- Development of an immobilized biocatalyst based on Bacillus psychrosaccharolyticus NDT for the preparative synthesis of trifluridine and decytabine
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The immobilization of Bacillus psychrosaccharolyticus nucleoside 2′-deoxyribosyltransferase was deeply investigated and finally optimized. The best immobilization procedure resulted to be ionic adsorption on PEI 600 Da agarose followed by crosslinking with 70% oxidized dextran (20 kDa). The percentage of recovered activity was further improved (from 21% to 33%) by the addition of 20% glycerol to the immobilization mixture. The resulting biocatalyst showed a stability profile similar to that of the soluble enzyme and it was used for the preparative synthesis of trifluridine and decytabine obtaining conversions ranging from 50% to 76%.
- Fresco-Taboada, Alba,Serra, Immacolata,Arroyo, Miguel,Fernández-Lucas, Jesús,De La Mata, Isabel,Terreni, Marco
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- Decitabine intermediate compound VI
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The invention belongs to the technical field of chemical synthesis, and provides a decitabine intermediate compound. A preparation route of the decitabine intermediate compound comprises the followingsteps: taking an oxymethyl compound of a hydroxyl group at a 1 site of 2-deoxy-D-ribose as a raw material, protecting a hydroxyl group at a 3 site and a hydroxyl group at a 5 site respectively, then performing acetylation substitution on a 1 site of sugar, and further treating to obtain the compound. The method is simple and convenient to operate, does not need special equipment, is good in product purity and high in yield, and is suitable for industrial production; decitabine is further synthesized by utilizing the compound, so that the stereoselectivity is high, and the purity isgood.
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- Decitabine intermediate compound V
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The invention belongs to the technical field of chemical synthesis, and provides a decitabine intermediate compound. A preparation route of the decitabine intermediate compound comprises the followingsteps: taking an oxymethyl compound of 2-deoxy-D-ribose 1 site hydroxyl as a raw material, respectively protecting 3 site and 5 site hydroxyl, and further treating to obtain the compound provided by the invention. The method is simple and convenient to operate, does not need special equipment, and is good in product purity, high in yield and suitable for industrial production; and decitabine is further synthesized by utilizing the compound, so that the compound is high in stereoselectivity and good in purity.
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- Preparation method of decitabine
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The invention belongs to the technical field of organic synthesis, and provides a preparation method of decitabine. The preparation method specifically comprises the following steps: first carrying out reflux extraction to obtain a mixture of decitabine alpha and beta isomers, and then separating the isomers by applying the supercritical fluid technology to obtain high-purity decitabine. Comparedwith the prior art, the technical method which is simple in operation process, high in separation efficiency, high in product yield, high in final product purity and suitable for industrial productionis provided.
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Paragraph 0010; 0035-0036; 0038-0039; 0041-0042; 0044-0045
(2021/01/15)
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- 2-deoxy-D-ribose derivative
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The invention belongs to the field of medicine synthesis, and provides a 2-deoxy-D-ribose derivative (III). When the derivative (III) is used for preparing decitabine, the stereoselectivity is good, and the yield is high. The invention provides a preparation method of the derivative. The preparation method comprises the following steps: step a, carrying out oxygen methylation on 1-position hydroxyl of 2-deoxy-D-ribose; and step b, protecting hydroxyl groups at positions 3 and 5, and further carrying out sulfonation on 1-position oxymethyl. The method is simple and convenient to operate, free of special equipment, good in product purity, high in yield and suitable for industrial production.
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Paragraph 0086-0090
(2020/08/09)
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- Synthetic method of decitabine
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The present invention relates to a synthetic method of decitabine, and discloses a method for synthesizing a compound as shown in a formula I, The method comprises the steps of: reacting a compound IIwith a compound III by a following reaction in a solvent under the action of TMSOTf to obtain a compound I. The synthetic method of the invention has the advantages that the raw materials are easy toobtain, the operation is safe, the conditions are mild and easy to control, and a solid product obtained by an acylation protection is easy to be crystallized and purified, which is favorable for thenext reaction and improves the selectivity of a final beta-isomer product, no further conversion to hydroxymethyl is required, the reaction step is simplified, the reaction yield of each step is good, the atomic economy is high, and the method is suitable for a large number of industrial production and the like.
