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Preparation method of high-purity antineoplastic drug triflucytidine

An anti-tumor drug, triflucytidine, is applied in the field of preparation of high-purity anti-tumor drug triflucytidine, which can solve problems such as metal residues, long routes, unfavorable drug preparation, etc., and achieve mild reaction conditions, cheap and easy raw materials The effect of being convenient for industrialized preparation

Active Publication Date: 2021-06-18
JIANGSU JITRI MOLECULAR ENG INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Among the above methods, the raw materials used in method 1 are expensive, the route is long, the yield is low, and the process controllability is poor
Method 2 is a free radical reaction process, the process is poorly controllable, and it is not easy to scale up due to factors such as exothermic effects. At the same time, the raw materials are expensive, the yield is low, the product purity is low and it is difficult to purify, and the overall cost is relatively high.
Method 3 uses metal copper and strong alkali, which will cause metal residues, which is not conducive to drug preparation. The reaction process requires conditions such as anhydrous and oxygen-free. The process control is difficult, and the raw materials are expensive and difficult to obtain.

Method used

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  • Preparation method of high-purity antineoplastic drug triflucytidine
  • Preparation method of high-purity antineoplastic drug triflucytidine
  • Preparation method of high-purity antineoplastic drug triflucytidine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of Compound III: At room temperature, take 34.7 mL of hexamethyldisilamine and 3.18 mL of trimethylchlorosilane into the reaction flask, add 15 g of Compound II under stirring, raise the temperature to 125 ° C, stir for 4 hours, and cool to 60°C, distilled under reduced pressure at 80-90°C to obtain 25.5 g of a colorless transparent liquid with a yield of 94.4%.

Embodiment 2

[0039] Preparation of Compound V: At room temperature, 20 g of Compound III was added into a reaction flask, and 26.4 g of Compound IV was added under stirring. The reaction was stirred at room temperature for 30 minutes and then heated to 50° C. for 3 hours. After the reaction, cool to room temperature and add ethyl acetate to dissolve the solid, filter, concentrate the filtrate until no solvent flows out, add 220 mL of ethyl acetate and ethanol mixed solvent (volume ratio 1:6) to recrystallize the residue, filter out the crystal, and use an appropriate amount of The mixed solvent was rinsed, and the filter cake was vacuum-dried to obtain 24.6 g of off-white solid, with a yield of 69.7%.

[0040] ESI-MS m / z =573.0 [M+H] + , Calculated MW: 572.0; 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.96 (s, 1H), 8.12 (d, J = 1.1 Hz, 1H), 8.03-7.96 (m, 2H), 7.95-7.90(m, 2H), 7.64-7.56 (m, 2H), 7.56-7.51 (m, 2H), 6.15 (t, J = 6.9 Hz, 1H), 5.59(dt, J = 6.5, 2.8 Hz, 1H), 4.67-4.48 (m, 3H), 2...

Embodiment 3

[0042] Preparation of Compound VI: Dissolve 10 g of Compound V in 100 mL of dichloromethane at -5°C, add 4.2 mL of pyridine and 4.4 mL of trifluoromethanesulfonic anhydride successively under stirring, react at room temperature for 4 hours, and , add 35 mL of 2mol / L ammonia ethanol solution, and react at room temperature for 4 hours. After the reaction, the reaction solution was concentrated, the residue was dissolved in ethyl acetate, the organic phase was washed 3 times with water, and the organic phase was dried over anhydrous sodium sulfate. The concentrated crude product was separated and purified by silica gel column chromatography to obtain 7.5 g of a yellow solid. The yield was 75.0%.

[0043] ESI-MS m / z =594.0 [M+Na] + , Calculated MW: 571.1; 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.06 (d, J = 1.1 Hz, 1H), 8.04-7.94 (m, 3H), 7.94-7.84 (m, 2H),7.66-7.45 (m, 4H), 7.10 (s, 1H), 6.14 (t, J = 6.8 Hz, 1H), 5.59 (dt, J = 6.7,2.6 Hz, 1H), 4.67-4.48 (m, 3H), 2.69-2.52 (m, 2...

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Abstract

The invention discloses a preparation method of a high-purity antineoplastic drug triflucytidine, which comprises the following steps: 1) obtaining 2,6-bis(trimethylsilyl-5-trifluoromethylpyrimidine) from 5-(trifluoromethyl)uracil and hexamethyldisilazane under the action of trimethylchlorosilane; 2) carrying out condensation reaction on the 2, 6-bis(trimethylsilyl-5-trifluoromethylpyrimidine) and the 3',5'-p-chlorobenzoyl-2'-deoxy-1-chloro-D-ribofuranose, and carrying out recrystallization to obtain 3', 5'- p-chlorobenzoyl-2'-deoxy-5-trifluoromethyl uridine; (3) carrying out reaction on the 3',5'-p-chlorobenzoyl-2'-deoxy-5-trifluoromethyl uridine and trifluoromethanesulfonic anhydride, and carrying out nucleophilic substitution by using ammonia, so as to obtain 3',5'-p-chlorobenzoyl-2'-deoxy-5-trifluoromethyl cytidine; and 4) carrying out deprotection on the 3',5'-p-chlorobenzoyl-2'-deoxy-5-trifluoromethyl cytidine under the action of sodium methoxide, and filtering and washing to obtain the triflucytidine. The preparation method of the high-purity antineoplastic drug triflucytidine disclosed by the invention is convenient for industrial preparation.

Description

technical field [0001] The invention belongs to the field of organic synthesis chemistry, and in particular relates to a preparation method of a high-purity antitumor drug triflucytidine. Background technique [0002] Trifluridine is a common antineoplastic drug, which can be used in patients with metastatic colorectal cancer, gastric cancer, and unresectable tumors after receiving 5-fluoropyrimidine, oxaliplatin and irinotecan-based chemotherapy. Or recurrent advanced colorectal cancer, gastric cancer patients. [0003] Trifluridine is a prodrug of trifluridine, which can be converted into trifluridine in the human body to exert therapeutic effects. It has been proved by relevant studies that during the transformation process of trifluridine, tumor tissue obtains a higher concentration of trifluridine than normal tissue, and the compound preparation of trifluridine is more effective than the compound preparation of trifluridine (TSA-102). Have a better antitumor effect. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/00C07H19/073A61P35/00
CPCC07H1/00C07H19/073A61P35/00Y02P20/55
Inventor 廖道红李益政汪晓明雷晓光张秀国
Owner JIANGSU JITRI MOLECULAR ENG INST CO LTD