtered, washed with 400 ml of ethyl acetate, and dried to give 245.2 g of a decitabine intermediate compound (yield = 51.1%, purity = 97.4%).

¹ H-NMR (DMSO, 300 MHz): 1.9-2.1 (m, 6H, acetyl CH ₃ ), 2.3-2.75 (m, 2H), 4.1-4.3 (m, 2H), 4.7-5.2 (m, 2H), 6.0 (s, 1H), 7.5 (bs, NH ₂ ), 8.3 (s, 1H, triazine ring)

¹³ C-NMR (DMSO, 75MHz): 170.8, 166.9, 156.8, 154.0, 88.0, 84.5, 74.8, 64.3, 38.0, 21.4

Step 3: Preparation of Decitabine (Formula 1)

245 g of the recrystallization product obtained in step 2 and 2.0 L of methanol were added thereto, and the temperature of the reaction product was adjusted to 15-20 ° C. 16.6 g of 28% sodium methoxide was added thereto and reacted. The reactants dissolved to form a solution, which gradually precipitated a solid. If the protected decitabine content in the intermediate assay was 1% or less, the reaction was filtered, washed with 740 ml of methanol and dried with nitrogen to obtain purified decitabine (71 g, yield = 40.0%, purity = 99.5%).

¹ H-NMR (DMSO, 300 MHz): 2.16 (m, 2H), 3.58 (m, 2H), 3.79 (m, 1H), 4.22 (m, 1H), 5.03 (s, OH), 5.23 (s, OH ), 6.0 (t, 1H), 7.51 (bs, NH ₂ ), 8.48 (s, 1H, triazine ring)

¹³ C-NMR (DMSO, 75 MHz): 166.55, 156.59, 153.87, 88.29, 85.80, 70.60, 61.54, 41.21

Step 4: Preparation of Purified Decitabine

Thereafter, 70 g of decitabine obtained before purification and 8.4 L of methanol were added thereto, and the reactant was heated to dissolve and 7 g of activated carbon was added thereto. The mixture was refluxed for 1 hour, filtered to remove activated carbon, and the filtrate was concentrated under reduced pressure, leaving about 1/2 volume, and the reaction mixture was stirred at room temperature for 3 hours to crystallize, filtered and dried with nitrogen to obtain purified decitabine (yield = 83 %, Purity = 99.8%).

¹ H-NMR (DMSO, 300 MHz): 2.16 (m, 2H), 3.58 (m, 2H), 3.79 (m, 1H), 4.22 (m, 1H), 5.03 (s, OH), 5.23 (s, OH ), 6.0 (t, 1H), 7.51 (bs, NH ₂ ), 8.48 (s, 1H, triazine ring)

¹³ C-NMR (DMSO, 75 MHz): 166.55, 156.59, 153.87, 88.29, 85.80, 70.60, 61.54, 41.21

Example 2 Preparation of Decitabine 2

Except for using 14.5% by weight ammonia dissolved in methanol instead of 28% sodium methoxide in step 3 of Example 1, the same method as in Example 1 was performed on 20 g of decitabine obtained before purification To give decitabine (6.14 g, yield 42.0%, purity 99.28%).

Example 3 Preparation of Decitabine 3

The same method as in Example 1 for 20 g of decitabine obtained before purification, except that it was a low temperature reaction using sodium ethoxide and ethanol instead of 28% sodium methoxide and a solvent of methanol in step 3 of Example 1. Was carried out to give decitabine (3.2 g, yield 22%).

Example 4 Preparation of Decitabine 4

Example 1 was carried out in the same manner as in Example 1 with respect to 1 g of decitabine obtained before purification except for using potassium carbonate instead of 28% sodium methoxide and crystallization using MTBE in step 3 of Example 1 Was obtained (semi-solid, purity 88%).

Example 5 Preparation of 1,3,5-triacetyl-2-dioxyribose (Formula 2)

Step A: Preparation of 2-Deoxyribose Methylglycoside (Formula 7)

50 g of 2-dioxy-D-ribose were dissolved in 450 ml of methanol and the reaction temperature was adjusted to 20-25 ° C. 100 ml of 1% HCl solution dissolved in methanol was added thereto, and when the reaction was completed, sodium bicarbonate was added to neutralize and filtered. After washing with 100 ml of methanol, the mixture was concentrated under reduced pressure to obtain 55 g of 2-dioxyribose methylglycoside as a light brown liquid.

