TW200936604A - Method of producing 2'-deoxy-5-azacytidine (decitabine) - Google Patents

Abstract

Method of producing 2'-deoxy-5-azacytidine (Decitabine) by providing a compound of formula (I): wherein R is a removable substituent known per se; and R1is a removable substituent; further providing a silylated base of formula (II): wherein R2 is a protecting group, preferably a trimethylsilyl (TMS)-residue; reacting the compound of formula (I) and the compound of formula (II) together in a suitable anhydrous solvent and in the presence of a suitable catalyst; and removing the substituents R from the compound obtained in order to obtain the compound 2'-deoxy-5-azacytidine (Decitabine), characterized in that said catalyst is selected from the group comprising a salt of an aliphatic sulphonic acid or a salt of a strong inorganic acid.

Description

200936604 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a process for producing 2'-deoxy-5-azacytidine (decitazepine) in the presence of a selected catalyst. Preferably, it is a glycoside donor of 5 ❹ 10 15 ,, or preferably an imiline of a trichloromethyl derivative, or a thiomonoalkyl derivative of a blocked monosaccharide, and a selected decane. Base reaction. [Prior Art] Dexitabine is a nucleoside and is a known pharmaceutically active compound. It is known in the U.S. Patent No. 3,817,98, the disclosure of which is incorporated herein by reference to the entire disclosure of the entire entire entire entire entire entire entire entire entire entire entire The glycosyl donor reaction of the blocked monosaccharide derivative. The catalyst used is, for example, selected from the group consisting of SnCl4, TiCl4, ZnCl2, BF3 etherate, A1C13 and SbCl5. The main disadvantage is that the catalysts are susceptible to hydrolysis to produce irritating hydrolysates, such as HC1 and/or to form insoluble oxides (Ti〇2, Sn〇2), which are difficult to remove from the reaction product. These catalysts are especially difficult to handle, especially in large scale production. US Patent No. US-A-40,829,911 relates to a similar manufacturing process which reacts a guanidinated nucleoside base with a protected derivative of a sugar and attempts to use a strong organic such as trimethyldecyltrifluoromethanesulfonate. A trialkyl decyl acid ester is used as a catalyst. An improved method of U.S. Patent No. US-A-4,829, 811, which is incorporated herein by reference in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety, in the in the the The trifluoromethanesulfonate is formed in situ from the free acid by reacting the free acid with, for example, a trialkylsulfite decylating agent, and 20 200936604 is present in an appropriate molar amount. A decylating agent such as a trialkyl gas decane is a trialkyl decyl ester which is very reactive and rapidly reacts to form a free acid present in the reaction mixture. SUMMARY OF THE INVENTION 5 Ο 10 I have found that a 1-halo monosaccharide derivative can be reacted with a quinone alkylated or alkylated 5-azacytosine in the presence of a salt as a catalyst, wherein the catalyst is selected from, for example, three A group of aliphatic sulfonates of fluoromethanesulfonate or a strong mineral acid salt such as peroxyacid salt. It is not necessary to use an ester compound as a catalyst. This greatly simplifies the production of 2,_deoxy-5-azacytidine (decitazepine) described herein. Further, it is possible to obtain a selectivity which is advantageous for the improvement of the oxime-isomer using the catalyst of the present invention, for example, a selectivity of at least 1:2. The reaction of the present invention is carried out such that about three-quarters of the reaction yield is a ruthenium isomer, and based on the specific reaction conditions, the ratio of the α-oxime isomer is 12:88. Furthermore, according to the present invention, the present invention is present in the final thick. Calculated by the total amount of the spinning isomer of the reaction mixture, a reaction yield higher than 95% can be obtained, and is often in the range of 97 to 99%. ~ The use of the catalytic type according to the present invention (10) is stable in the case of hydration, is easy to handle, does not produce irritating hydrolyzate, and can be easily removed. Moreover, in order to obtain the selectivity of the desired spinning isomer reaction, for example, the ratio of α to the isomer is ' and the final yield is considerably improved. The invention is as defined in the scope of the patent application. The present invention relates to a method for the preparation of 2 deoxyazacytidine (disostatin) by providing a compound of the formula ® (blocked monosaccharide derivative): 20 (I) 200936604