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Paragraph 0052; 0053
(2019/08/01)
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- Preparation method of beta-nucleoside compound
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The invention provides a method for preparing beta-nucleoside or analogue thereof, comprising the following steps: 1) enabling nitrogenous base or analogue thereof to generate silylanizing reaction under the existence of trimethylsilyl trifluoromethanesulfonate (TMSOTf), to obtain the nitrogenous base or analogue thereof protected by trimethylsilyl; 2) enabling a reaction liquid to directly perform glycosylation reaction with quintuple cyclose or hexahydric cyclose sealed by a hydroxy protection group, so as to obtain a sealed beta-nucleoside or analogue thereof; 3) performing protection groupremoval reaction, to obtain the beta-nucleoside or analogue thereof. The method disclosed by the invention is simple in operation, energy-saving and environment-friendly, a key intermediate of the beta-nucleoside or analogue thereof is prepared by a one-pot methoid, and the yield of beta configuration substance is remarkably increased, and the preparation method is suitable for industrial application.
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Paragraph 0108; 0112; 0113; 0114; 0115; 0120; 0127; 0136
(2018/07/30)
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- A used with the industrial production method for the synthesis of
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The invention relates to a decitabine synthesis and industrial production method, which comprises the following steps of: using 2-Deoxy-D-ribose as a raw material, performing a reaction between the raw material and methanol to obtain glucoside, protecting 3,5-dihydroxy by the use of 9-fluorenylmethyloxycarbonyl, reacting with hydrogen chloride to obtain 1-chlorflurecol sugar, performing a reaction between 1-chlorflurecol sugar and silanized 5-azacytosine, carrying out deprotection, and refining to obtain decitabine. The invention is characterized in that stannic chloride is not required during the condensation reaction between 1-chlorflurecol sugar and silanized 5-azacytosine so as to avoid the problem of excessive contents of heavy metals in pharmaceutical materials; and simultaneously the amount of trimethylsilyl trifluoromethanesulfonate and reaction conditions are controlled so as to increase the body burden of beta in the product.
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Paragraph 0041; 0053-0056
(2018/02/04)
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- Enzymatic synthesis and phosphorolysis of 4(2)-thioxo- and 6(5)-azapyrimidine nucleosides by E. coli nucleoside phosphorylases
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The trans-2-deoxyribosylation of 4-thiouracil (4SUra) and 2-thiouracil (2SUra), as well as 6-azauracil, 6-azathymine and 6-aza-2-thiothymine was studied using dG and E. coli purine nucleoside phosphorylase (PNP) for the in situ generation of 2-deoxy-α-D-ribofuranose-1-phosphate (dRib-1P) followed by its coupling with the bases catalyzed by either E. coli thymidine (TP) or uridine (UP) phosphorylases. 4SUra revealed satisfactory substrate activity for UP and, unexpectedly, complete inertness for TP; no formation of 2′-deoxy-2-thiouridine (2SUd) was observed under analogous reaction conditions in the presence of UP and TP. On the contrary, 2SU, 2SUd, 4STd and 2STd are good substrates for both UP and TP; moreover, 2SU, 4STd and 2′-deoxy-5-azacytidine (Decitabine) are substrates for PNP and the phosphorolysis of the latter is reversible. Condensation of 2SUra and 5-azacytosine with dRib-1P (Ba salt) catalyzed by the accordant UP and PNP in Tris·HCl buffer gave 2SUd and 2′-deoxy-5-azacytidine in 27% and 15% yields, respectively. 6-Azauracil and 6-azathymine showed good substrate properties for both TP and UP, whereas only TP recognizes 2-thio-6-azathymine as a substrate. 5-Phenyl and 5-tert-butyl derivatives of 6-azauracil and its 2-thioxo derivative were tested as substrates for UP and TP, and only 5-phenyl- and 5-tert-butyl-6-azauracils displayed very low substrate activity. The role of structural peculiarities and electronic properties in the substrate recognition by E. coli nucleoside phosphorylases is discussed.
