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Synthesis of N-acyl-5'-desoxy-5-flucytogly derivative

A technology of flucytidine and its derivatives, which is applied in the field of synthesizing N4-acyl-5'-deoxy-5-fluorocytidine derivatives, which can solve the problems of complex separation and purification operations, consumption of acylating agents, and increased costs. To achieve the effect of abundant sources, short operation time and high selectivity

Inactive Publication Date: 2007-01-17
SHANGHAI AURISCO INT TRADING
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the cycle of this method is long, and with the side reaction, the acyl group on the amino group is removed, thus requiring complicated separation and purification operations
[0007] Chinese patent CN1053194C describes a method in which the protective group introduced by the hydroxyl group of the 5'-deoxy-5-fluorocytidine sugar part and the acyl group to be introduced in the amino group adopt the same group. Although the process is simplified, it consumes a lot of Expensive acylating agents, which increase the cost

Method used

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  • Synthesis of N-acyl-5'-desoxy-5-flucytogly derivative
  • Synthesis of N-acyl-5'-desoxy-5-flucytogly derivative
  • Synthesis of N-acyl-5'-desoxy-5-flucytogly derivative

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example 1

[0049] The preparation of example 1 compound III

[0050] Dissolve 57.3g of compound II (0.233mol) in 400ml of anhydrous dichloromethane, add 76.0ml of pyridine (0.932mol), add 100ml of a dichloromethane solution of 75.3g of triphosgene (0.256mol) dropwise at room temperature, and drop The mixture was raised to 40°C and stirred for 2 hours. After TLC (EtOAc / petroleum ether=1:7) confirmed that the reaction of the raw materials was complete, the reaction solution was poured into 1000 ml of water, separated, the organic layer was washed with saturated sodium bicarbonate solution, and the aqueous phase was extracted twice with 500 ml of dichloromethane. Combined organic layers, anhydrous Na 2 SO 4 After drying, suction filtration and rotary evaporation, 56.2 g of Compound III was obtained as a light yellow oil, with a yield of 89.0%.

example 2

[0051] The preparation of example 2 compound III

[0052]Dissolve 61.3g of compound II (0.25mol) in 400ml of anhydrous dichloromethane, add 122g of N,N-dimethylaminopyridine (1mol), and add 75.3g of triphosgene (0.256mol) of dichloromethane dropwise at room temperature 100ml of methane solution, the mixture was raised to 30°C and stirred for 2 hours after dropping. After TLC (EtOAc / petroleum ether=1:7) confirmed that the reaction of the raw materials was complete, the reaction solution was poured into 1000 ml of water, separated, the organic layer was washed with saturated sodium bicarbonate solution, and the aqueous phase was extracted twice with 500 ml of dichloromethane. Combined organic layers, anhydrous Na 2 SO 4 After drying, suction filtration and rotary evaporation, 63.7 g of Compound III was obtained as a light yellow oil, with a yield of 94.0%.

example 3

[0053] The preparation of example 3 compound IV

[0054] Dissolve 56.2g of compound III (0.207mol) in 1000ml of anhydrous dichloromethane, add 27.7ml of pyridine (0.340mol), cool to 0°C, and add 93.2g of chloroacetoxy-n-pentane (0.621 mol), the mixture was raised to room temperature and stirred for 2 hours. After TLC (EtOAc / petroleum ether=1:7) confirmed that the reaction of the starting material was complete, the solvent was evaporated under reduced pressure. The residue was poured into 2000 ml ether and saturated aqueous sodium bicarbonate (1 / 1). The organic layer was washed with saturated brine and water, and washed with anhydrous Na 2 SO 4 Dry and rotary evaporate. 59.3 g of compound IV was obtained as a white solid, with a yield of 74.4%.

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Abstract

Synthesis of N4-acyl-5,-deoxidation-5-fluorine cytidine is carried out by inducing dual-carbonic ether as sugar-structured hydroxyl into protective intra-annular ester acidating agent, taking 5,-deoxidation-5-fluorine cytidine(compound II) as initial raw material, and reacting intermediate compound(III) and with compound(IV) by three-step method to obtain final product. It is simple, has more yield and short reactive time. It can be used for industrial production.

Description

Technical field: [0001] The invention belongs to the technical field of medicinal chemistry. Specifically related to a synthetic N 4 - A method of acyl-5'-deoxy-5-fluorocytidine derivatives. Background technique: [0002] N represented by structural formula (I) 4 -Acyl-5'-deoxy-5-fluorocytidine derivative (compound (I)), which has antitumor activity [Japanese Journal of Cancer Research, Vol.81, pp.188-195(1990)]: [0003] [0004] In the formula (I), R is an alkyl group, a cycloalkyl group, an alkenyl group, an aralkyl group or an aryl group. [0005] When R is n-pentyl, compound (I) is called capecitabine (Capecitabine), and its antitumor activity has been extensively studied, as reported in WO2005049031 and US2005119337. [0006] Compound (I) can be prepared starting from 5'-deoxy-5-fluorocytidine. As described in European Patent EP0316704A and Chinese Patent CN1035675C. This method is quite time-consuming and difficult to operate on an industrial scale, and inclu...

Claims

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Application Information

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IPC IPC(8): C07H19/06
CPCC07H19/067
Inventor 俞迪虎
Owner SHANGHAI AURISCO INT TRADING
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