- An improved and scalable process for the synthesis of 5-azacytidine: An antineoplastic drug
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An improved, practical, and scalable process for the manufacture of antineoplastic drug, 5-azacytidine (1), is described. A thorough understanding of the reaction parameters and stability of the reaction intermediates led us to the development of a robust process. The challenges in the isolation and systematic approach used to streamline the process into a very robust and practical manufacturing process are described.
- Vujjini, Satish Kumar,Varanasi, Ganesh,Arevelli, Srinivas,Kandala, Sreenatha Charyulu,Tirumalaraju, Satyanarayana Raju,Bandichhor, Rakeshwar,Kagga, Mukkanti,Cherukupally, Praveen
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- Synthesis, Hydrolytic Stability, and Antileukemic Activity of Azacytidine Nucleoside Analogs
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New azacytidine nucleoside analogs with modified carbohydrate moieties were synthesized. Screening identified a highly active 2′-fluoro-containing azacytidine analog that could potentially be of interest as an agent for treating acute myelogenous leukemia and myelodysplastic syndrome.
- Bozhok,Kalinichenko,Kuz’mitskii,Golubeva
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- Azacytidine methylate substance and preparation method, pharmaceutical composition and application thereof
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The invention discloses an azacytidine methylate substance and a preparation method, a pharmaceutical composition and application thereof. The molar ratio of azacytidine to methanol in the azacytidinemethylate substance is 1 to (0.4 to 1.0), preferably, the molar ratio is 1 to (0.4 to 0.8), much preferably, the molar ratio is 1 to (0.4 to 0.6), and especially and preferably, the molar ratio of 1to 0.5. The azacytidine methylate substance has high solubility and is soluble in water and can be used as a raw drug for azacytidine freeze-dried preparations.
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Paragraph 0050-0052
(2020/01/14)
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- Preparation method of azacitidine (by machine translation)
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The invention belongs to the field, and belongs to the field of medicine synthesis. The preparation method comprises the following steps: 5 - aza cytidine and trimethylchlorosilane are reacted, and the azacitidine intermediate I is 70 - 80 °C dissolved, and 2 hours is reacted with 1 - chlorine -2, 3, 5 - three - O O-p-chlorobenzoyl - β-D - ribose under the catalysis of boron trifluoride. the reaction is finished, washed, dried, filtered and filtered, and the filtrate is distilled under reduced pressure to obtain the azacitidine intermediate II; and the method, the method comprises the following steps. The azacitidine intermediate II is purified by ammonia alcoholysis to obtain the azacitidine with high purity by purifying the crude azacitidine crude product. The method has the advantages of mild reaction conditions, short reaction time, high yield, and suitability for industrial production. (by machine translation)
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Paragraph 0024; 0027; 0028; 0031; 0032; 0035; 0036; 0039
(2019/10/01)
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- Method for preparing azacitidine by high-purity and low-calcination residue
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The invention relates to the field of a pharmaceutical synthesis technology, and discloses a method for synthesizing azacitidine. The method improves the quality and product purity of azacitidine, andthe reaction conditions are easy to control and reduce the production cost, and the method is suitable for industrial preparation.
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Paragraph 0014; 0043; 0046-0048; 0051-0053; 0056-0058;
(2019/10/01)
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- Preparation method of azacitidine
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The invention relates to a preparation method of azacitidine. According to the method, the azacitidine is prevented from making contact with water, degradation of the azacitidine is reduced, the operation is simple, and yield and purity are greatly increased. In addition, in the further purification process of the azacitidine, ethyl alcohol is used as a crystal transformation solvent, the cost isgreatly reduced, and the method is more suitable for industrial application.