RO

•, R1 RO wherein 5 ❹ 10 R is itself known as a removable substituent (protecting group), preferably (C _C8) alkylcarbonyl or optionally substituted phenylcarbonyl, or optionally substituted benzylcarbonyl The substituent which is removable is preferably a halogen, preferably chlorine, bromine, fluorine, more preferably chlorine, or an urethane, preferably a tris-methylethylenimine or a sulfur-alkyl derivative. Further, preferably -S-methyl; further providing an alkylation base of formula (II):

15 ❿ wherein R 2 is a protecting group, preferably a trimethyl decane * (TMS) _ residue; a compound of formula (1) and formula (π) in a suitable anhydrous solvent and in the presence of a suitable catalyst The compounds are reacted together, whereby a compound of the formula (πι) can be obtained:

(ΠΙ) and removing the substituent R to obtain 2,-deoxy-5_azalin (descitabine) s, characterized in that the catalyst is selected from the group consisting of aliphatic acid salts or strong helmets. Group of acid salts. ' 20 200936604 The invention also relates to the use of the catalyst of the invention to produce a compound of the formula (Ιπ), which produces the desired selectivity, preferably favoring the isomer, preferably at least 1.2. The ratio 'and preferably wherein about three-quarters of the reaction yield is the beta isomer. More preferably, it is a β-glycoside of the formula (m). 5 The catalyst used in the reaction is an aliphatic sulfonate, preferably a methyl sulphate (methyl sulphate) or an ethyl sulphate, or a fluorination such as a trifluoromethane sulphonate. Aliphatic acid salt, penta-ethyl ethyl citrate, or heptafluoropropyl phthalate. If the catalyst used in the reaction is a strong mineral acid salt, the catalytic agent is (iv)' which contains the cations and strong nucleophilic anions for the strong unshipped salts as defined herein. The non-nucleophilic anion does not form a complex with the cation in solution. Preferably, the strong inorganic acid salt is selected from the group consisting of MBPh4, MB(Me)4, MPF6, MBF4, MC1〇4, MBr〇4, mk)4, m2so4, MN〇3, and M3P〇4 (m= Metal cation; F = gas; 15 C1 = chlorine, dress = desert; B = boron; Ph = phenyl; Me = methyl; p = filled; j = magnetic). Preferred are MBPh4, MB(Me)4, MpF6, mbF4, ΜΒ1Ό4, MJO4, preferably perchloric acid (MC1〇4) salts and tetrafluoroboric acid (MBF4) salts. Most preferably, the salt is M = lithium. Preferred salts are methanesulfonate (methanesulfonate), trifluoromethane 20 sulfonic acid, salts and perchlorates. Preferred aliphatic acid salt, fluorinated aliphatic acid salt and strong inorganic acid salt, metal salt and alkaline earth metal salt, preferably lithium salt, sodium salt, potassium salt or magnesium salt . More preferably, it is a lithium salt, preferably lithium methanesulfonate (lithium methanesulfonate), lithium trifluoromethanesulfonate (LiOTf, lithium_triflate), 200936604 lithium percarbonate, and lithium tetrafluorophosphate. There are also other _, such as the salt of Sc(〇Tf)3, such as the salt of Zn(0Tf)2, or a copper salt such as. In any case, lithium salts, and especially Li〇Tf, are preferred. The preferred solvent for carrying out the reaction according to the present invention is an organic solvent of xylene, or a chlorinated solvent such as dichloromethane, di-, benzene, or acetonitrile or propylene carbonate: or a solvent. Compared with (iv) toluene and chlorinated solvents. Preferably, the isomer is used in a chlorinated solvent, a fluorocarbonic acid acid clock (LiOTf), preferably in an aromatic gas, a gas, a chlorobenzene, and/or an aromatic solvent such as toluene or xylene. In the case of 'per-solvent mixture, there will be differences. For those skilled in the art, there is no problem in mixing the catalyst and/or the solvent to achieve the desired selectivity. The compound of the formula (I) is used as a sugar donor compound. The compound of the formula (1) is known per se. The substituent R to be removable is preferably (CVC4 into a county, or a substituted benzoyl group, such as stupid, toluene, xylene, or agglomerate. Preferably, it is an ethylidene group or a p-chlorophenylcarbonyl group. The removable substituent Rj is preferably, preferably chlorine, preferably chlorine or imidate. Preferably, trichloromethane [-NH-(0)C-CC13], or sulfur- The pyridyl derivative, preferably the δ-methyl oxime () δ product, and its preparation are known, and the compound is freely reacted with trimethyl chloroproper or with a hexammine amine.夂200936604 When reacting the compounds of formula (1) and (11) together, the reaction temperature is generally in the range of from 〇 ° C to about 90 ° C, preferably at about room temperature, whereby the component is present in an approximate molar concentration Equivalent amount of reaction or reaction with a compound of formula (II). The catalyst is preferably used at a concentration of from about 10 mol% to 1 mol%, which is calculated as the total mole of the two reaction components. The amount is present. There is no problem in optimizing the composition of the skilled person. In order to remove the substituent R from the compound of formula (III) to obtain a free hydroxyl group 2,- Oxo-5-azacytidine (decitabine guest) compounds can be used known methods. Preferably, R is a substituent group may be removed, e.g., by