¹ H-NMR (CDCl ₃ , 300 MHz): 1.9-2.3 (m, 2H, α and β-anomer), 3.38 (s, OCH ₃ , β-anomer), 3.40 (s, OCH ₃ , α-anomer), 3.62 (m, 4H, α and β-anomer), 3.98-4.20 (m, 3H, α and β-anomer), 4.45 (m, 1H, α-anomer), 5.1-5.15 (m, 2H, α and β -anomer)

¹³ C-NMR (CDCl ₃ , 75 MHz): 105.3, 86.9, 72.2, 63.4, 55.1, 41.8

Step B: Preparation of 3,5-diacetyl-2-deoxyribose methylglycoside (Formula 8)

55 g of the 2-dioxyribose methylglycoside was dissolved in 500 ml of ethyl acetate and the reaction temperature was adjusted to 20-25 ° C. 8.8 g of pyridine and 105 ml of acetic anhydride were added and heated to a reaction temperature of 70-80 ° C., after 24 hours, when the reaction was completed, the mixture was concentrated under reduced pressure to give 3,5-diacetyl-2-dioxyribose as a light brown liquid. 80 g of methylglycoside was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz): 2.0-2.16 (m, 12H, acetyl CH ₃ α and β-anomer), 2.18-2.24 (m, 2H, β-anomer), 2.28-2.42 (m, 2H, α-anomer), 3.34 (s, OCH ₃ , β-anomer), 3.40 (s, OCH ₃ , α-anomer), 4.08-4.18 (m, 6H, α and β-anomer), 5.02-5.26 (m, 4H, α and β-anomer)

¹³ C-NMR (CDCl ₃ , 75 MHz): 170.6, 105.2, 81.4, 74.6, 64.5, 54.9, 38.6, 20.7, 20.5

Step C: Preparation of 1,3,5-triacetyl-2-deoxyribose (Formula 2)

80 g of the 3,5-diacetyl-2-dioxyribose methylglycoside was dissolved in 635 ml of acetic acid and the reaction temperature was adjusted to 20-25 ° C. 30 g of sulfuric acid and 160 ml of acetic anhydride were added thereto, and when the reaction was completed, 5.3 L of water and 3.0 L of methylene chloride were added thereto, and after stirring for 1 hour, the organic layers were collected, washed with 1.6 L of water and 1.6 L of saturated sodium bicarbonate and concentrated under reduced pressure. . The product was dissolved in 260 ml of methanol, 9 g of activated carbon was added thereto, refluxed for 1 hour, cooled to room temperature, filtered, and the activated carbon was removed and concentrated under reduced pressure. Then, GC (gas chromatography) was performed to obtain a light yellow liquid 1, 63 g of 3,5-triacetyl-2-dioxyribose (Formula 2) was obtained (yield = 65%, purity = 95.0%).

<GC analysis condition>

Column = DB5 (30m × 0.25mm × 0.25um)

Inlet = 250 ° C.

Detector = 300 ℃

Split ratio = 25: 1

Gas flow = 1.0 ml / min.

Temp. = Initial 100 ° C. for 2 minutes, rise to 10 ° C./min., Final 250 ° C. for 5 minutes

¹ H-NMR (CDCl ₃ , 300 MHz): 2.0-2.16 (m, 18H, acetyl CH ₃ α and β-anomer), 2.25-2.38 (m, 2H, β-anomer), 2.42-2.56 (m, 2H, α-anomer), 5.05-5.16 (m, 1H, α-anomer), 5.24-5.28 (m, 1H, β-anomer), 6.36-6.42 (m, 2H, α and β-anomer)

¹³ C-NMR (CDCl ₃ , 75 MHz): 170.6, 98.2, 83.0, 73.8, 64.1, 38.2, 21.1, 20.8, 20.6

Claims (12)