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Paragraph 0009; 0028-0043
(2019/02/19)
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- A new process for deprotection of acetyl and benzoyl groups in synthesis of azacitidine
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4-Amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one or azacitidine is a promising DNA demethylation inhibitor used for the treatment of myloneplastic, bone cancer and breast cancer. An efficient, cost-effective and convenient manufacturing process for the synthesis of azacitidine is described. The present research relates to the synthesis, deprotection, isolation and purification of azacitidine (1). In this process, more particularly 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is used as deprotection reagent for deprotection of O-acetyl, O-benzoyl to acquire azacitidine (1). The new process allows for the reliable and efficient production of drug substance similar overall yield. The new improved process has merits including enantiomeric purity, better crystallization and the product complies with the requirements of USP30.
- Kumar, Srujana Suneel,Sethuraman
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p. 1521 - 1524
(2018/06/12)
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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 0051
(2014/05/20)
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- SYSTHESIS OF 5-AZACYTIDINE
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Provided herein are processes for the preparation of 5-azacytidine, useful for treating, preventing, and/or managing diseases or conditions including cancer, disorders related to abnormal cell proliferation, hematologic disorders, and myelodysplastic syndromes (MDS), wherein 5-azacytidine is represented by the structure:
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Page/Page column 71
(2012/10/18)
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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 6
(2011/10/13)
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- THERAPEUTIC FOR HEPATIC CANCER
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A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
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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
(2010/03/02)
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- PROCESS FOR PREPARING AZACYTIDINE INTERMEDIATE
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The present invention provides a processes for preparing 5 -Azacytidine, and intermediates thereof, said process Comprising reacting a silylated 5-azacytosine of the formula (II), a sugar moiety having of the formula (III): and a protic acid; wherein R is a substituted or non substituted C1-C20 acyl moiety, R1, R2 and R3 are each independently H or an alkyl group, and X is a halogen. The present invention further provides an analytical method for determining the purity of 5-Azacytidine in a sample.
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Page/Page column 18
(2010/04/03)
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- AZACITIDINE PROCESS AND POLYMORPHS
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Processes for preparing azacitidine. Further included are processes for the preparation of crystalline azacitidine crystalline Form (I) and mixtures of azacitidine crystalline Forms (I) and (II).
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Page/Page column 26
(2010/04/03)
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- PROCESS FOR PREPARING AZACYTIDINE INTERMEDIATE
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The present invention provides a processes for preparing 5-Azacytidine, and intermediates thereof. The present invention further provides an analytical method for determining the purity of 5-Azacytidine in a sample.
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- Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
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Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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- STABLE HIGHLY PURE AZACITIDINE AND PREPARATION METHODS THEREFOR
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Disclosed herein are methods of obtaining highly pure 5-azacytidine, which contains minimal amounts of degradation impurities and methods of assessing the impurity profile of the degradation of cytidine analogues, such as 5-azacytidine
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Page/Page column 15-16
(2009/03/07)
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- Synthesis of 5-azacytidine
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The present invention provides a method for the preparation of 5-azacytidine, wherein 5-azacytidine is represented by the structure: The method involves the silylation of 5-azacytosine, followed by the coupling of silylated 5-azacytosine to a protected β-D-ribofuranose derivative. The coupling reaction is catalyzed by trimethylsilyl trifluoromethanesulfonate (TMS-Triflate).
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- Forms of 5-azacytidine
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The invention provides novel polymorphic and pseudopolymorphic crystalline forms of 5-azacytidine, along with methods for preparing said forms, wherein 5-azacytidine is represented by the formula: The invention also includes pharmaceutical compositions comprising said forms.
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- Methods for isolating crystalline form I of 5-azacytidine
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The invention includes methods for isolating crystalline Form I of 5-azacytidine substantially free of other forms, wherein 5-azacytidine is represented by the formula: The invention also includes pharmaceutical compositions comprising Form I of 5-azacytidine.