The treatment in the fine solution; however, other known methods are also possible; ^;; The examples illustrate the invention. J [Embodiment] 15 ❾ 20 (A) 5-azacytosine (2 gram, 178 4 mil) and hexamethyl bismuth == gram; the mixture is heated under reflux until the supernatant is obtained . . Guang) Shi Xi amine burned in 603⁄4 in the real line towel was removed. , bauxite - will be 264 grams of two (four) m _ millimonone chloro sugar" (10) (27.84 grams, thiol-2_deoxy-enzyme nucleus, - a pair of chlorobenzoic acid ^ should be a compound of formula (1)] Addition to the one in the step (A): 4 millimoles, the residue obtained in 1) (9) degrees (9) · 25 〇 c), the husk compound produces a compounding isomer 99.2%, selective two reaction 200936604 (D) Thereafter, the solvent was removed in a vacuum apparatus at 4 ° C, and the obtained residue was dissolved in 60 g of ethyl acetate. The solution was at 3 Torr. The hydrazine was added dropwise to the aqueous hydrogen carbonate. A mixture of 220 g of a solution (2.5 wt% solution), 174 g of ethyl acetate, 36 g of cyclohexane and 70 g of acetonitrile and the obtained reaction mixture was cooled to 0 ° C and stirred for 3 hours (h). The end (protected) precipitate of the aminotriazine was filtered off, washed with water and finally a mixture of acetonitrile and ethyl acetate (1:1). ❹ Total yield 79.2 g (87.8%) of compounded isomers ; α / β ratio 31: 69. This chemical reaction is illustrated in Scheme 1. 10 Example 2: Compound corresponding to formula (ΠΙ) obtained as in Example 1 'Alcoholic solution in ammonia is further known by known methods deal with To obtain 2 _deoxy-5-azacytidine (dixitabine) as a substantially quantitative yield.

