Doxifluridine derivative and preparation method and pharmaceutical application thereof

A technology of medicinal salt and cytidine, which is applied in the field of doxifluridine derivatives and can solve problems such as limited application prospects

Inactive Publication Date: 2012-07-11
SHANGHAI RUIGUANG BIOCHEM TECH DEV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, oral administration of 5'-deoxy-5-fluorouridine has cer

Method used

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  • Doxifluridine derivative and preparation method and pharmaceutical application thereof
  • Doxifluridine derivative and preparation method and pharmaceutical application thereof
  • Doxifluridine derivative and preparation method and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Preparation of 5'-deoxy-5-fluoro-thiouridine (compound 1)

[0065] A, 2', 3'-di-O-acetyl-5'-deoxy-5-fluorouridine (compound of general formula B, wherein R 9 for acetyl)

[0066] With reference to the literature method (Dong Hui et al. Chinese Journal of Pharmaceutical Industry, 33:108 (2002) to obtain the starting material 5'-deoxy-5-fluorouridine (compound A). Get 2g (8.1 mmol) of compound A and dissolve it in 40ml without In water pyridine, add dropwise 1.8ml (18 mmol) acetic anhydride, and stir overnight at room temperature. Then add 5ml methyl alcohol and continue to stir for 15 minutes, and the solution is evaporated to dryness. The solid is dissolved in 40ml dichloromethane, and is dissolved in 40ml of 10% sodium bicarbonate aqueous solution Wash, and then extract the aqueous phase with 10ml of dichloromethane × 2. Combine the dichloromethane liquids, dry over anhydrous sodium sulfate, filter, and evaporate to dryness. The residue is recrystallized with 10ml of ...

Embodiment 2

[0072] Preparation of 5'-deoxy-5-fluoro-N 4 -Oximocytidine (compound 2)

[0073] A, 2', 3'-di-O-acetyl-5'-deoxy-5-fluoro-N 4 -Hydroxycytidine (compound of general formula D)

[0074] Get 2g (5.8 mmol) 2', 3'-di-O-acetyl-5'-deoxy-5-fluoro-thiouridine and join in 30ml ethanol, then add 0.48g (7 mmol) hydroxylamine hydrochloride and 0.55g (8 mmol) of potassium carbonate, stirred at 60°C for 10h, and evaporated to dryness. The residue was dissolved in 100ml ethyl acetate, washed with 50ml x 2 10% HCl aqueous solution, and the aqueous phase was extracted with 50ml ethyl acetate. The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue can be directly used in the next reaction without purification.

[0075] B. 5'-deoxy-5-fluoro-N 4 -Oximocytidine (compound 2)

[0076] Take 2g (5.8 mmol) of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N 4 -Oxime cytidine was dissolved in 30 ml tetrahydrofuran and then 10 ml methanol a...

Embodiment 3

[0078] Preparation of 5'-deoxy-5-fluoro-N 4 -aminocytidine (compound 3)

[0079] Take 2g (7.7 mmol) of 5'-deoxy-5-fluoro-thiocytidine, dissolve it in 50ml of methanol, cool to 0°C, slowly drop into 3ml of 50% hydrazine hydrate solution, stir for half an hour and use The 732 type cation exchange resin is neutralized to about pH=7. The resin was filtered off, the solution was evaporated to dryness, and the residue was purified by a silica gel column to obtain 1.4 g of a solid with a yield of 69.6%. 1 H-NMR (DMSO-d 6 )δ (ppm): 1.21 to 1.22 (3H, d, 4'-CH 3 ), 3.60 to 3.63 (1H, d, 3'-H), 3.73 to 3.77 (1H, d, 4'-H), 3.98 to 4.01 (1H, d, 2'-H), 5.00 (1H, s, OH), 5.22 (1H, s, OH), 5.61 to 5.64 (1H, d, 1'-H), 7.16 (1H, d, CHCF), 10.12 (1H, s, NH)

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Abstract

The invention relates to a doxifluridine derivative and preparation method and pharmaceutical application thereof, particularly to a compound shown in a formula (I), and a crystal or pharmaceutical salts of the compound, wherein R1 can be =N-OR4 and the like; R2 can be hydrogen, hydroxyl and X; R3 is can be hydrogen, C2-C6 acyl group and the like; R4 can be hydrogen and the like; and X is F, Cl, Br, I and the like. The invention also relates to a preparation method of the compound. The invention further provides an anti-tumour medicine composition containing the compound, and the application of the compound in preparation of an anti-tumour medicine.

Description

technical field [0001] The present invention relates to doxifluridine derivatives with anti-tumor activity, and also relates to the preparation method of the compounds and the application of the compounds in pharmacy. Background technique [0002] For decades, nucleoside drugs have been widely used in clinical anti-tumor, and fluorinated pyrimidine drugs have played an important role in anti-tumor and other aspects. Since 5-fluorouracil was synthesized in 1957, it has been widely used in the treatment of various tumors because of its good selectivity and low adverse reactions. However, most of 5-fluorouracil is intravenous injection, which is inconvenient to administer. For the convenience of patients, a prodrug-5'-deoxy-5-fluorouridine suitable for oral administration has been developed. However, oral administration of 5'-deoxy-5-fluorouridine has certain enterotoxicity, so the application prospect is not wide. [0003] The technical field requires the development of pro...

Claims

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Application Information

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IPC IPC(8): C07H19/06A61K31/7072A61K31/7068A61P35/00
Inventor 汪元璋张峥李启升张明刚耿冬平
Owner SHANGHAI RUIGUANG BIOCHEM TECH DEV
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