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Floxuridine compound and preparation method and application thereof

A technology of floxuridines and compounds, which is applied in the field of medicine and can solve problems such as limited application prospects

Inactive Publication Date: 2012-09-26
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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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 certain intestinal toxicity, so the application prospect is not wide

Method used

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  • Floxuridine compound and preparation method and application thereof
  • Floxuridine compound and preparation method and application thereof
  • Floxuridine compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Preparation of 5'-deoxy-5-fluoro-thiouridine (compound 1)

[0047] A, 2', 3'-di-O-acetyl-5'-deoxy-5-fluorouridine (compound of general formula B, wherein R 9 for acetyl)

[0048] 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

[0054] Preparation of 5'-deoxy-5-fluoro-N 4 -Oximocytidine (compound 2)

[0055] A, 2', 3'-di-O-acetyl-5'-deoxy-5-fluoro-N 4 -Hydroxycytidine (compound of general formula D)

[0056] 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×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.

[0057] B. 5'-deoxy-5-fluoro-N 4 -Oximocytidine (compound 2)

[0058] 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 and...

Embodiment 3

[0060] Preparation of 5'-deoxy-5-fluoro-N 4 -aminocytidine (compound 3)

[0061] 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 the medicine technology field, and relates to a floxuridine compound with antitumor activity, a preparation method, and an application in preparation of antitumor drugs thereof. Experiments show that the compound of the invention, compound crystals or its medicinal salts can prevent intestinal toxicity of 5'-deoxy-5-floxuridine, and an enzyme (dThdPase) related to the compound has a higher concentration in tumor tissue than in normal tissue. Therefore, the compound of the invention or its medicinal salts can be used for preparing antitumor drugs.

Description

technical field [0001] The invention relates to the technical field of medicine, and relates to a floxuridine compound with antitumor activity, a preparation method thereof and an application in preparation of antitumor drugs. Background technique [0002] Nucleoside drugs have been widely used in clinical anti-tumor, among which fluorinated pyrimidine drugs play 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 of 5-fluorouracil, 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 d...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00A61K31/7068A61P35/00A61P35/02
Inventor 李科冯继禄孙海玲王甜甜吕志良牛春娟张一凯钟涵宇耿冬平张明峰陈焕
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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