Ο TM S 15 〆丫 Η 氮 aza-cytosine 〇

Blocked Amino Triazine 20 200936604 Example 3: Example 1 was repeated and 1.0 equivalent of lithium sulfonate was used in place of lithium trifluoromethanesulfonate. The reaction yield after the step (C) was 95.2%, and the selectivity α/β = 60:40. 5 Ο 10 15 20 The total yield after the work-up step (D) is 85.2%, and the ratio of α/β is 63:37. Example 4: Example 1 was repeated and 1.0 equivalent of lithium perchlorate was used in place of lithium trifluoromethanesulfonate. Reaction yield after the step (C): compounding the isomer is 99.4%, and the selectivity α/β = 37:63. The total yield after operation (D) was 85.2%, and the α/β ratio was 36:64. Example 5: Example 1 was repeated and 1.0 equivalent of lithium tetrafluoroborate was used in place of lithium trifluoromethanesulfonate. Reaction yield after the step (C): 94.5% of the racemic isomers, and the selectivity α/β = 59:41. The total yield after operation step (D) was 47.9%, and the ratio of α/β was 70:30. Example 6: Example 1 was repeated and 1.0 equivalent of sodium trifluorosulfonate was used in place of lithium trifluoromethanesulfonate. Reaction yield after the step (C): compounding the isomer is 99.2%, and the selectivity α/β = 40:60. The total yield after operation step (D) was 80.7%, and the α/β ratio was 40:60. Example 7: Example 1 was repeated and 1.0 equivalent of potassium trifluorosulfonate was used in place of lithium trifluoromethanesulfonate. Reaction yield after step (C): compounding the isomer is 99.0%; 11 200936604 selectivity α/β = 44: 56. The total yield after the operation (D) was 79.9%, and the α/β ratio was 46:54. 5 ❹ 10 15 〇 20 Example 8: By repeating Example 1 [except for step (D)], 1.0 equivalent of zinc trifluoromethanesulfonate was used in place of lithium trifluoromethanesulfonate. Reaction yield after the step (C): compounding the isomer 96.0%: Selective α/β54: 46. Example 9: Example 1 was repeated and the same volume of terpene was used as a solvent in place of dichloromethane. Reaction yield after step (C): 99.4% of compounding isomers, selectivity α/β=27: 73 ° Total yield after operation step (D) 88.7% compounding isomers; α/ β ratio 31 : 69 . Example 10: Example 1 was repeated and the same volume of acetonitrile was used as a solvent in place of the dichloromethane. Reaction yield after the step (C): compounding the isomer is 99.2%, and the selectivity α/β = 50:50. The total yield after operation step (D) was 82.5%, and the ratio of α/β was 52:48. Example 11 (Α) 5-azacytosine (0.5 g, 4.46 mmol, 1 equivalent), ammonium sulfate (40 mg, 0.3 mmol, 0.07 equivalent), and hexamethyldioxane ( A mixture of 4 grams, 24.8 millimoles, 5.6 equivalents was heated at reflux to 200936604 until the supernatant was obtained. Excess methyldiamine was removed in a vacuum at 60 °C. (B) Thereafter, 10 ml of dichloromethane, lithium trifluoromethanesulfonate (0.33 g, 2.11 mmol; 0.47 equivalent) and "chloro sugar" C-137: 1-chloro-3,5-5 Di-indole-p-benzophenanthr-2-deoxy-α-D-enzyme ribose [0.73 g, 1.70 mmol, 0.38 equivalent; corresponding to the compound of formula (I)], added in the step ( A) The residue obtained. The mixture was stirred at ambient temperature A (20-25 ° C) for 4 hours. The reaction resulting from the η reaction is 99.1%; α/β = 16/84. Ίο Example 12: Example 11 was repeated and 0.47 equivalents of copper trifluoromethanesulfonate was used in place of lithium trifluoromethanesulfonate. The reaction yield after the step (Β) was 98.0%, and the selectivity α/β = 42:58. Example 13: Example 11 was repeated and 0.47 equivalent of trifluoromethanesulfonate 15 acid was used in place of lithium trifluoromethanesulfonate. 