Preparing method for cytarabine

A technology of cytarabine and arabinoside, which is applied in the field of preparation of nucleotide drug cytarabine, can solve the problems of high price, increased production cost, and high price of pyridine, and achieve low price, low quantity, and control The effect of high production cost and production yield

Active Publication Date: 2005-02-23
ZHEJIANG HISUN PHARMA CO LTD
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Problems solved by technology

[0022] ①. When preparing compound VII, this document reacts araburidine and acetic anhydride in pyridine, where the ratio of pyridine to arabouridine exceeds 1:10 (26.5g arabouridine requires 275 grams of pyridine), Because pyridine is expensive and difficult to recycle, using such a large amount of pyridine not only affects the environment, but also greatly increases the cost;
[0023] 2., when this document is preparing compound IX, after 1.2.4-triazole, phosphorus oxychloride and triethylamine are reacted in acetonitrile, react with compound VII again, the ratio of the method acetonitrile consumption and compound VII is 1: 22, acetonitrile is also an expensive solvent, which is difficult to recycle and apply mechanically in this step reaction, and the same reason as above will also increase the p

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  • Preparing method for cytarabine
  • Preparing method for cytarabine
  • Preparing method for cytarabine

Examples

Experimental program
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Example Embodiment

[0037] Example 1: Preparation of ethyl arabinouridine (compound VII):

[0038] Add 26.2 kg of pyridine to the reaction tank, stir, add 11.5 kg of arabinouridine and 18.6 kg of acetic anhydride in sequence, and stir for 3 hours at room temperature. After the reaction was completed, 11.5 liters of methanol was added, stirred for 0.5 hours, and concentrated under reduced pressure until the pyridine could not be evaporated. Add ethanol, stir and heat to dissolve. Cool to below 0°C overnight. After discharging, filtering with suction, and drying, 15.8 kg of compound VII was obtained with a yield of 91%.

Example Embodiment

[0039] Example 2: Preparation of Uridine Triazole (Compound IX):

[0040] Add 150L of chloroform into the reaction tank, stir, and add 15kg of triazole. Cool to below 5°C and add 9.225kg of phosphorus oxychloride. After adding phosphorus oxychloride, continue stirring to below 5°C, and add 33.75L of triethylamine dropwise. Control the dripping acceleration so that the maximum temperature rise does not exceed 8°C. Add 15 kg of ethyl arabinouridine (compound VII) into the above reaction tank. Stir at room temperature overnight. When the reaction is complete, add 150L of water and stir to release the chloroform layer. The aqueous phase was extracted twice with chloroform 60L×2, the organic phase was combined with the former chloroform layer, and dried with anhydrous magnesium sulfate. Suction and filter to remove magnesium sulfate, the filtrate is concentrated to dry chloroform and then added with absolute ethanol, stirred and refluxed for dissolution. Cool to below 0°C overnight. Af...

Example Embodiment

[0041] Example 3: Preparation of Cytarabine:

[0042] Add 68.5 kg of dioxane into the reaction tank, stir and cool to 15°C, and vent ammonia for 5-6 hours. Add 13.7 kg of uridine triazole (compound X) and 9.6 kg of ammonia, and stir overnight at room temperature. The dioxane was concentrated under reduced pressure until no more liquid distilled out. 54.8kg methanol ammonia was added and reacted overnight. After the reaction, it was concentrated to dryness under reduced pressure. Dissolve the residue in 60L of non-ionized water and load 001X4 ion exchange resin. First rinse with deionized water, then eluted with 5% diluted ammonia water, collect the product-containing eluate, and concentrate it under reduced pressure to dryness as a crude product. The crude product was dissolved in water and ethanol under reflux. Filter while it is hot, and the filtrate enters the fine drying package crystallization tank. Crystallize overnight. After suction filtration, the crystals are filtered ou...

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Abstract

Cytosine arabinoside is prepared by: reacting uridine arabinoside and ethyl anhydride or acetyl chloride or acetyl bromine together in pyridine to get uridine arabinoside ethylester, reacting uridine arabinoside ethylester and triazoazole compound in presence of trichlorooxyphosphorus and inertia organic solvent to obtain triazoazole uridine, finally, aminolyzing triazoazole uridine to get cytosine arabinoside. Its advantages includes, cheaper and less solvent used, high yields on large scale production, cost low, and selecting strong acid cation exchange resin to separate and purify crude cytosine arabinoside to meet the standard of Europe and American pharmacopoeia.

Description

field of invention [0001] The invention relates to the field of chemical pharmacy, in particular, the invention relates to a preparation method of nucleotide drug cytarabine. Background technique [0002] The chemical name of cytarabine is: 1-β-D-arabinosylcytosine, the English name is Cytarabine, referred to as Ara-C, and its chemical structure is as follows: [0003] Cytarabine [0004] Cytarabine is an antiviral drug that is also used against tumors, especially leukemia. The preparation method of cytarabine reported in literature has: [0005] 1. Total synthesis method using arabinose as raw material (DE2027305A and DE2601399A): [0006] [0007] The preparation step of this method propylonitrile is longer, and needs to use the propynamide that is prone to explosion, is difficult to adapt to suitability for suitability for industrialized production; [0008] 2. Use cytidine as raw material to synthesize cytarabine via cyclocytidine: [0009] [0010] There ar...

Claims

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Application Information

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IPC IPC(8): C07H19/06
Inventor 金春华吴忠伟贾国荣李红梅吴晓丽
Owner ZHEJIANG HISUN PHARMA CO LTD
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