- Synthesis of (±)-Emtricitabine and (±)-Lamivudine by Chlorotrimethylsilane-Sodium Iodide-Promoted Vorbrüggen Glycosylation
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By simple combination of water and sodium iodide (NaI) with chlorotrimethylsilane (TMSCl), promotion of a Vorbrüggen glycosylation en route to essential HIV drugs emtricitabine (FTC) and lamivudine (3TC) is achieved. TMSCl-NaI in wet solvent (0.1 M water)
- Jamison, Timothy F.,Mear, Sarah Jane,Nguyen, Long V.,Rochford, Ashley J.
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- Emtricitabine synthesis method
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The invention provides an emtricitabine synthesis method, which comprises: carrying out condensation on cheap and easily available dihaloacetic acid as a raw material and L-menthol, hydrolyzing to obtain menthyl glyoxylate hydrate, condensing with 2,5-dihydroxy-1,4-dithiane, carrying out halogenation, coupling with silylated 5-flucytosine, reducing, carrying out salt forming with salicylic acid toobtain emtricitabine salicylate, and finally re-crystallizing to obtain optically pure emtricitabine. According to the present invention, the whole synthesis process has characteristics of inexpensive and easily available raw materials, simple synthesis process and mild synthesis conditions, such that the synthesis cost of emtricitabine is substantially reduced; various raw materials have characteristics of good reaction selectivity and high utilization rate, such that the yield of the obtained emtricitabine is high; and the chiral substrate is easily removed during the synthesis, and the generated three-waste pollutants are less, such that the method is suitable for industrial large-scale production of emtricitabine.
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- Preparation process of emtricitabine intermediate
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The invention discloses a preparation process of an emtricitabine intermediate, namely (2R,5S)-5-(5'-fluoro-cytosine-1-yl)-1,3-dioxathiolane-2-carboxylic acid-L-menthyl ester shown as a structural formula (I). The preparation process comprises the following steps: (A) taking 5-fluorocytosine shown as a structural formula 7 as a raw material, and enabling the 5-fluorocytosine to react with N,N-dimethylformamide shown as a structural formula 20 and hexamethyldisilazane shown as a structural formula 8 to prepare 2-O-trimethylsilyl-4-N-[(N',N'-dimethyl)amino]methylene-5-fluorocytosine shown as a structural formula 21; (B) condensing the compound 21 and a chlorine substitute shown as a structural formula 6 to generate (2R,5S)-5-(4'-N-((N',' dimethyl)amino)methylene-5'-fluoro-cytosine-1-yl)-1,3-dioxathiolane-2-carboxylic acid-L-menthyl ester shown as a structural formula 22; and (C) hydrolyzing the compound 22 in an acidic solution to prepare the compound I. According to the preparation process, side reaction can be reduced so that the purity of a product is improved and the consumption of raw materials is reduced. The formula (I) is as shown in the specification.
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Paragraph 0074-0076; 0081; 0085; 0086; 0091; 0095
(2017/08/29)
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- Preparation method of emtriva
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The invention discloses a preparation method of emtriva. The preparation method comprises following steps: step A, in an alcoholic solvent I, an emtriva crude product and a halogen hydride are subjected to salt forming reaction so as to obtain a emtriva halogen acid salt, wherein the HPLC purity of the emtriva crude product is controlled to be 85.0% or higher, the halogen hydride is selected from hydrogen chloride, hydrogen bromide, or hydrogen iodide, and X is used for representing chlorine, bromine, or iodine; and step B, in an alcoholic solvent II, the emtriva halogen acid salt prepared in step A and an organic alkali are subjected to neutralization reaction so as to obtain emtriva, wherein X is used for representing chlorine, bromine, or iodine. The preparation method is simple in operation, simple in postprocessing, and high in yield; the purity of prepared emtriva is high; HPLC purity is higher than 99.60%; the content of the maximum single impurity is less than 0.10%; bulk pharmaceutical chemical standards are satisfied; production cost is low; and the preparation method is suitable for industrialized production.
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Paragraph 0047; 0048; 0049
(2017/08/28)
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- Preparation method for emtricitabine hydrohalide
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The invention discloses a preparation method for emtricitabine hydrohalide. The preparation method for the emtricitabine hydrohalide provided by the invention comprises the following steps: subjecting crude emtricitabine and hydrogen halide to a salt-forming reaction in an alcohol solvent so as to obtain emtricitabine hydrohalide, wherein the HPLC purity of the crude emtricitabine is larger than 85%; the hydrogen halide is selected from the group consisting of hydrogen chloride, hydrogen bromide or hydrogen iodide; and X is selected from the group consisting of chlorine, bromine or iodine. The preparation method provided by the invention has the advantages of simple operation, simple and convenient postprocessing and high yield; and the prepared emtricitabine product has high purity, can reach standards of raw medicines, has an HPLC purity larger than 99.60% and a largest single impurity less than 0.10%, is low in production cost, and is applicable to industrial production.
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Paragraph 0048; 0049; 0050
(2017/08/27)
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- PROCESS FOR PRODUCING LAMIVUDINE AND EMTRICITABINE
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This invention provides for flow and batch synthesis processes for the production of Lamivudine and Emtricitabine, including flow and batch synthesis processes wherein at least of the synthesis steps are conducted in a solvent free environment.
