Fragrant acid ester derivative of 5-fluorine-2'-deoxidized uridine and synthesis thereof

A technology of deoxyuridine arylate and synthesis method, which is applied in the direction of sugar derivatives, drug combination, organic chemistry, etc., can solve the problems of low regioselectivity, difficult product separation, and many reaction steps, and achieve the goal of overcoming low selectivity , The reaction process is simple and easy to control, and the product is easy to produce

Inactive Publication Date: 2009-08-19
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When the general chemical method is used for direct esterification, the regioselectivity is low, a large number of by-products are easily produced, and the product separation is difficult; in order to synthesize an acylated product with a certain position, it is necessary to protect and deprotect ...

Method used

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  • Fragrant acid ester derivative of 5-fluorine-2'-deoxidized uridine and synthesis thereof
  • Fragrant acid ester derivative of 5-fluorine-2'-deoxidized uridine and synthesis thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Example 1: Synthesis of 3'-phenylacetate of 5-fluoro-2'-deoxyuridine

[0027] Add 5-fluoro-2'-deoxyuridine (101mg, 0.41mmol), vinyl phenylacetate (1.64mmol), and 30mL tetrahydrofuran into a sealed Erlenmeyer flask, followed by adding 200mg of Burkholderia The immobilized lipase of cepacia) was shaken in a constant temperature oscillator at 50° C. and 200 rpm under normal pressure, and the reaction was monitored by TLC. After the reaction, filter, concentrate the filtrate under vacuum, and finally purify by column chromatography to obtain 134 mg of the product, the yield is 90%, white powder, and the purity is greater than 99%. The Rf value and NMR data of 3'-phenylacetate of 5-fluoro-2'-deoxyuridine on TLC are as follows: Rf=0.31 (PE / EA=1 / 1); 1 H NMR (DMSO-d 6 )δ: 2.27 (apparent d, 2H, H 2′ ), 3.64(s, 2H, H 2″ ), 3.74(s, 2H, H 5′ ), 4.02(s, 1H, H 4′ ), 5.26(s, 1H, H 3′ ), 5.33 (br s, 1H, OH), 6.17 (t, J=7.2Hz, 1H, H 1′ ), 7.25-7.35 (m, 5H, H o , H p , H m ), ...

Embodiment 2

[0028] Example 2: Synthesis of 5'-(3-phenylpropionic acid) ester of 5-fluoro-2'-deoxyuridine

[0029] Add 5-fluoro-2'-deoxyuridine (101mg, 0.41mmol), 3-phenylpropionate acetone oxime ester (1.64mmol), 4mL n-hexane / pyridine (1 / 6, volume ratio) into a Erlenmeyer flask with a seal stopper Next, 100 mg of Bacillus subtilis protease was added, placed in a constant temperature shaker at 60° C. and 250 rpm under normal pressure, and the reaction was monitored by TLC. After the reaction, filter, concentrate the filtrate under vacuum, and finally purify by column chromatography to obtain 133 mg of the product, with a yield of 86%, as a white powder, with a purity greater than 99%. The Rf value and NMR data of 5'-(3-phenylpropionic acid) ester of 5-fluoro-2'-deoxyuridine on TLC are as follows: Rf=0.33 (PE / EA=1 / 2); 1 H NMR (DMSO-d 6 )δ: 2.11-2.24 (m, 2H, H 2′ ), 2.68(t, J=7.6Hz, 2H, H 2″ ), 2.87(t, J=7.6Hz, 2H, H 3″ ), 3.93 (br s, 1H, H 3′ ), 4.20-4.25 (m, 3H, H 4′ , H 5′ ), 5.34(b...

Embodiment 3

[0030] Example 3: Synthesis of 3'-(3-phenylpropionic acid) ester of 5-fluoro-2'-deoxyuridine

[0031] 5-fluoro-2'-deoxyuridine (101mg, 0.41mmol), 3-phenylpropanoic acid vinyl ester (8.2mmol), 30mL[C 4 MIm]BF 4 Put it into a Erlenmeyer flask with a sealed stopper, then add 50 mg of immobilized lipase derived from Burkholderia cepacia, place it in a constant temperature shaker at 40°C and 200 rpm under normal pressure, and monitor the reaction by TLC. After the reaction, filter, extract, remove the solvent under vacuum, and finally purify by column chromatography to obtain 139 mg of the product, the yield is 90%, white powder, and the purity is greater than 99%. The Rf value and NMR data of 3'-(3-phenylpropanoic acid) ester of 5-fluoro-2'-deoxyuridine on TLC are as follows: Rf=0.36 (PE / EA=1 / 1); 1 H NMR (DMSO-d 6 )δ: 2.18-2.29 (m, 2H, H 2′ ), 2.69(t, J=7.6Hz, 2H, H 2″ ), 2.88(t, J=7.6Hz, 2H, H 3″ ), 3.63 (br s, 2H, H 5′ ), 3.95 (br s, 1H, H 4′ ), 5.22(t, J=2.4Hz, H 3′ ),...

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Abstract

The invention discloses an aromatic acid ester derivative of 5-fluoro-2'-deoxyuridine and a synthesis method thereof. The synthesis method comprises the following steps: adding the 5-fluoro-2'-deoxyuridine with the concentration of 1.0-40mg/ml and an acyl donor to a non-aqueous medium, wherein, mol ratio of the 5-fluoro-2'-deoxyuridine to the acyl donor is 1:1.1-30; adding enzyme at a ratio of 0.1-10:1 based on the weight of the 5-fluoro-2'-deoxyuridine; performing an acylation reaction at the temperature of 20-60 DEG C and the normal pressure, and at an oscillation speed of 100-300rpm; and separating to obtain the aromatic acid ester derivative of 5-fluoro-2'-deoxyuridine. The method helps synthesize various aromatic acid ester derivatives of 5-fluoro-2'-deoxyuridine with novel structures and potential pharmaceutical value. The method has the advantages of mild condition, environmental protection, high regioselectivity of the reaction, simple and controllable reaction process, easy product separation and the like.

Description

technical field [0001] The invention relates to an aroate derivative of 5-fluoro-2'-deoxyuridine and an enzyme-catalyzed preparation method thereof. Background technique [0002] 5-Fluoro-2′-deoxyuridine is a kind of fluorodeoxynucleoside, which is widely used in clinical treatment of various cancers. But clinically, this anti-tumor agent also exhibits various side effects, such as causing hepatitis and sclerosing cholangitis (Grem J.L. Invest. New Drugs, 2000, 18: 299-313). Similar to other nucleoside drugs, 5-fluoro-2'-deoxyuridine has poor membrane penetration, is not easy to be absorbed, and has low oral bioavailability; it is unstable in the body and is easily detected by nucleoside phosphorylase Metabolized to 5-fluorouracil with low anticancer activity (its anticancer activity is 5000 times lower than that of 5-fluoro-2'-deoxyuridine). [0003] Although 5-fluoro-2'-deoxyuridine has the above disadvantages as a clinical drug, studies have found that chemical modifica...

Claims

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Application Information

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IPC IPC(8): C07H19/073C12P19/40A61P35/00
Inventor 宗敏华李宁
Owner SOUTH CHINA UNIV OF TECH
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