- Stepchenko, Vladimir A.,Miroshnikov, Anatoly I.,Seela, Frank,Mikhailopulo, Igor A.
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p. 2588 - 2601
(2017/01/09)
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- Synthesis method of decitabine for treating primary or secondary leukemia
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The invention discloses a synthesis method of decitabine for treating primary or secondary leukemia. The method comprises the following steps: 1) adding 1-chloro-2-deoxy-D-ribofuranose, cobalt nitrate and (R)-1,1'-linked-2-naphthol in DMF, stirring and mixing for 1-2 hours at 45-60 DEG C, then cooling to room temperature, and filtering to obtain mixture M containing 1-chloro-2-deoxy-D-ribofuranose complex; and 2) in the presence of triethylamine, adding 2,4-bis-trimethylsilyl-S-triazine in the mixture M obtained in the step 1), stirring for reacting for 6-8 hours at 30-40 DEG C, soaking in water, extracting with dichloromethane, washing with dilute hydrochloric acid, washing with saturated sodium bicarbonate, concentrating, and carrying out ethanol recrystallization to obtain decitabine. The method for preparing decitabine effectively improves the selectivity of a beta product and the yield of decitabine, thereby providing a new way for preparing decitabine.
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Paragraph 0026; 0027; 0028; 0029
(2017/01/09)
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- An anti-cancer drug to the preparation method of Decitabine (by machine translation)
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The invention discloses anti-cancer drugs in Decitabine preparation method, the method comprises: 1) the 1 - chloro - 2 - deoxy - D - ribofuranosyl, two palladium chloride, (S)- (-) - 1, 1 '- binaphthyl - 2, 2' - double-b (3, 5 - xylyl) phosphine is added to in DMF, 45 - 60 °C stirring and mixing 1 - 2 hours, then cooling to room temperature, filter, containing the 1 - chloro - 2 - deoxy - D - ribofuranosyl complex mixture M; 2) in the presence of triethylamine, to 2, 4 - bistrimethylsilyl - S - triazine adding step 1) the resulting mixture in the M 30 - 40 °C stirring for 6 - 8 hours, tilting in a water, dichloromethane extraction, dilute hydrochloric acid washing, saturated sodium bicarbonate washing, concentrating, ethanol recrystallize to get in Decitabine. The preparation of this invention in Decitabine of β method effectively improves the product selectivity and the yield of Decitabine, for preparation in Decitabine provides new means. (by machine translation)
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Paragraph 0026; 0027; 0028; 0029; 0030; 0031; 0032-0061
(2017/01/26)
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- Decitabine a process for the preparation of
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The invention discloses a preparation method of decitabine. The preparation method comprises the steps: oxygen methylation of 1st-site hydroxyl of 2-deoxy-D-ribose; protection for hydroxyls on a 3rd site and a 5th site; acylation of 1st-site oxygen methyle; activation of 5-azacytosine; and coupled reaction of protected 2-deoxy-D-ribose and the activated 5-azacytosine, purification of a coupling product; deprotection; and obtaining of a target product. According to the preparation method, the purity of the decitabine is improved, the purification steps of a final product are simplified, and the product cost is lowered.
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Paragraph 0069; 0070; 0073; 0077; 0081; 0085
(2018/07/10)
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- A SITAR hamanaka process for the preparation of intermediates
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The invention discloses a preparation method of a decitabine intermediate compound 1-acetoxyl-2-deoxidized-3,5-bi-O-fluorene methyl cyslohexyl-D-ribofuranose. The structural formula of the compound is shown in img file='DDA0000455164900000011.TIF' wi='648' he='304'/, and the preparation method comprises the following steps: o-methylation of 2'-deoxidized-D-ribose 1-bit hydroxyl; b) protection of 3,5-bit hydroxyl; and c) acylation of 1-bit-O-methyl. The invention also discloses a method for preparing decitabine employing the intermediate as a raw material.
