Method for preparing 5-aza-2'-deoxycytidine and its intermediates

A technology of deoxycytidine and azacytosine is applied in the field of preparing the new azacytosine deoxynucleoside and the intermediate field of preparing 5-aza-2'-deoxycytidine, and the process is simple and reproducible. Good performance and low content

Inactive Publication Date: 2012-01-11
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0019]Usually, laboratories also commonly use the method of preparing 2'-deoxynucleosides by removing the 2'-position oxygen atom on the existing nucleoside sugar ring. In theory, 5-aza-2'-deoxycytosine can also be synthesized by removing the 2'-oxygen atom on 5-azacytidine (European Journal of Medicinal Chemistry, 35(11), 1011-1019, 2000), However, the price of raw materials, protecting groups and catalysts used in this method is relatively expensive, and it is not suitable for industrial production and development.

Method used

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  • Method for preparing 5-aza-2'-deoxycytidine and its intermediates
  • Method for preparing 5-aza-2'-deoxycytidine and its intermediates
  • Method for preparing 5-aza-2'-deoxycytidine and its intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Preparation of 1-(2'-deoxy-3',5'-di-O-p-chlorobenzoyloxy-D-arabinofuranosyl)-5-azacytosine Weigh 5-azacytosine 313.6g, put in a reaction bottle, add 8L of hexamethyldisilazane, stir, add 200ml of trimethylchlorosilane, protect with nitrogen, heat to reflux, react for 24 hours, the raw materials are dissolved, the reaction is completed, heat and evaporate to dryness under reduced pressure Solvent, obtain the 5-azacytosine of silanization, do not need to deal with and carry out the following reaction continuously.

[0044] Add silanized 5-azacytosine to 16L of 1,2-dichloroethane, stir to dissolve, add 1-chloro-3,5-di-O-p-chlorobenzoyl-2-deoxy-D-ribose 395.6g (0.92mol), cooled to 5°C, temperature-controlled addition of a mixture of 333.6ml of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2L of acetonitrile, and reacted at room temperature for 3.5h.

[0045] Pour the reaction solution into 30L of cold water, extract twice with dichloromethane, 20L each time, combin...

Embodiment 2

[0051] Preparation of 5-aza-2'-deoxycytidine

[0052] Put 100L of methanol in a reaction flask, add 16 grams of sodium methoxide, stir, and add 1-(2'-deoxy-3',5'-di-O-p-chlorobenzoyloxy-D in Example 1 -Arabinofuranosyl)-5-azacytosine 510 grams, reacted at room temperature for 20 hours, concentrated to an appropriate volume, left to cool, filtered, washed with methanol, and dried in vacuo to obtain 150 grams of white crystal product, the related substances determined by HPLC were less than 1.5% .

[0053] Methanol was recrystallized again, as determined by HPLC, the related substance was 0.5%.

[0054] mp: 191.1-193.2;

[0055] [α] D 22 =+68.1° (30min), +57.8° (6hr) (c=0.5, H2O).

[0056] MS[M+H]+: 228.09;

[0057] Elemental analysis C8H12N4O4: theoretical C42.10, H5.30, N, 24.55, measured C42.02, H5.33, N, 24.35;

[0058] 1HNMR test (DMSO-d6) δ: 2.13~2.21(m, 2H), 3.54-3.61(m, 2H), 3.82(t, 1H),

[0059] 4.24 (m, 1H), 5.01 (m, 2H), 5.20 (d, 1H), 6.03 (t, 1H), 7.47 (s, 2H...

Embodiment 3

[0062] Preparation of α-isomer of 2'-deoxy-5-azacytosine nucleoside

[0063] The mother liquor of 5-aza-2'-deoxycytidine prepared by the method of Reference Example 2 was subjected to column chromatography (gradient elution of chloroform-methanol system), and the fraction containing α-isomers was collected and recrystallized from a mixed solvent of methanol / ether to obtain The alpha isomer of 5-aza-2'-deoxycytidine was used as white powder crystals.

[0064] 1HNMR (DMSO-d6): 8.26 (s, 1, H6), 7.4 (e, 2, NH2), 5.94 (d, 1, Hl'), 5.21 (d, 1, OH3'), 4.83 (t, 1 , OH5'), 4.25(m, 2, H3', 4'), 3.4(m, 2, H5'), 2.3(m, 2, H-2');

[0065] Mp: Decompose at 181-182°C.

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Abstract

The invention relates to methods for preparing 5-Aza-2'-deoxycytidine and an intermediate product thereof. The method for preparing the preparing 5-Aza-2'-deoxycytidine comprises the following steps: a compound (shown in formula 2) is hydrolyzed under alkaline matter to remove acyl-oxygen protecting group, a diastereomeric compound (shown in formula 3) is obtained, and then the diastereomeric compound is separated by a general separation technology to obtain an isomer. The invention also relates to a compound (shown in formula 2) used as the intermediate product and a preparation method thereof, wherein the preparation method comprises the following steps: 5-Aza cytimidine is activated by a silanization method, and then makes displacement reaction with a compound (shown in formula 4), andfurther removes the protecting group to obtain the compound (shown in formula 2). The preparation method has simpler process, good reproduction quality and little toxicity and is suitable to the industrialized production; and meanwhile, used raw materials and reagent are easy to obtain.

Description

technical field [0001] The present invention relates to a preparation method of 5-aza-2'-deoxycytidine, and relates to a new azacytidine deoxynucleoside, which is an intermediate for preparing 5-aza-2'-deoxycytidine , and also relates to a method for preparing the novel azacytosine deoxynucleoside. Background technique [0002] 5-Aza-2′-deoxycytidine, namely decitabine, chemical name: 4-amino-1-(2-deoxy-β-D-erythro-ribofuranose)-1, 3,5-Triazin-2(1H)-one is a drug developed by SuperGen Corporation of the United States for the treatment of myelodysplastic syndrome and the like. The molecular structural formula of 5-aza-2'-deoxycytidine is shown in Formula 1 below: [0003] [0004] As a specific DNA methyltransferase inhibitor, decitabine can reverse the methylation process of DNA, induce tumor cells to differentiate into normal cells or induce tumor cell apoptosis. In tumor cells, decitabine is phosphorylated by deoxycytidine kinase and binds to DNA in the form of phos...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/073A61P43/00
CPCY02P20/55
Inventor 姜力勋储刚王正泽黄海燕李纬
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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