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Preparation method for uracil fluoride nucleoside analogue

A technology for synthesizing uridine and analogs, which is applied in the field of preparing fluorinated uridine analogs, can solve the problems of low reaction yield, unsuitability for industrial production, and high requirements for corrosion resistance, and achieves high reaction yield , The effect of easy control of reaction conditions and low cost

Inactive Publication Date: 2015-12-16
SHANGHAI ACEBRIGHT PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the raw material cost that this method adopts is lower, this method also is to adopt glacial acetic acid to deprotect the group under reflux condition, the requirement to equipment corrosion resistance is higher, and reaction yield is lower (two-step total molar yield is only 24.6 %), more unsuitable for industrial production

Method used

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  • Preparation method for uracil fluoride nucleoside analogue
  • Preparation method for uracil fluoride nucleoside analogue
  • Preparation method for uracil fluoride nucleoside analogue

Examples

Experimental program
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Effect test

Embodiment 1

[0029]

[0030] Dissolve 30g of the compound shown in formula II-1 in 100mL of tetrahydrofuran, then lower the temperature to 0-10°C, add 20.4g of the compound shown in formula III-1 and 17.1g of titanium tetrachloride, raise the temperature to reflux, and keep the reflux to react to the formula The compound shown in III-1 reacted completely (about 5 to 20 hours); add saturated aqueous sodium bicarbonate solution to adjust the pH value of the reaction system to 8 to 9, carry out liquid separation, collect the organic phase, concentrate the organic phase under reduced pressure, and use methanol After purification and other post-treatments, 15.35 g of the compound represented by formula I-1 was obtained, with a molar yield of 61.5% and an HPLC purity of 99.1%.

Embodiment 2

[0032]

[0033] Dissolve 30g of the compound shown in formula II-2 in 100mL of toluene, then lower the temperature to 0-10°C, add 26.8g of the compound shown in formula III-2 and 19g of titanium tetrachloride, raise the temperature to reflux, and keep the reflux to react to formula III The compound shown in -2 reacts completely (about 5 to 20 hours); add saturated aqueous sodium bicarbonate solution to adjust the pH value of the reaction system to 8 to 9, carry out liquid separation, collect the organic phase, concentrate the organic phase under reduced pressure, and refine with methanol After post-processing, 16.9 g of the compound represented by formula I-2 was obtained, the molar yield was 59.6%, and the HPLC purity was 98.9%.

Embodiment 3

[0035]

[0036] Dissolve 30g of the compound shown in Formula II-3 in 100mL of dichloromethane, then cool down to 0-10°C, add 36.2g of the compound shown in Formula III-3 and 32.0g of trimethylsilyl trifluoromethanesulfonate, and heat up To reflux, keep the reflux reaction until the compound shown in formula III-3 reacts completely (about 5 to 20 hours); add saturated aqueous sodium bicarbonate solution to adjust the pH value in the reaction system to be 8 to 9, carry out liquid separation, collect the organic phase, After concentrating the organic phase under reduced pressure and refining with methanol, 21.8 g of the compound represented by formula I-3 was obtained, with a molar yield of 58.3% and an HPLC purity of 98.2%.

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Abstract

The invention discloses a preparation method for uracil fluoride nucleoside analogue comprising reaction b or reaction a to reaction b in the synthesis route shown in the description. R' and R'' are independently selected from trimethylsilyl group, tertbutyldiphenylsilyl group, TBS group or triethylsilyl group; R1 and R2 are independently selected from H, C1-C10 alkyl group, C1-C10 alkylsulfonyl group or aryl-substituted C1-C10 alkylsulfonyl group, wherein the aryl group is phenyl group, biphenylyl group or naphthyl group; A is selected from chlorine, bromine, iodine, hydroxyl group, OC(=O)R3, OS(=O)2OR3, wherein R3 is selected from C1-C5 alkyl group. The preparation method has short reaction route, simple operation, high reaction yield, low cost, is easy to control the reaction condition, has cheap and easily available used raw materials and reagents, has no special requirement for the device, and is suitable for large scale production.

Description

technical field [0001] The invention relates to a method for preparing fluorinated uridine nucleoside analogs, belonging to the technical field of medicinal chemistry. Background technique [0002] Fluorinated uridine nucleoside analogues are an important class of organic synthesis intermediates with the following general chemical structure: [0003] where: R 1 and R 2 independently selected from H 、 C 1 -C 10 Alkyl, C 1 -C 10 Alkylsulfonyl or C substituted by aryl 1 -C 10 Alkylsulfonyl, the aryl is selected from phenyl, biphenyl or naphthyl; base wherein is a pyrimidine base with the following structural formula: [0004] [0005] The above-mentioned fluorinated uridine nucleoside analogs are key intermediates for the preparation of the latest anti-hepatitis C new drug sofosbuvir. [0006] At present, there are mainly the following two methods for the preparation of fluorinated uridine nucleoside analogues: [0007] Method 1. The following route disclosed in...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H1/00
Inventor 李金亮赵楠邓宇
Owner SHANGHAI ACEBRIGHT PHARMA GRP
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