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Page/Page column 19; 20; 21; 22
(2018/01/20)
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- Preparation method for nucleoside analogue
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The invention discloses a preparation method for nucleoside analogue. The preparation method comprises a reaction shown in the description, wherein R in the formula is hydrogen or fluorine. The preparation method is characterized in that preparation of a compound in formula III is achieved through chlorination between a compound in formula II and oxalyl chloride. By means of the method, the nucleoside analogue intermediate used for preparing lamivudine or emtricitabine can be prepared, the enantioselectivity is high, the chemical purity can reach 99% or above or even to 99.5% or above, the mol yield can reach 85% or above, and the preparation method has the advantages of being low in toxicity and environmentally friendly and has remarkable value for industrialization of the lamivudine or the emtricitabine.
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Paragraph 0024; 0026; 0027; 0028; 0029; 0030
(2017/01/02)
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- Highly stereoselective synthesis of lamivudine (3TC) and emtricitabine (FTC) by a novel N -glycosidation procedure
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The combined use of silanes (Et3SiH or PMHS) and I2 as novel N-glycosidation reagents for the synthesis of bioactive oxathiolane nucleosides 3TC and FTC is reported. Both systems (working as anhydrous HI sources) were devised to act as substrate activators and N-glycosidation promoters. Excellent results in terms of chemical efficiency and stereoselectivity of the reactions were obtained; surprisingly, the nature of the protective group at the N4 position of (fluoro)cytosine additionally influenced the stereochemical reaction outcome.
- Caso, Maria Federica,Dalonzo, Daniele,Derrico, Stefano,Palumbo, Giovanni,Guaragna, Annalisa
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p. 2626 - 2629
(2015/06/16)
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- A STEREOSELECTIVE PROCESS FOR PREPARATION OF 1,3-OXATHIOLANE NUCLEOSIDES
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The present invention relates to a stereoselective glycosylation for the preparation of 1,3-oxathiolane nucleoside in high yield and high optical purity. The invention specifically relates to a process of the preparation of Lamivudine and Emtricitabine using zirconium (IV) chloride (ZrCl4) as a catalyst in glycosylation.
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- NOVEL PROCESS FOR THE PREPARATION OF CIS-NUCLEOSIDE DERIVATIVE
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The present invention relates to an improved process for the preparation of cis-nucleoside derivative of formula-1 involving chlorination of the compound of formula-2 followed by reaction with compound of formula-3 in presence of a base to get compound of formula-4, reacting the compound of formula-4 with an alkyl halide (RiX) to get a quaternary ammonium salt then with cytosine derivative of formula-5 to provide the compound of formula-6, optionally de-protecting the compound of formula-6 to the compound of formula-7, reducing compound of formula-7 with metal catalyst in presence of a buffer solution, then adding an organic acid to get the compound of formula-8, and converting the compound of formula-8 to cis-nucleoside derivative of formula-1. The present invention further relates to novel cis-nucleoside derivative of formula-8. The present invention also relates to a pharmaceutical composition comprising cis-nucleoside derivative of formula-1 with excipients.
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- IMPROVED PROCESS FOR NUCLEOSIDES
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The present invention relates to improved process for the preparation of lamivudine or emtricitabine. Thus, (1'R,2'S,5'R)-menthyl- 5(R,S)-acetoxy-[1,3]-oxathiolane-2(R)-carboxylate is reacted with N-propinoyl cytosine in hexamethyl disilazane and then added trityl perchlorate to obtain a solid containing (1'R,2'S,5'R)-menthyl-5S-(N-4''-propionylcytosin-1''-yl)-[1,3]-oxathiolane -2R-carboxylate. The solid obtained above is reacted with methane sulfonic acid to obtain (2R,5S)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)- [1,3]-oxathiolane-2-carboxylic acid, 2S-isopropyl-5R-methyl-1R-cyclohexyl ester. The above compound is reduced with sodium borohydride to obtain lamivudine.
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Page/Page column 15-16
(2011/08/03)
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- PROCESS FOR PRODUCING 5-FLUORO-1-(2R,5S)-[2-(HYDROXYMETHYL)-1,3-OXATHIOLAN-5-YI]CYTOSINE
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Disclosed herein an improved process for producing 5-Fluoro-1-(2R, 5S)-[2- (hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine and its pharmaceutical acceptable salts.
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Page/Page column 8-9
(2009/08/14)
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- CRYSTALLINE L-MENTHYL (2R, 5S)-5-(4-AMINO-5-FLUORO-2-OXO-2H-PYRIMIDIN-1-YL)[1, 3]OXATHIOLAN-2-CARBOXYLATE AND PROCESS FOR PREPARATION THEREOF
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Provided herein is crystalline L-menthyl (2R, 5S)-5-(4-amino-5-fluoro-2-oxo-2H- pyrimidin-l-yl)[l,3]oxathiolan-2-carboxylate and a process for preparation thereof.
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Page/Page column 8
(2008/06/13)
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- PROCESS AND INTERMEDIATES FOR PREPARING EMTRICITABINE
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A novel process for preparing emtricitabine, and more particularly a process for preparing emtricitabine characterized by the formation and isolation of intermediate compounds in salified form, is described.
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