'Reaction yield after the step (Β): 88.0% of the racemic isomers, and the selectivity of α/β = 43:57. Example 14: Example 11 was repeated and 0.47 equivalent of magnesium trifluoromethanesulfonate was used in place of lithium trifluoromethanesulfonate. 2〇 Reaction yield after the step (Β): compounding the isomer is 89.0%, and the selectivity α/β = 58:42. Example 15: Example 11 was repeated and the same volume of acetonitrile was used as a solvent in place of dichloromethane. 13 200936604 Reaction yield after step (B): compounding the isomer of 97.6%, selectivity α/β=39:61. Mutual: Example 11 was repeated and the same volume of gas was used as a solvent instead of dichloromethane. Reaction yield after the step (B): compounding the isomer is 96.2%, and the selectivity α/β26: 74. The retort was repeated and the same volume of propylene carbonate was used as a solvent instead of dichloromethane. ❹ 15 反应 Reaction yield after the step (Β): compounding the isomer of 96.8%, selectivity α/β=42:58. Example 11 was repeated and 10 ml of dichloromethane and 3 5 ml of diphenylbenzene were used as a solvent instead of 10 ml of pure dichloromethane. The reaction yield after the step (Β) was 93 3% of the compounding isomer and α/β = 27:73. Rabbit over 19 (Α) will be 5-azacytosine (0.5 g, 4.46 mol, i equivalent), ammonium sulfate (40 mg, 0.3 mmol, 0.07 when. come... Tian set), and Liujia The bis-amine amide (4 g, 24.8 mmol, 5.6 eq, recognized) was heated at reflux until a supernatant was obtained. (8) After 10 ml of U-di-benzene, n-acid 33 g, 2.11 mmol; 0.47 equivalent) and "chloro sugar" c] 37: ι 氯 - 3 » 〇 _ Benzene hydrazine - 2-deoxy-aD is a nucleus; 15 g, 2 anvil, 0.60 equivalent; a compound corresponding to the formula (1) added to the residue obtained in the dream (A). The mixture is at ambient temperature ( 2〇_2 generation) was given a fall of 4 hours. 20 200936604 The reaction produced a compounding isomer 91.2%; α/β=27/73. Example 20: Repeating Example 19 and using the same volume of 1,2 - Dichloroethane as a solvent in place of 1,2-dichlorobenzene. 5 Ο 10 15 反应 Reaction yield after the step (Β): 93.4% of the compounding isomer, selectivity α/β = 27 : 73 Example 21 (Α) 5-azacytosine (0.5 g, 4.46 mmol, 1 equivalent), ammonium sulfate (40 mg, 0.3 mmol, 0.07 equivalent), and hexamethyldioxane (4 g, 24.8 mmol, 5.6 equivalents) was heated under reflux until the supernatant was obtained. Excess hexamethylenediamine was removed in a vacuum at 60 ° C. (B) 10 ml of dichloro Decane, lithium trifluoromethanesulfonate (0.33 g, 2.11 mmol; 0 .47 equivalents) with "glycan" C-137: 1-chloro-3,5-di-O-p-benzoyl-2-deoxy-α-D-enzyme ribose; [0.38 g, 0.88 Millol, 0.20 equivalent; corresponding to the compound of formula (I)] is added to the residue obtained in step (A). The mixture is stirred at ambient temperature (20-25 ° C) for 4 hours. Structure 99.3%; (χ/β=12/88. 15

