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Synthesis of N-benzyl-N-benzyloxy urea

A benzyloxyurea and benzyl technology, applied in the field of synthesis of hydroxyurea derivatives, can solve the problems of small molecular weight of HU, large toxic and side effects of hydroxyurea, low bioavailability, etc., and achieve improved bioavailability and reduced toxic and side effects , the effect of enhanced activity

Inactive Publication Date: 2008-06-25
NANCHANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, HU has small molecular weight (MW=76.06) and high polarity (logPo\w=1.80), and its lipid membrane penetration ability is weak, which is also the main reason for the high toxicity and side effects and low bioavailability of hydroxyurea

Method used

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  • Synthesis of N-benzyl-N-benzyloxy urea
  • Synthesis of N-benzyl-N-benzyloxy urea

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0011] Example 1: Synthesis of N-benzyl-N-benzyloxyurea: Take 2.16g benzyloxyurea and dissolve it in 80ml methanol, add 0.95gKOH, heat to reflux, slowly add dropwise 20ml of methanol solution of 1.60ml benzyl chloride , stirred and refluxed for 16 hours, tracked the reaction with TLC (developing agent: chloroform: acetone=5:1, then sprayed ferric chloride solution, no blue spots were the reaction end point), after the reaction was complete, the reaction solution was reduced at 35 ° C. Pressure distillation, the solid residue was extracted with ether, the extract was concentrated under reduced pressure, and then passed through a silica gel column, the mobile phase was acetone: chloroform = 1: 4, the same point was collected, evaporated to dryness under reduced pressure, and then used acetone: n-hexane = 5: 1.5 recrystallized to obtain 1.07 g of white crystals. m.p = 97-98°C.

Embodiment 2

[0012] Example 2: Synthesis of N-(4-methylbenzyl)-N-(4-methylbenzyloxy)urea: get 2.34g2, and dissolve 4-methylbenzyloxyurea in 80ml methanol, add 0.95gKOH, heated to reflux, slowly added dropwise 20ml of methanol solution of 1.8ml p-methylbenzyl chloride, stirred and refluxed for 17 hours, tracked the reaction with TLC (developing agent: chloroform: acetone=5:1, then sprayed ferric chloride solution , no blue spot is the reaction end point), after the reaction is complete, the reaction solution is distilled under reduced pressure at 35°C, the solid residue is extracted with ether, the extract is concentrated under reduced pressure, and then passed through a silica gel column, the mobile phase is acetone:chloroform=1: 4. The same points were collected, evaporated to dryness under reduced pressure, and then recrystallized with acetone:n-hexane=5:1.5 to obtain 1.26 g of white crystals. m.p = 128-130°C.

Embodiment 3

[0013] Example 3: Synthesis of N-(4-methylbenzyl)-N-(4-methylbenzyloxy)urea: get 2.5g3, and dissolve 4-methoxybenzylurea in 80ml methanol, add 0.95gKOH, heated to reflux, slowly added dropwise 20ml of methanol solution of 2.04ml p-methoxybenzyl chloride, stirred and refluxed for 19 hours, tracked the reaction with TLC (developing agent: chloroform: acetone=5:1, then sprayed ferric chloride solution, no blue spots are the reaction end point), after the reaction is complete, the reaction solution is distilled under reduced pressure at 35°C, the solid residue is extracted with ether, the extract is concentrated under reduced pressure, and then passed through a silica gel column, the mobile phase is acetone:chloroform=1 : 4, the same point was collected, evaporated to dryness under reduced pressure, and then recrystallized with acetone: n-hexane = 5: 2 to obtain 1.48 g of white crystals. m.p = 99-101°C.

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Abstract

The invention relates to a N-benzyl-N-benzyloxy urea, the general formula of which is as follows: R1 symbolizes H, CH3, OCH3, halogen R2 symbolizes H, CH3 and OCH3; the halogen N-benzyl-N-benzyloxy urea is obtained through the reaction between the benzyloxy urea and the benzyl chloride. The invention has the advantages that the aromatic base or replaced aromatic base is added on the basis of the hydroxyurea so as to increase both the molecular weight and fat solubility of the compounds, change the spatial structure of the compounds, enhance the bioavailability of the target compounds to a certain extent, strength the activity of the compounds and lower the side effect of the compounds.

Description

technical field [0001] The present invention relates to the synthesis of a hydroxyurea derivative, in particular to the synthesis of N-benzyl-N-benzyloxyurea. Background technique [0002] Hydroxyurea (Hydroxyurea HU) is mainly used for the treatment of chronic myelogenous leukemia (CML), melanoma, accelerated phase and blast phase of CML, polycythemia vera, and primary squamous cell carcinoma of the head and neck, recurrent and metastatic Ovarian cancer also has a certain curative effect; in recent years, it has been found to have a certain curative effect on sickle cell anemia, β-thalassemia, and psoriasis. There are also research reports that the combination of HU and nucleic acid congener DDI (didanosine) can treat AIDS, and the data show that there is no obvious rebound after one year of treatment. The clinical toxicity of hydroxyurea mainly manifests as bone marrow suppression, skin toxicity, mild gastrointestinal toxicity and abnormal liver an...

Claims

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Application Information

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IPC IPC(8): C07C275/64C07C273/18
Inventor 麦曦李少华黄惠明陆小三夏红英
Owner NANCHANG UNIV
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