Decitabine synthesis and industrial production method
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A technology of decitabine and ribose, which is applied in the field of compound preparation, can solve the problems of excessive heavy metals, low yield, excessive burning residues, etc., and achieve the effect of avoiding excessive heavy metals
Active Publication Date: 2012-12-19
JIANGSU HANSOH PHARMA CO LTD
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[0019] The route deprotection reagents are weakly basic organic bases triethylamine and pyridine, the product is not easy to ring-open, the reaction yield is high, and the operation is simple, the experimental conditions are mild (reaction at normal temperature), which is beneficial to industrial production, but the condensation reaction uses SnCl 4 , resulting in excessive heavy metals and burning residues in the product, and the yield is low
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Embodiment 1
[0042] Step 1 (cycling)
[0043] In a 10L reaction flask, add methanol solution (7.6L) containing 0.1% (w / v) hydrogen chloride, then add 2-deoxy-D-ribose (0.380kg, 2.83mol), stir vigorously at room temperature for 30min, and detect by TLC Control the completion of the reaction, add anhydrous pyridine, and control the pH value to 7.5-8.0. Concentrate under reduced pressure below 70°C to obtain yellow viscous intermediate 2, which is directly used in the next reaction.
[0044] Step 2 (Protection)
[0045] Put intermediate 2 (obtained in the previous step) and pyridine (6.0L) into a 10L reaction flask, stir until dissolved, cool to 0°C, carefully add fluorenylmethoxycarbonyl chloride (1.520kg, 5.87mol), and the addition is complete. Stop cooling, naturally warm up to room temperature, keep the room temperature and continue to react for about 3 hours, TLC detects that the reaction is complete, extract with diethyl ether (5L) and water (5L), separate the organic phase, and extra...
Embodiment 2～12
[0058] Preparation of 2-deoxy-1-α,β-(4-amino-1,3,5-triazin-2-1(H)-on-1-yl)-3,4-di-(O-Fmoc) -D-ribose (intermediate 5)
[0059] Operation is the same as in Example 1, and the results are shown in Table 1, Table 2 and Table 3.
[0060] The impact of table 1 intermediate 4' and intermediate 4 molar ratio on yield and isomer ratio
[0061]
[0062] The impact of table two TMSOTf and intermediate 4 molar ratio on yield and isomer ratio
[0063]
[0064]
[0065] The impact of table three reaction time on yield and isomer ratio
[0066]
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Abstract
The invention relates to a decitabine synthesis and industrial production method, which comprises the following steps of: using 2-Deoxy-D-ribose as a raw material, performing a reaction between the raw material and methanol to obtain glucoside, protecting 3,5-dihydroxy by the use of 9-fluorenylmethyloxycarbonyl, reacting with hydrogen chloride to obtain 1-chlorflurecol sugar, performing a reaction between 1-chlorflurecol sugar and silanized 5-azacytosine, carrying out deprotection, and refining to obtain decitabine. The invention is characterized in that stannic chloride is not required during the condensation reaction between 1-chlorflurecol sugar and silanized 5-azacytosine so as to avoid the problem of excessive contents of heavy metals in pharmaceutical materials; and simultaneously the amount of trimethylsilyl trifluoromethanesulfonate and reaction conditions are controlled so as to increase the body burden of beta in the product.
Description
technical field [0001] The invention relates to a preparation method of a compound for treating myelodysplastic syndrome, in particular to a synthesis and industrial production method of decitabine. Background technique [0002] Decitabine is a natural nucleoside-2-deoxycytidine analog synthesized in 1964. In patients with myelodysplastic syndrome, it can induce DNA methylation, thereby controlling cell differentiation and proliferation, and realizing its drug Therapeutic significance. [0003] 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 phosphate. High concentration of decitabine binding can inhibit DNA synthesis, thereby inducing cell death and exerting its cytotoxic effect; low concentration of decitabine binding can replace cyto...
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