764659-79-2

Usage

Chemical Properties

White Solid

Uses

Intermediate in the synthesis of ent-Emtricitabine (E525005).

Upstream product

• 111878-21-8 2-trimethylsilyloxy-4-trimethylsilylamino-5-fluoropyrimidine 
• 288325-76-8 5S-chloro-[1,3]oxathiolane-2R-carboxilic acid 2-(1'R,2'S,5'R)-isopropyl-5-methyl-cyclohexyl ester 
• 147126-62-3 (2R,5R)-5-hydroxy-1,3-oxathiolane-2-carboxylic acid (1R,2S,5R)-5-methyl-2-isopropylcyclohexyl ester 
• 1144099-18-2 (1'R,2'S,5'R)-menthyl-5(R,S)-acetoxy-[1,3]-oxathiolane-2R-carboxylate 
• 1321928-75-9 5-(4-acetylamino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-[1,3]oxathiolane-2-carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester 
• 1321928-66-8 5-(pyridin-2-yloxy)-[1,3]oxathiolane-2-carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester 
• 1309459-32-2 5-hydroxy-[1,3]oxathiolane-2-carboxylic acid 2-isopropyl-5-methylcyclohexyl ester 
• 2022-85-7 Flucytosine 
• 147027-09-6 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (2R,5R)-5-(methylcarbonyloxy)-1,3-oxathiolane-2-carboxylate 
• 111969-64-3 L-menthyl glyoxylate monohydrate 
• 200396-19-6 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 5-hydroxy-1,3-oxathiolane-2-carboxylate 
• 2216-51-5 (-)-menthol 
• 21758-30-5 (1R,2S,5R)-(-)-menthyl dichloroacetate 
• 26315-61-7 L-menthyl glyoxylate 

Relevant academic research and scientific papers

Synthesis of (±)-Emtricitabine and (±)-Lamivudine by Chlorotrimethylsilane-Sodium Iodide-Promoted Vorbrüggen Glycosylation

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)

Emtricitabine synthesis method

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.

Preparation process of emtricitabine intermediate

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.

Preparation method of emtriva

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.

Preparation method for emtricitabine hydrohalide

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.

PROCESS FOR PRODUCING LAMIVUDINE AND EMTRICITABINE

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.

Preparation method for nucleoside analogue

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.

Highly stereoselective synthesis of lamivudine (3TC) and emtricitabine (FTC) by a novel N -glycosidation procedure

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.

A STEREOSELECTIVE PROCESS FOR PREPARATION OF 1,3-OXATHIOLANE NUCLEOSIDES

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.

IMPROVED PROCESS FOR NUCLEOSIDES

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.