As shown in Scheme 1 below, 5-Azacytosine with 1,3,5-triacetyl-2-dioxyribose of formula (2) and silyl group of formula (3) was introduced in methylene chloride or EDC solvent in the presence of trimethylsilyltrifluoromethanesulfonate Lewis acid. Reacting to obtain a compound of formula 4 (step 1); Obtaining the compound of formula 5 using ethyl acetate as a recrystallization solvent from the compound of formula 4 obtained in step 1 (step 2); And Obtaining decitabine of the formula (1) in which the acetyl group is deprotected from the compound of formula (5) obtained in step 2 (step 3) of the yield and purity improved manufacturing method of decitabine. Scheme 1

The method of claim 1, wherein the solvent of step 1 is methylene chloride. The method of claim 1, wherein the reaction of step 1 is carried out at 0-5 ° C. The method of claim 1, wherein the reaction of step 1 is carried out for 12-24 hours. The method of claim 1, wherein the recrystallization of step 2 is performed for 1-3 hours. The method of claim 1, wherein the beta-anomer (beta--anomer) is 90% or more through the reaction of step 2, the yield and purity of the improved decitabine, characterized in that to obtain a compound of formula 5 in the form of a preamine Manufacturing method. The method of claim 1, wherein the step 3 is the production of decitabine with improved yield and purity, characterized in that the deacetylation of the acetyl group using NaOMe, NaOEt, NH ₃ or K ₂ CO ₃ as a base in methanol or ethanol solvent. Way. The method of claim 7, wherein the solvent is methanol and the base is NaOMe. The purification step (step 3) of claim 1, comprising the step of dissolving and refluxing the decitabine of Formula 1 obtained by performing step 3 in a methanol solvent, concentrating under reduced pressure, and stirring at room temperature. Method for producing decitabine with improved yield and purity comprising a. As shown in Scheme 2 below, Reacting 2-dioxy-D-ribose of Formula 6 with 20-25 ° C. in methanol solvent in the presence of hydrochloric acid to obtain 2-dioxyribose methylglycoside of Formula 7 (step A);  2-dioxyribose methylglycoside of Formula 7 obtained in step A was dissolved in 20-25 ° C. ethyl acetate solvent, acetic anhydride and pyridine were added, and warmed to 70-80 ° C. to protect with acetyl group. Obtaining 3,5, -diacetyl-2-deoxyribose methylglucoside of (step B); And  Dissolving 3,5, -diacetyl-2-dioxyribose methylglucoside of Formula 8 obtained in step B in an acetic acid solvent at 20-25 ° C., followed by addition of acetic anhydride and sulfuric acid to react (step C) 1,3,5-triacetyl-2-deoxyribose manufacturing method of the formula (2) comprising a. Scheme 2

 The method of claim 10, wherein the 2-deoxyribose methylglycoside of Formula 6 obtained in step A is used in step B without further purification. As shown in Scheme 3 below, Reacting 2-dioxy-D-ribose of formula (6) by adjusting to 20-25 [deg.] C. in a methanol solvent in the presence of hydrochloric acid to obtain 2-dioxyribose methylglycoside of formula (7); 2-dioxyribose methylglycoside of Formula 7 obtained in step i) was dissolved in 20-25 ° C. ethyl acetate solvent, acetic anhydride and pyridine were added, and warmed to 70-80 ° C. to protect the acetyl group. Obtaining 3,5, -diacetyl-2-dioxyribose methylglucoside of 8 (step ii)); After dissolving 3,5, -diacetyl-2-dioxyribose methylglucoside of Formula 8 obtained in step ii) in an acetic acid solvent at 20-25 ° C., acetic anhydride and sulfuric acid were added to add 1,3 Obtaining, 5-triacetyl-2-deoxyribose (step iii)); Reaction of 1,3,5-triacetyl-2-dioxyribose of Formula 2 and 5-azacytosine having a silyl group of Formula 3 introduced in step iii) in methylene chloride or EDC solvent in the presence of TMSOTf Lewis acid To obtain a compound of formula 4 (step iv));  Obtaining the compound of formula 5 using ethyl acetate as the recrystallization solvent from the compound of formula 4 obtained in step iv) (step v)); Obtaining decitabine of the formula (1) in which the acetyl group is deprotected from the compound of formula (5) obtained in step v) (step vi)) improved yield and purity method for producing decitabine. Scheme 3