High optical purity nucleoside intermediates and preparation method thereof

Abstract

The invention relates to high optical purity nucleoside intermediates, namely compounds in a formula II, and a preparation method thereof. In the formula, R1 is alkyl acyl. The high performance liquid chromatography (HPLC) purity of the high optical purity nucleoside intermediates is more than or equal to 95 percent; and the chiral HPLC purity is more than or equal to 95 percent. By adopting the high optical purity nucleoside intermediates, high optical purity nucleoside medicines, namely compounds shown in a formula I are easier to prepare; and the method for preparing the high optical purity compounds shown as the formula II has the advantages that: raw materials are readily available, the method is easy and convenient to operate and the obtained product has high optical purity.

Description

technical field [0001] The present invention belongs to the field of chemistry or medicinal chemistry, and in particular relates to a high-optical-purity nucleoside drug intermediate formula II compound and a preparation method thereof, and the preparation of a high-optical-purity nucleoside drug formula I compound by using the high-optical-purity formula II compound method, where R 1 is alkanoyl, R 2 is H or F, when the R of the compound of formula I 2 Is H is lamivudine, when the R of formula I compound 2 is F for emtricitabine. [0002] Background technique [0003] Nucleoside drugs are an important class of antiviral drugs. Nucleoside drugs in the human body, after phosphorylation into nucleoside triphosphate drugs, have antiviral effects, can inhibit the activity of DNA polymerase and reverse transcriptase of viruses; and compete with nucleosides for incorporation into the DNA chain of viruses , Terminate the elongation and synthesis of the DNA chain, inhibit th...

AI Technical Summary

Problems solved by technology

The silylating agent trimethylsilyl trifluoromethanesulfonate used is a fuming liquid with a pungent odor and is a spontaneously flammable liquid that is extremely sensitive to air and expensive

Due to the low optical purity of the prepared compound of formula II, the optical purity of the finally obtained emtricitabine is not high, and multiple refinements are required to obtain a product that meets the pharmaceutical requirements

[0016] CN1563002 discloses a kind of preparation method suitable for industrialization of emtricitabine, uses methyl ether as solvent in the preparation of glyoxylic acid-(1'R, 2'S, 5'R)-menthyl ester, and the boiling point of methyl ether is -24.9°C, the flash point of methyl ether is -41.4°C, it is a colorless, tasteless, odorless gas at normal temperature and pressure, it is a liquid under pressure, it is unsafe to use, and cannot be operated industrially; trans-5-hydroxy -1,3-oxathiolane-2-carboxylic acid-[(1'R, 2'S, 5'R)-5'-methyl-2'-(1-methylethyl) ring Hexyl] ester in a suitable solvent, cooled to below 10°C with an ice-water bath, and undergo acylation reaction to obtain the intermediate product (5R)-acetoxy-1,3-oxathiolane-(2R)-carboxylic acid -[(1'R,2'S,5'R)-5'-methyl-2'-(1-methylethyl)cyclohexyl]ester, the yield is only 40%, and the optical purity of the product Low, less than 95% pure by HPLC, less than 90% pure by chiral HPLC; 5-fluorocytosine reacts with hexamethylaziasilane to form disilane-protected 5-fluorocytosine, disilane-protected 5-fluorocytosine Then with (5R)-acetoxy-1,3-oxathiolane-(2R)-carboxylic acid-[(1′R, 2′S, 5′R)-5′-methyl-2 The product 5S-(5'-fluorocytosinyl-1')-1,3-oxathiolane-2-carboxylic acid- (1'R, 2'S, 5'R)-menthyl ester has low optical purity and a large amount of hexamethylazuridine; 5S-(5'-fluorocytosine-1')-1,3-oxathia Emtricitabine obtained by reduction of cyclopentane-2-carboxylic acid-(1′R, 2′S, 5′R)-menthyl ester with red aluminum needs to be absorbed by silica gel in order to obtain a product with higher optical purity The method of recrystallization after separation by column chromatography is complicated and difficult to operate, and requires multiple refinements to meet the medicinal requirements

[0017] Generally speaking, in the method for preparing nucleoside drugs such as lamivudine and emtricitabine in the above-mentioned prior art, there are low optical purity of intermediates, resulting in the preparation of nucleosides such as lamivudine or emtricitabine The optical purity of similar drugs is low, and it needs to be refined many times to meet the medicinal requirements, which leads to the increase of product cost, and the industrial operation is complicated

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