Thalidomide and its derivatives preparation method

A technology for thalidomide and its derivatives, which is applied in the field of preparation of thalidomide and its derivatives, and can solve the problems that carbonyldiimidazole is expensive and unsuitable for production

Inactive Publication Date: 2003-03-26
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the prices of N-carbonylethoxyphthalimide and carbonyldiimidazole (CDI) used in this method are all more expensive, so this method is not suitable for production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] Add 2.0g of phthalic anhydride and 2.0g of glutamine into the reactor preheated to 120±10°C, heat and stir, and slowly raise the temperature to 200±10°C after reacting for 40 minutes, and connect the system to a vacuum pump at the same time , the reaction was stopped after 2 hours to give a yellow solid. Add 15g of 1,4-dioxane, heat and stir to make the system into a solution, distill out the dioxane under reduced pressure, add 15g of acetone, stir, a precipitate is formed, filter, wash with water several times, then wash with acetone several times, vacuum Dry to obtain 0.85g of pure white solid, yield: 24.1%, thin-layer chromatography shows that this substance has only one point, melting point 273-274 ℃ (literature value 273-275 ℃). 1 HNMR (DMSO-d6): σ11.12 (s, 1H), 7.94-7.88 (m, 4H), 5.18-5.14 (dd, 1H), 3.00-2.80 (m, 1H), 2.65-2.50 (m, 2H ), 2.15-2.00 (m, 1H), consistent with the NMR spectrum of thalidomide in the literature.

Embodiment 2

[0014] Add 3.0g of 3-methylphthalic anhydride and 2.0g of glutamine to the reactor preheated to 140±10°C, heat and stir, and slowly raise the temperature to 180±10°C after reacting for 30 minutes, while the system A vacuum pump was connected, and the reaction was stopped after 6 hours to obtain a white solid. Add 24g of 1,4-dioxane, heat and stir to make the system into a solution, distill out the dioxane under reduced pressure, add 24g of acetone, stir, a precipitate is formed, filter, wash with water several times, then wash with acetone several times, vacuum After drying, 1.09 g of a derivative of thalidomide substituted with a methyl group at the 3-position was obtained, with a yield of 29.0% and a melting point of 254-256°C. 1 HNMR (DMSO-d6): σ11.14 (s, 1H), 7.68-7.56 (m, 3H), 5.21-5.16 (dd, 1H), 2.90-2.86 (m, 1H), 2.76 (s, 3H), 2.64-2.54 (m, 2H), 2.10-2.06 (m, 1H).

Embodiment 3

[0016] Add 3.0g of 4-methyl phthalic anhydride and 2.0g of glutamine to the reactor preheated to 130±10°C, heat and stir, and slowly raise the temperature to 170±10°C after 40 minutes of reaction, while the system A vacuum pump was connected, and the reaction was stopped after 10 hours to obtain a white solid. Add 21g of 1,4-dioxane, heat and stir to make the system into a solution, distill out dioxane under reduced pressure, add 21g of acetone, stir, a precipitate is formed, filter, wash with water several times, then wash with acetone several times, vacuum After drying, 1.21 g of a derivative of thalidomide substituted with a methyl group at the 4-position was obtained, with a yield of 32.2% and a melting point of 197-199°C. 1 HNMR (DMSO-d6): σ11.18 (s, 1H), 7.98-7.85 (m, 3H), 5.21-5.16 (dd, 1H), 2.90-2.86 (m, 1H), 2.75 (s, 3H), 2.64-2.55 (m, 2H), 2.09-2.07 (m, 1H).

[0017] Use 3 or 4 CH 2 CH 3 , OCH 3 Substituted phthalic anhydride instead of 4-methylphthalic anhydrid...

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Abstract

The method for synthesizing thalidomide and its derivative includes the following steps: adding phthalic anhydride and glutamine at 120-150 deg.C, addition quantity of phthalic anhydride is 1-5 times that of glutamine, heating, stirring, reacting for 20-40 min., then slowly heating to 160-220 deg.C, vacuum pumping, after 2-20 hr, stopping reaction, adding 1,4-dioxane, heating and stirring to make said material into solution, decompressing and evaporating out dioxane, adding acetone, stirring, filtering, washing with water and settling, washing with acetone and vacuum drying to obtain the invented thalidomide. Said invention utilizes 2-position or 4-position CH3, CH2CH3, OCH3, F, Cl, Br or NO2 substituted phthalic anhydride and glutamine, and makes them react together, so that the correspondent thalidomide derivative can be obtained.

Description

technical field [0001] The invention relates to a preparation method of thalidomide and its derivatives. Background technique [0002] Thalidomide (Thalidomide), also known as reaction stop. It was originally synthesized by Chem.Grǔnenthal Company in West Germany in 1953 and launched in October 1957. It is used for sedation, hypnosis and antiemetic for women in early pregnancy. Compared with barbiturates, the sedative effect of thalidomide is not accompanied by anesthesia, unlike barbiturates which have a process of excitement first and then sedation. Organ toxicity was very low and thus received high marks. But in the following years, this drug caused the birth of hundreds of thousands of deformed children in Europe and North America, and since then this drug has been banned in many countries. However, in recent years, due to the discovery of the biological activity of this drug in anti-cancer, immunosuppression, anti-HIV virus and other aspects, it has attracted much at...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
Inventor 高连勋袁修华郭海泉刘旭东
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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