Fludarabine phosphate preparation method

A technology of fludarabine phosphate and triethyl phosphate, which is applied in the field of synthesis of antimetabolite and antitumor drugs, can solve the problems of low yield and the purity of the product cannot meet the pharmaceutical standards, and achieves high yield and easy separation. Purification and the effect of small residual organic solvent

Inactive Publication Date: 2016-08-17
HENAN NORMAL UNIV
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

The main raw materials for the synthesis of fludarabine phosphate are fludarabine, phosphorus oxychloride and triethyl phosphate (TEP). The synthetic method reported in the literature is prone to produce by-products in the preparation process, resulting in low yield and high product purity. less than pharmaceutical standard

Method used

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  • Fludarabine phosphate preparation method
  • Fludarabine phosphate preparation method
  • Fludarabine phosphate preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Add 20g of fludarabine to a 500mL flask, then add 200mL of triethyl phosphate, put the flask into a low-temperature reaction bath at -6°C, and slowly add 20mL of phosphorus oxychloride dropwise after 20 minutes (stir while adding) , reacted for 12 hours (TCL tracking). After the reaction meets the requirements, quickly add 80mL water and 200mL dichloroethane to the flask, let it stand for 30 minutes, extract the aqueous phase and the organic phase, and adjust the pH value of the aqueous phase to 2-3. Recrystallization appears white floc with a cloth Filtered through a funnel, vacuum dried and weighed to obtain 20.71g of white powder, yield 81.02%, HPLC mass fraction 99.95%, elemental analysis results are all mass fractions (C 33 h 30 N 4 o 2 ) Theoretical value (measured value): C 32.81 (32.89), H 3.65 (3.59), N 19.14 (19.17); ESI m / z (%, M-1): 364.2. 1 HNMR(DMSO-D6,400MHz)δ(ppm): 1 HNMR (DMSO-D6) δ3.94(2H, m), 4.09(2H, m), 4.152(1H, t, J=9.2Hz), 5.80(2H, d), 6.15(...

Embodiment 2

[0015] When synthesizing fludarabine phosphate, other conditions are fixed and only the reaction time is changed. This embodiment examines the influence of reaction time on the yield of fludarabine phosphate. figure 1 ,Depend on figure 1 It can be seen that when the reaction time is short, the yield is low; and when the reaction time is long, the yield does not increase much, the by-products increase, and the product mass fraction decreases (the HPLC mass fraction is only 96.1%). The optimal reaction time should be controlled within 12 hours, the reaction yield is high, the product mass fraction is high (the HPLC mass fraction of the refined product is 99.95%) and it is more economical.

Embodiment 3

[0017] When synthesizing fludarabine phosphate, fix other conditions unchanged, only change the amount of phosphorus oxychloride, the present embodiment has investigated the influence of the amount of phosphorus oxychloride on the yield of fludarabine phosphate see figure 2 ,Depend on figure 2 It can be seen that with the increase of the amount of phosphorus oxychloride, the yield gradually increases; and when the amount of phosphorus oxychloride is too much, the yield of fludarabine phosphate decreases, the by-products increase, and the product mass fraction decreases. The optimal dosage of phosphorus oxychloride is 20mL, and the dosage of fludarabine is 20g. At this time, the reaction yield is high, the product mass fraction is high and it is more economical.

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Abstract

The invention discloses a fludarabine phosphate preparation method. The method comprises the specific steps that fludarabine and triethyl phosphate are added into a reaction container, the reaction container is placed into a subzero 6 DEG C low-temperature reaction bath, phosphorus oxychloride is added on the stirring condition, water and dichloromethane are added into the reaction container after the reaction is performed for 12 h, standing is performed, then, extraction is performed to obtain a water phase and an organic phase, the pH value of the water phase is adjusted to 2-3, recrystallization is performed to obtain white focculus, and filtering and vacuum drying are performed to obtain a target product of fludarabine phosphate with the purity being 99.95%. The method has the advantages that reaction conditions are mild, operation is easy, the product is easy to separate and purify, the yield is high, the product is environmentally friendly, high in purity, small in organic solvent residual quantity and capable of meeting the medicinal standard, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of anti-metabolism and anti-tumor drugs, and in particular relates to a preparation method of fludarabine phosphate. Background technique [0002] Fludarabine Phosphate (Fludarabine Phosphate) chemical name: 9-β-D-arabinic acid-furanose-2-fluoroadenine-5-phosphate, trade name: Fudahua, fludarabine phosphate for clinical injection It is a white freeze-dried powder injection, which belongs to anti-metabolism and anti-tumor drugs. It can be metabolized into fludarabine triphosphate in the human body to inhibit the synthesis of DNA, thereby inhibiting the growth of tumor cells. Fludarabine phosphate has good clinical curative effect and good tolerance, and is currently the first-line anti-tumor drug for chemotherapy of chronic lymphocytic leukemia. The main raw materials for the synthesis of fludarabine phosphate are fludarabine, phosphorus oxychloride and triethyl phosphate (TEP). The synthetic me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/20C07H1/00C07H1/06
CPCC07H1/00C07H1/06C07H19/20
Inventor 郝二军付丹丹蒋小涵司幸伟张梦成郭利兵刘玉侠王东超郭海明李恭欣
Owner HENAN NORMAL UNIV
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