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- Agents for corneal or intrastromal administration to treat or prevent disorders of the eye
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Methods and preparations for treating disorders of the eye and/or causing dissolution of corneal proteoglycans and organized healing of corneal stroma, softening of the cornea for non-surgical refractive correction of eyesight, removing corneal haze and opacification, inhibiting fibroblasts and preventing corneal fibrosis and scar formation, treating pterigiums and treating corneal neovascularization as well as iris neovascularization. Preparations containing a) urea, b) urea derivatives (e.g., hydroxyurea, thiourea), c) antimetabolites, e) urea, urea derivatives, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidinium, guanidinium chloride, guanidinium salts, thymidine, thymitadine, uradine, uracil, cysteine), reduced thioctic acid, uric acid, calcium acetyl salicylate, ammonium sulfate, isopropyl alcohol, ethanol, polyethylene glycol, polypropylene glycol or other compound capable of causing nonenzymatic dissolution of the corneal protoeglycans or f) any of the possible combinations thereof, are administered to the eye in therapeutically effective amounts.
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- Agents for intravitreal administration to treat or prevent disorders of the eye
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Methods and preparations for treating disorders of the eye and/or causing posterior vitreous disconnection or disinsertion. Preparations containing a) urea, b) urea derivatives (e.g., hydroxyurea, thiourea), c) a non-steroidal anti-inflamatory agents, d) antmetabolites, e) urea, urea derivatives, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidinium, thymidine, thimitadine, uradine, uracil, cystine), uric acid, calcium acetal salicylate, ammonium sulfate or other compound capable of causing non-enzymatic dissolution of the hyaloid membrane or e) any of the possible combinations thereof, are administered to the eye in therapeutically effective amounts.
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- Investigation of the polarographic properties and potential carcinogenity of some hydroxyurea derivatives by DC polarography
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Polarographic reduction was studied for a series of 7 urea derivatives and the results were used to assess their potential carcinogenity. The polarographic reduction was examined in absolutely anhydrous dimethylformamide by DC polarography. In the conditions applied, the majority of the compounds was reduced within a single two-electron step, only biuret and its formyl derivative were reduced in two one-electron steps. The potential carcinogenity of the substances was assessed based on the tg a value of the slope of dependence of the polarographic wave height on the concentration of α-lipoic acid added as a test substance. For hydroxyurea, which is the only substance in this series for which a carcinogenic activity has been demonstrated, the tg a parameter attained a value of 0.290. Still higher values were obtained for the formyl derivatives - formylbiuret (0.362) and 2-carbamoyl-1-formylguanidine (0.510). So high tg a values warn of a significant potential carcinogenity. The other substances studied exhibited considerably lower tg α values, indicating that their potential carcinogenity will be low.
- Novotny, Ladislav,Vachalkova, Anna,Piskala, Alois
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p. 656 - 662
(2007/10/03)
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- Silylation-Mediated Oxidation of 2,2'-Anhydro-5,6-dihydro-5-azacytidine
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Reaction of 5,6-dihydro-5-azacytidine hydrochloride 1 with 2-acetoxy-isobutyryl chloride produced 5'-O-(2,5,5-trimethyl-1,3-dioxolan-4-on-2-yl)-3'-O-acetyl-5,6-dihydro-2,2'-anhydro-1-β-D-arabinofuranosyl-5-azacytosine hydrochloride 2, which upon partial hydrolysis with EtOH/HCl at 4 deg C gave 3'-O-acetyl-5,6-dihydro-2,2'-anhydro-1-β-D-arabinofuranosyl-5-azacytosine hydrochloride 3.The hydrolysis of 3 with EtOH/HCl at 25 deg C gave 2,2'-anhydro-5,6-dihydro-1-β-D-arabinofuranosyl-5-azacytosine hydrochloride 4.Silylation oxidation of 3 and 4 with BSTFA of BSA in acetonitrile produced the N-substituted derivatives of 1-β-D-arabinofuranosyl-5-azacytosine 8 and 7, respectively.
- Abbasi, M. M.,El-Wassimi, M. T.,Osman, F. H.,Kamel, M. M.
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p. 209 - 216
(2007/10/02)
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