Preparation method of decitabine

A technology of decitabine and citabine, applied in the field of drug preparation, can solve the problems of high cost, long reaction cycle, and low total yield

Active Publication Date: 2011-11-02
SHANGHAI QINGSONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] (2) In the process from formula V to formula I, decitabine (formula I) is obtained by column chromatography purification, which is not easy for industrialization
[0016] The problem that this preparation method exists is: (1) the reaction time of formula VII to formula V is 4 days, and the reaction period is long; (2) the reaction of formula VII to formula V adopts column chromatography to purify for many times, is difficult for industrialization; (3) In the process from formula V to formula I, the reaction time is 5 days, and the reaction cycle is long; (4) the process from formula V to formula I adopts column chromatography purification, which is not easy for industrialization; (5) the total yield is very low, less than 5%, ( 6) The cost is too high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 11-methyl--2-deoxy-D-ribose (formula II)

[0031] 2-Deoxy-D-ribose (136 g, 1 mol) was added to methanol (500 ml), concentrated sulfuric acid (2 ml) was added dropwise, and stirred at room temperature for 2 hours. Sodium carbonate (4 g) was then added to neutralize. After suction filtration, the filtrate was evaporated to dryness under reduced pressure to obtain the compound of formula II, which was directly used in the next reaction.

Embodiment 2

[0032] Example 21-methyl-3,5-diacetoxy-2-deoxy-D-ribose (formula III)

[0033] Formula II was dissolved in pyridine (500ml, 6mol), cooled to 0°C, slowly added dropwise with acetic anhydride (210ml, 3mol), reacted at room temperature for 12h, added dropwise with water (350ml), dichloromethane (1000ml), and stirred for 2h. Separation, the organic phase was successively washed with water (350ml), 2N HCl (350ml), saturated sodium bicarbonate (350ml), dried over anhydrous sodium sulfate, filtered and evaporated to dryness to obtain oily formula III (231.2g), yield 90% ( Calculated as 2-deoxy-D-ribose).

[0034] 1 H-NMR (CDCl 3 )6.0(t, 1H), 5.2(s, 1H), 5.1(t, 1H), 5.07(d, 1H), 5.0(t, 1H), 4.3-4.1(m, 6H), 3.4(s, 1H ), 3.3(s, 1H), 2.3(m, 2H), 2.1(m, 2H)

[0035] Gas Chromatography Conditions

[0036]

Embodiment 3

[0037] Example 3 3',5'-diacetoxy-5-aza-2'-deoxycytidine (Formula V)

[0038] Add 5-azacytosine (50.7g, 452.1mmol), hexamethyldisilazane (500ml, 2.4mol), ammonium sulfate (2g) in the 1000ml three-necked flask, heat and reflux under nitrogen until clarification, evaporate under reduced pressure The solvent was removed to obtain 2,4-bis-(trimethylsilyl)-5-azacytosine (Formula IV). Formula IV was dissolved in 1,2-dichloroethane (250ml).

[0039] Formula III (100g, 430.6mmol) was dissolved in 1,2-dichloroethane (500ml), then dropped into the above-mentioned 1,2-dichloroethane solution of formula IV, and anhydrous tetrachloride was added dropwise at 5°C Tin (52.5ml, 452.1mmol), stirred overnight at room temperature. Add saturated sodium bicarbonate solution dropwise and wash until neutral, suction filter, the filtrate is washed with saturated sodium bicarbonate solution (500ml), separate liquids, the organic phase is dried with anhydrous sodium sulfate, filter and evaporate to dryn...

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Abstract

The invention discloses a preparation method of 2'-deoxycytidine analogue decitabine (formula I) capable of effectively inhibiting growth of tumour cells. The method comprises the steps of using 1-methyl-2-deoxy-D-ribose (formula II) as initial raw material, subjecting the initial raw material and acetic anhydride to a reaction to obtain 1-methyl-3,5-diacetoxyl-2-deoxy-D-ribose (formula III); subjecting the compound of formula III and 2,4-bi-(trimethyl silicon)-5-azacytosine (formula IV) to a reaction to obtain 3',5'-diacetoxylgroup-5-aza-2'-deoxycytidine (formula V); hydrolysing the compoundof formula V under the action of D315 macro-porous weakly basic anion exchange resin to obtain the decitabine (formula I). The raw materials of the invention are easily obtained, the reaction conditions are moderate and the operation is simple and convenient. The preparation method is suitable for commercial production.

Description

technical field [0001] The present invention relates to the preparation method of medicine. Specifically relates to a preparation method of decitabine, an anti-tumor cell growth drug. Background technique [0002] Decitabine is a 2′-deoxycytidine analogue that can effectively inhibit the growth of tumor cells. Its chemical name is: 5-aza-2′-deoxycytidine, and its structural formula is as follows: Formula I: [0003] [0004] Formula I [0005] Decitabine was approved by the European EMEA and the US FDA in April and May 2006, respectively. It is a drug for the treatment of primary and secondary myelodysplastic syndromes (MDS). It is converted into 5-monophosphate deoxycytidine analogue in vivo, incorporated into DNA under the action of DNA polymerase, inhibits DNA synthesis, inhibits DNA methylation, thereby inhibiting the growth of tumor cells, and has anti-tumor effect. Research on this drug is currently receiving a great deal of attention. [0006] The literature (C...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/12C07H1/00
Inventor 张磊张健谭宙宏杨琍苹
Owner SHANGHAI QINGSONG PHARMA
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