Uracil nucleoside derivative and method for preparing doxifluridine medicine by using uracil nucleoside derivative

A technology of uridine derivatives and derivatives is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., and can solve the problems of many by-products, incompatible functional groups in reaction conditions, and long conversion routes of functional groups, etc. To achieve the effect of efficient reaction and mild reaction system

Active Publication Date: 2020-04-28
KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the conversion route of the functional group is relatively long, usually the obtained by-products are more, and the reaction conditions are not compatible with many functional groups

Method used

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  • Uracil nucleoside derivative and method for preparing doxifluridine medicine by using uracil nucleoside derivative
  • Uracil nucleoside derivative and method for preparing doxifluridine medicine by using uracil nucleoside derivative
  • Uracil nucleoside derivative and method for preparing doxifluridine medicine by using uracil nucleoside derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Preparation of 1-[2-(1-styryl)benzoate]-2,3-di-O-benzoyl-5-deoxy-D-ribofuranose

[0060]

[0061] Under the protection of argon, 2,3-di-0-benzoyl-5-deoxy-D-ribofuranoside (274mg, 0.77mmol), p-cresol (124mg, 1.0mmol) were dissolved in 6mL In dry dichloromethane, boron trifluoride diethyl ether (0.618 mL, 5 mmol) was then slowly added dropwise at 0°C. The reaction solution was naturally raised to room temperature and reacted for 3 hours, and the reaction was complete as monitored by thin-layer chromatography. Add triethylamine to quench the reaction, add saturated sodium bicarbonate solution, extract three times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and the filtrate is concentrated with a rotary evaporator, silica gel column chromatography (ethyl acetate / petroleum ether=1 / 7) to obtain 296 mg of light yellow liquid, yield 86%. The light yellow liquid obtained above was dissolved in a mixed solution of 13ml of acet...

Embodiment 2

[0064] Preparation of 2',3'-di-O-benzoyl-5'-deoxy-5-fluoro-uridine

[0065]

[0066] 5-Fluorouracil (23 mg, 0.179 mmol) was suspended in 1.8 mL of anhydrous acetonitrile under the protection of argon, N, O-bis(trimethylsilyl) trifluoroacetamide (96 μl, 0.364 mmol) was added, and then The reaction solution was reacted at 50° C. for 30 minutes. Take another reaction bottle and add 1-[2-(1-styryl)benzoate]-2,3-di-O-benzoyl-5-deoxy-D-furan under the protection of argon Ribose (49mg, 0.089mmol), 360mg of 3A molecular sieves and 1.8mL of anhydrous acetonitrile, the reaction solution was stirred at room temperature for 30 minutes, then the freshly prepared uracil solution was added, and after stirring at room temperature for 15 minutes, N- Iodosuccinimide (30 mg, 0.134 mmol) and trimethylsilyl trifluoromethanesulfonate (8.0 μl, 0.045 mmol). The reaction solution was naturally raised to room temperature and continued to react for 2 hours, and the reaction was complete as monitore...

Embodiment 3

[0069] Preparation of 5'-deoxy-5-fluoro-uridine (doxifluridine)

[0070]

[0071] Under the protection of argon, 2',3'-di-O-benzoyl-5'-deoxy-5-fluoro-uridine (37 mg, 0.081 mmol) was dissolved in 0.8 mL of dry methanol, Then, sodium methoxide (4.5mg, 0.081mmol) was added at room temperature, and the reaction solution was maintained at this temperature for 1 hour, and the reaction was complete as monitored by TLC. 3N hydrochloric acid was added to adjust the pH to 5-6, and concentrated under reduced pressure to obtain the crude product, which was subjected to silica gel column chromatography (dichloromethane / methanol=10 / 1) to obtain 19 mg of white solid doxifluridine, with a yield of 95%.

[0072] [α] D 25 =4.59(c0.14,CH 3 OH); 1 H NMR (400MHz, Methanol-d 4 )δ7.73(d, J=6.5Hz, 1H), 5.76(dd, J=4.0, 1.5Hz, 1H), 4.16(dd, J=5.6, 4.1Hz, 1H), 4.00(p, J=6.3 Hz, 1H), 3.79(t, J=5.8Hz, 1H), 1.39(d, J=6.4Hz, 3H); 13 C NMR (101MHz, Methanol-d 4 )δ158.14, 157.88, 149.49, 141.65, 13...

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Abstract

The invention discloses a 5-deoxy-D-ribofuranose 1-[2-(1-styryl) benzoate] derivative as shown in a general formula (I) and a preparation method of the derivative, wherein the structure of the generalformula (I) is as follows, and the invention discloses a method for preparing a uracil nucleoside derivative and an antitumor drug doxifluridine by taking the derivative as shown in the general formula (I) as a raw material. The 5-deoxy-D-ribofuranose 1-[2-(1-styryl) benzoate] derivative used as a reaction raw material can be activated as a glycosyl donor under the condition of a catalytic amountof lewis acid trimethylsilyl trifluoromethanesulfonate and N-iodosuccinimide. The method avoids traditional use of equivalent or excessive lewis acid, has a mild reaction system, has no other side reaction, has efficient reaction, and has a yield up to 98%.

Description

technical field [0001] The present invention relates to the technical field of medicinal chemistry, and more specifically relates to a method for preparing doxifluridine by using 5-deoxy-D-ribofuranose 1-[2-(1-styryl)benzoate] derivatives Drugs and methods of synthesis of the derivatives. Background technique [0002] 5-deoxy-D-ribofuranose 1-[2-(1-styryl)benzoate] derivatives are important raw materials for the synthesis of ribose drugs, and can be directly glycosylated with pyrimidine or purine compounds. Generate nucleoside molecules with important physiological activities. [0003] Doxifluridine is a prodrug of 5-Fluorouracil (5-FU). In the tumor tissue, it is converted into fluorouracil by thymidine phosphorylase, thereby inhibiting the biosynthesis of DNA and RNA in tumor cells and exerting its anti-tumor effect. Therefore, it has strong anti-tumor specificity and low toxicity, and is often used clinically for gastric cancer, colorectal cancer, and breast cancer. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/18C07H1/00C07H19/06
CPCC07H15/18C07H1/00C07H19/06Y02P20/55
Inventor 肖国志何海清李朋华陈子汐
Owner KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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