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Paragraph 0090
(2016/10/08)
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- SYNTHESIS OF NUCLEOSIDES
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A process for the preparation of nucleosides, derivatives and analogues thereof by coupling reaction of a protected suitable nitrogeneous purine or pyrimidine base, a derivative or analogue thereof and a protected suitable sugar in the presence of SnCl4 comprising the removal of SnCl4 by adding DMSO directly into the reaction mixture is described. Preferably said process is used for the preparation of antiviral and antitumor agents having a nucleoside or nucleoside-like structure, still more preferably for the preparation of azacytidine, decitabine, chlorfarabine, cladribine, mizoribine. A residual tin content lower than 300 ppm is obtained with said process.
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Paragraph 0054
(2014/05/20)
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- Process for the synthesis of azacitidine and decitabine
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Described herein is a process for the synthesis of azacitidine or decitabine, comprising the silylation of azacytosine in the presence of N,O-bis-trimethylsilyl)-trifluoroacetamide. Such reaction is performed in an organic solvent, preferably aprotic, even more preferably selected from among dichloromethane, dichloroethane and/or acetonitrile. According to a further aspect of the process, 2 to 3 moles of N,O-bis-trimethylsilyl-trifluoroacetamide are used per mole of azacytosine, preferably from 2.2 to 2.5.
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Page/Page column 9
(2011/10/13)
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- PROCESS FOR THE SYNTHESIS OF AZACITIDINE AND DECITABINE
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Described herein is a process for the synthesis of azacitidine or decitabine, comprising the silylation of azacytosine in the presence of N,O-bis-trimethylsilyl-trifluoroacetamide. Such reaction is performed in an organic solvent, preferably aprotic, even more preferably selected from among dichloromethane, dichloroethane and/or acetonitrile. According to a further aspect of the process, 2 to 3 moles of N,O-bis-trimethylsilyl-trifluoroacetamide are used per mole of azacytosine, preferably from 2.2 to 2.5.
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Page/Page column 7
(2011/10/13)
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- PREPARATION OF DECITABINE
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The present application relates to processes for the preparation and purification of decitabine, and to processes for the preparation of a crystalline form of decitabine.
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Page/Page column 28
(2010/11/18)
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- SYNTHESIS OF DECITABINE
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The present invention provides a method for producing a protected precursor of Decitabine as well as the Decibatine final product in high yield and purity.
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Page/Page column 5-6
(2010/04/27)
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- PROCESSES FOR PRODUCING DECITABINE
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New processes for producing decitabine are provided.
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Page/Page column 6
(2010/10/19)
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- Process for Making 5-Azacytosine Nucleosides and Their Derivatives
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A process of synthesizing a 5-azacytosine nucleoside, such as azacitidine and decitabine, comprises coupling a silylated 5-azacytosine with a protected D-ribofuranose of formula in the presence of a sulfonic acid catalyst.
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Page/Page column 7-8
(2010/03/02)
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- Method of producing 2' -deoxy-5-azacytidine (Decitabine)
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Summary 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 R1 is a glycoside donor preferably a 1-halogen derivative, an imidate preferably the trichloromethyl derivative, or a thio-alkyl derivative; 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 and/or the salt of a optionally substituted aromatic sulphonic acid.
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Page/Page column 4
(2009/05/29)
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- Method for producing nucleosides by direct glycosylation of the nucleoside base
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Summary Method of producing a free nucleoside compound by reacting a a glycoside donor preferably a 1-halogen derivative, or 1-0-acyl, 1-o-alkyl, or an imidate preferably a trichloromethyl derivative, or a thio-alkyl derivative of a blocked monosaccharide or oligosaccharide preferably ribose and 2-desoxyribose derivatives with a protected nucleoside base, in a suitable anhydrous solvent and in the presence of a catalyst, and removing the protecting groups from said blocked nucleoside compound, wherein said catalyst is selected from the group comprising salts of an aliphatic sulphonic acid and/or salts of a optionally substituted aromatic sulphonic acid.
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Page/Page column 3
(2009/05/29)
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- Compositions and formulations of decitabine polymorphs and methods of use thereof
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Pharmaceutical compositions and methods for treatment of neoplastic conditions using polymorphs of decitabine are provided. Also provided are methods for manufacturing and administering such pharmaceutical compositions.
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Page/Page column 15
(2008/06/13)
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