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Method for preparing decitabine

A technology of decitabine and citabine, which is applied in the field of compound preparation, can solve the problems of low preparation process yield, high production cost, unsuitability for large-scale industrial production, etc., and achieve easy availability of raw materials and high total yield Effect

Inactive Publication Date: 2010-05-26
SHANGHAI CHENPON PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to provide a kind of new preparation method of decitabine, solve the problems such as low preparation process yield, high production cost, and not being suitable for large-scale industrialized production in existing decitabine production technology

Method used

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  • Method for preparing decitabine

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Example 1 Preparation of 1,3,5-tri-O-pivaloyl-2-deoxy-D-ribose (formula ii)

[0028] Add 20 g (149.11 mmol) of 2-deoxy-D-ribose in 100 mL of anhydrous pyridine to a 250 mL three-neck flask, slowly add 104.97 mL (517.41 mmol) of pivalic anhydride under nitrogen protection at 0-5°C, and rise to React at room temperature for 2 to 3 hours. The reaction of the raw material 2-deoxy-D-ribose was detected by TLC (dichloromethane:methanol=8:1 V / V). The solvent was evaporated under reduced pressure, the residue was dissolved in 400mL of dichloromethane, washed twice with saturated sodium bicarbonate solution (200mL×2), washed twice with saturated brine (200mL×2), dried over anhydrous sodium sulfate, filtered, evaporated After drying, 57.06 g (yield: 99.01%) of 1,3,5-tri-O-pivaloyl-2-deoxy-D-ribose (formula ii) was obtained, which was directly used in the next reaction.

Embodiment 2

[0029] Example 2 Preparation of 2-trimethylsilylamino-4-trimethylsilyloxy-1,3,5-triazine (formula iv)

[0030] Add 19.94g (177.89mmol) of 5-azacytosine, 90.14mL (427.27mmol) of freshly distilled hexamethyldisilazane and 99.70mL of anhydrous pyridine into a 500mL three-necked flask, and stir at room temperature for 10-15min. Add a catalytic amount of trimethylchlorosilane 1.12mL (8.89mmol) at room temperature, gradually raise the temperature to reflux at 110-120°C, keep the reaction for 3-4 hours, then cool down to room temperature naturally, evaporate the solvent under reduced pressure, add anhydrous Chloromethane 200mL, atmospheric distillation to take away the residual solvent. 44.71 g (yield: 98.01%) of 2-trimethylsilylamino-4-trimethylsilyloxy-1,3,5-triazine was obtained, which was directly used in the next reaction.

Embodiment 3

[0031] Example 3 Preparation of 1-(3,5-di-O-pivaloyl-2-deoxy-D-ribose)-5-azacytosine (formula v)

[0032] 57.06 g (147.64 mmol) of 1,3,5-tri-O-pivaloyl-2-deoxy-D-ribose (formula ii) as obtained in Example 1 and 2-trimethylsilyl as obtained in Example 3 Amino-4-trimethylsilyloxy-1,3,5-triazine (Formula iv) 40.51g (157.98mmol) was dissolved in 360mL of dichloromethane, stirred at room temperature for 10-15min, then cooled to 0-5°C , add TMSOTf5.34mL (29.53mmol) dropwise within 5~10min, while controlling the reaction temperature at 15~20°C. The reaction of tri-O-pivaloyl-2-deoxy-D-ribose was complete (petroleum ether: ethyl acetate=3:1 v / v). The reaction solution was washed twice with saturated sodium bicarbonate solution (200mL×2), the resulting aqueous phase was extracted three times with dichloromethane (100mL×3), the combined extracts were washed twice with saturated brine (200mL×2), and depressurized Evaporated to dryness, obtained 1-(3,5-di-O-pivaloyl-2-deoxy-D-ribose)-5-...

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Abstract

The invention discloses a method for preparing decitabine. The method comprises the following steps of: using 2-deoxy-D-ribose as a raw material; protecting the raw material by a pivaloyl group, and then reacting the raw material with alkylated 5-azacytosine under the action of a proper amount of a catalyst namely trimethylsilyl trifluoromethanesulfonate; performing hydrolysis to prepare a crude product of the decitabine without purification by a chromatography column; and performing recrystallization to prepare pure decitabine under the condition of a proper solvent. The method for preparing the decitabine greatly improves the total yield, greatly reduces the product cost, and is more suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of a compound that can be used for treating myelodysplastic syndrome (MDS), and mainly relates to a preparation method of decitabine. Background technique [0002] The decitabine (decitabine) compound involved in the present invention is a kind of riboadenosine derivative, which reduces the methylation of DNA by inhibiting DNA methyltransferase, thereby inhibiting the proliferation of tumor cells and preventing the occurrence of drug resistance. It is mainly used for the treatment of myelodysplastic syndrome (MDS) and acute leukemia. [0003] One of the existing preparation techniques for decitabine is to use 2-halo-3-hydroxyl-4 hydroxymethylfuran as the starting material, react with alkylated 5-azacytosine, undergo hydrolysis and chromatography Prepared by column purification, see "A. Piskala, F. Sorm, Nucl. Acid Chem., 1978, 1, 435" and "M.W. Winkley, R.K. Robins, J. Org. Chem., 1970, 35, 491". The star...

Claims

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Application Information

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IPC IPC(8): C07H19/12A61P35/00
Inventor 杜狄峥吴晓毅方项吴波峰
Owner SHANGHAI CHENPON PHARM TECH CO LTD
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