Claims (1)

200936604 VII, the scope of application for patents: 1' a manufacturing 2,- by the method of providing (1) = nitrogen (decitabine) 0 10 〇15 (1) R t is a substituent which is known to be removable, preferably, 'a thiol group which may be optionally substituted, or a benzyl group which may be substituted by a tone; ~ R1 is a shiftable The substituent is preferably a halogen, preferably chlorine, bromine or fluorine, preferably gas or imidate, preferably trichloromethylimine or sulfur monoalkyl derivative. , preferably _S_ fluorenyl; further providing an alkylation base of formula (II): (I) wherein R2 is a protecting group, preferably a trimethylsulfonyl (TMS)-residue; a compound of formula (1) and a compound of formula (II) in a suitable anhydrous solvent and in the presence of a suitable catalyst Reacting together, thereby obtaining a compound of formula (III): 16 20 200936604 Q 2. R〇 10 (HI) If the substituent R is removed to obtain a compound of the formula (III) of the formula (III) of the purely aliphatic family. Method 'by providing a compound of formula (I): R1 0) wherein R itself is known as a removable substituent, preferably (crc8) alkanocarbonyl-15 group, or optionally substituted phenylcarbonyl, or optionally substituted benzylcarbonyl; Ri ^ removable The substituent is preferably a dentate, preferably a gas, a desert, or a fluorine, preferably a chlorine or an urethane, preferably a trichloromethylimine ester, or a sulfur monoalkyl derivative. Further providing a ruthenium alkylation base of formula (II): earth 17 20 200936604 5 wherein R 2 is a protecting group, preferably a trimethylsulfonyl (TMS)-residue; the sigma of formula (1) is reacted with formula (11) in a suitable anhydrous solvent and in the presence of a suitable catalyst The compounds are reacted together to thereby obtain a compound of the formula (III). The catalysis (4) is selected from the group consisting of a (iv) aliphatic or strong mineral acid salt.瓜❹ 10 15 ❹ 3. For example, the method of claim 1 or 2, characterized in that the catalyst is an aliphatic sulfonate, preferably a decyl sulfonate or an ethyl acrylate. The salt is a sutured fat-based salt, preferably a tris-sulfonate, a penta-ethylsulfonate or a heptafluoropropylsulfonate. 4. The method of claim 3, wherein the silking agent is a methyl methacrylate and/or a trifluoromethane acid salt. 5. The method according to any one of claims 1 to 4, characterized in that the catalyst is a metal salt or a soil metal salt, preferably a salt, a salt or a magnesium salt, more preferably a lithium salt. salt. 6. The method of any one of claims 1 to 5 wherein the catalyst is lithium methanesulfonate and/or lithium trifluoromethanesulfonate. The method of any one of clauses 1-4 to 4, wherein the catalyst is selected from the group consisting of a zinc salt preferably comprising Se(OTf)3^, preferably Zn(OTf)2 or preferably Cu ( The copper salt of 〇Tf)2, the salt of which is the method of claim 1 or 2, which is a salt of a strong inorganic acid which contains a cation and a non-nucleophilic agent: the anion is not in solution and the cation Forming a complex, preferably selected from the group consisting of: MBPh4, MB(Me)4, Μ%, _& parent characteristics 8. 20 200936604 MC104, ΜΒγ04, mjo4, m2S04, mno3, and m3po4 group 'better MBPh4, MB(Me)4, MPF6, MBF4, MCl〇4, MBr〇4, MJO4, and preferably perchlorate and/or tetrafluoroborate. 5 ❹ 10 9· The method of claim 8, wherein the catalyst is an alkali metal salt or an alkaline earth metal salt, preferably a lithium salt, a sodium salt, a potassium salt or a magnesium salt, more preferably a clock salt, Preferably, it is a perchloric acid clock and/or lithium tetrafluoroborate. 10. The method of claim 8, wherein the catalyst is a cerium salt, a zinc salt or a copper salt. The method of any one of claims 1 to 10, wherein the solvent for carrying out the reaction is selected from the group consisting of organic solvents, preferably benzene toluene, a stupid or chlorine. The solvent is more preferably dichloro-xyl alcohol, di-hexane, chloroform, chlorobenzene or toluene, xylene (tetra) 〇1) or acetonitrile, propylenedicarbonate and related solvents. The method of claim 5, wherein the solvent to be reacted is selected from the group consisting of organic solvents, preferably toluene, xylene, and a chlorinated solvent, and is preferably selected from the group consisting of gasification solvents. Such as the scope of patent application! The method according to any one of the preceding claims, wherein the catalyst is selected from the group consisting of dichloromethane and the organic solvent, preferably dichloromethane, dichloroform and/or Or a chlorinated solvent of chlorobenzene. 14. The method of any one of clauses 1 to 13, characterized in that the removable substituent R is (6) heart burned or may be optionally substituted 12. 13· 19 200936604 The benzyl or alkoxy group is preferably a benzyl group, a tolyl group or a fluorenylphenylcarbonyl group; more preferably an acetamino group or a p-chlorophenylcarbonyl group. The method of any one of claims 1 to 14, wherein the removable substituent 艮 is -〇-fluorenyl (CrCUh-O-alkyl (CrQ) or chlorine, preferably -〇-(〇)CCH3 or gas, more preferably gas. 20 200936604 IV. Designation of representative drawings: (1) The representative figure of the case is: (None). (2) The symbol of the symbol of this representative is simple: No. 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: No 200936604 Patent Description (Please do not change the format and order of this manual, please do not fill in the ※ part) ※Application number: 97 1 3Ό8 0 7 ※Application date: 1:1 category: 1. Name of the invention: (Chinese/English) Method 2:-deoxy-5-azacytidine (Decitabine) for the manufacture of 2 - de-milk-5_gas-cell (Decitabine) II. Summary of Chinese invention: C2€C: (2〇〇£.〇 A method for the manufacture of 2'-deoxy-5-azacytidine (disostatin) by providing a compound of formula (1): (I) R itself is known as a removable substituent; and is a removable substituent; further providing a oxime alkylation base of formula (Π): (II) wherein R2 is a protecting group, preferably a trimethylsulfonylalkyl group (TMS) residue; the compound of formula (1) is combined with a compound of formula (Π) in a suitable anhydrous solvent and in the presence of a suitable catalyst Reacting; and removing the substituent R from the obtained compound to obtain the compound 2'-deoxy-5-indolyl cytidine (dixitabine), the special invention patent specification 200936604 (Please do not change the format and order of this manual, please do not fill in the ※ part) ※Application number: 97 1 3Ό8 0 7 ※Application date: 1:1 category: 1. Name of the invention: (Chinese/English) Method 2:-deoxy-5-azacytidine (Decitabine) for the manufacture of 2 - de-milk-5_gas-cell (Decitabine) II. Summary of Chinese invention: C2€C: (2〇〇£.〇 A method for the manufacture of 2'-deoxy-5-azacytidine (disostatin) by providing a compound of formula (1): (I) R itself is known as a removable substituent; and is a removable substituent; further providing a oxime alkylation base of formula (Π): (II) wherein R2 is a protecting group, preferably a trimethylsulfonylalkyl group (TMS) residue; the compound of formula (1) is combined with a compound of formula (Π) in a suitable anhydrous solvent and in the presence of a suitable catalyst Reacting; and removing the substituent R from the obtained compound to obtain the compound 2'-deoxy-5-indolyl cytidine (dixitabine),