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Analogue of thalidomide and preparation method

A technology of thalidomide and its analogues, which can be applied in drug combinations, bone diseases, non-central analgesics, etc., and can solve problems such as fatigue and constipation

Inactive Publication Date: 2005-11-16
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

[0005] Prostate cancer has obvious curative effect, but there are side effects such as constipation, nausea, and fatigue

Method used

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  • Analogue of thalidomide and preparation method
  • Analogue of thalidomide and preparation method
  • Analogue of thalidomide and preparation method

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Embodiment 1

[0041] Add 4.0g of 3-nitrophthalic anhydride and 2.0g of glutamine into the reactor preheated to 140±10°C, heat and stir, and slowly raise the temperature to 180±10°C after 40 minutes of reaction. Connect the system to a vacuum pump, stop the reaction after 10 hours, add 24ml of 1,4-dioxane, heat and stir to make the system into a solution, distill out the dioxane under reduced pressure, add 20ml of methanol, reflux for 20 minutes, cool overnight, and a precipitate forms , filtered, and washed with methanol to obtain a pale white solid, which was dried in vacuo to obtain 1.46 g of thalidomide substituted with the 3-nitro group, with a yield of 35.2% and a melting point of 297-299°C. 1 HNMR (DMSO-d 6 ): б11.16 (s, 1H), 8.18-7.96 (m, 3H), 5.26-5.18 (dd, 1H), 2.96-2.87 (m, 1H), 2.68-2.56 (m, 2H), 2.15-2.08 (m, 1H); 13 CNMR (DMSO-d 6 ): δ: 172.7, 169.5, 165.2, 162.5, 144.4, 136.8, 133.0, 128.9, 127.3, 122.6, 49.5, 30.9, 21.8. Elemental analysis (%, C 13 h 9 N 3 o 6 Calcd): ...

Embodiment 2

[0043] In the autoclave, add the thalidomide 1.1g that substituted 3 nitro groups obtained in Example 1, 3.3ml of aqueous formaldehyde solution of 40%, methyl alcohol 100ml, 0.5g of palladium carbon of 10%, pass into hydrogen, make hydrogen The pressure was 30 atmospheres, the system was heated to 80°C, and the reaction was stopped after 40 hours. The system was filtered with filter aid, the filtrate was adsorbed by silica gel, the solvent was removed by rotary evaporation, and the 3 : EtOAc = 10: 1 is the eluent through a silica gel column to obtain a yellow solid, which is dried in vacuo to obtain 0.83 g of 3-position N, N-dimethyl-substituted thalidomide (7), with a yield of 82.5%, and a melting point of: 207-209°C. 1 HNMR (DMSO-d 6 ): б11.06(s, 1H), 7.65-7.61(dd, 1H), 7.28-7.22(m, 2H), 5.10-5.06(dd, 1H), 3.04(s, 6H), 2.89-2.85(m , 1H), 2.61-2.51(m, 2H), 2.06-2.00(m, 1H); 13 CNMR (DMSO-d 6 ): δ: 172.8, 170.0, 167.1, 166.3, 149.8, 135.1, 133.9, 122.5, 113.4, 112.9, 48.8...

Embodiment 3

[0045] 0.6g of the 3-position N, N-dimethyl-substituted thalidomide (7) obtained in Example 2 and 5g of zinc powder activated with hydrochloric acid reacted at 90°C for 40min in 50ml of glacial acetic acid and filtered while hot, 50ml Acetone washes three times, mother liquor adds silica gel adsorption, chloroform: ethyl acetate=4: 1 crosses chromatographic column, obtains and N, the analogue (8 )0.20g, yield 34.9%, melting point: 92-94°C. 1 HNMR (DMSO-d 6 ), δ: 10.96(s, 1H), 7.46-7.41(m, 1H), 7.00-6.97(d, 1H), 6.88-6.86(d, 1H), 5.08-5.02(dd, 1H), 4.38-4.18 (dd, 2H), 2.92(s, 6H), 3.01-2.85(m, 1H), 2.65-2.51(m, 1H), 2.40-2.36(m, 1H), 2.16-1.95(m, 1H). 13 CNMR (DMSO-d 6 ), δ: 173.3, 171.6, 168.1, 151.2, 145.6, 132.8, 120.1, 115.3, 114.5, 52.1, 47.0, 44.0, 31.7, 22.9. Elemental analysis (%, C 15 h 17 N 3 o 3 Calcd): C 62.549 (62.71), H 5.99 (5.96), N 14.80 (14.63).

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Abstract

A novel analog of thalidomide and its preparing process are disclosed.

Description

technical field [0001] The present invention relates to a series of analogues of thalidomide and their preparation methods. Background technique [0002] Thalidomide, also known as Thalidomide, is a drug marketed in the late 1950s, used for sedation, hypnosis and antiemetic in early pregnancy. But it was soon discovered that the drug had serious teratogenic effects on the fetus. The drug was withdrawn from the market in the early 1960s. In 1965, Israeli doctor Sheskin (Sheskin, J. Clin Pharmacol. Ther. 1965, 6: 303-306) reported that thalidomide could effectively treat erythematous nodular leprosy (ENL). In 1998, FDA (US Food and Drug Administration) approved thalidomide for the treatment of ENL. In my country, thalidomide is the national essential drug for the treatment of leprosy concomitant diseases. In addition to treating ENL, thalidomide has currently known biological activities including immunosuppression, anti-cancer, and anti-HIV-1 virus. The research on thalid...

Claims

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Application Information

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IPC IPC(8): C07D401/04
Inventor 袁修华高连勋
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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