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Synthesis method of 3-(7-hydroxy-1-oxoisoindole-2-yl) piperidine-2, 6-dione

A synthesis method and isoindole technology, applied in the direction of organic chemistry and the like, can solve the problems of easy ring opening and severe reaction of the synthesis method, and achieve the effects of easy operation, mild reaction conditions, and cheap and easily available raw materials.

Pending Publication Date: 2020-01-24
苏州爱玛特生物科技有限公司
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

[0004] At present, the synthesis of 3-(7-hydroxy-1-oxoisoindol-2-yl)piperidine-2,6-dione compounds mainly uses strong acid sulfuric acid as solvent, and strong acid sulfuric acid has strong corrosiveness and Oxidizing, so it needs to be used with caution. In addition, the current synthesis method reacts violently, so it is easy to open the ring

Method used

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  • Synthesis method of 3-(7-hydroxy-1-oxoisoindole-2-yl) piperidine-2, 6-dione
  • Synthesis method of 3-(7-hydroxy-1-oxoisoindole-2-yl) piperidine-2, 6-dione
  • Synthesis method of 3-(7-hydroxy-1-oxoisoindole-2-yl) piperidine-2, 6-dione

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Example 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindole-1,3-dione:

[0025]

[0026] Under ice-bath conditions, add 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2.73 g, 1mmol), and stirred for 1h. Then an appropriate amount of copper powder (0.013g, 0.2mmol) and NaNO 2 (0.69g, 1mmol) was slowly added to the mixture, and after stirring for 30min, the temperature was raised to 80°C for 1h. After the reaction, it was extracted with ether and dried over anhydrous magnesium sulfate. Most of the solvent was spun off, and purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (V / V=20 / 1) to obtain compound I-1 (2.47 g). Yield: 90%.

[0027] 1 H NMR (400MHz, CDCl 3 )δ9.20(s,1H),7.78(dd,1H),7.46(t,1H),7.11(dd,1H),5.50(t,1H),2.61(td,2H),2.23(m,2H ).

Embodiment 2

[0028] Example 2: Synthesis of 3-(7-hydroxyl-1-oxoisoindol-2-yl)piperidine-2,6-dione:

[0029]

[0030] Under ice-bath conditions, add 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2.73 g, 1mmol), and stirred for 1h. Then an appropriate amount of copper powder (0.013g, 0.2mmol) and NaNO 2 (0.69g, 1mmol) was slowly added to the mixture, and after stirring for 30min, the temperature was raised to 80°C for 1h. After the reaction, it was extracted with ether and dried over anhydrous magnesium sulfate. Most of the solvent was spun off, and purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (V / V=20 / 1) to obtain compound I-2 (2.34 g). Yield: 90%.

[0031] 1 H NMR (400MHz, CDCl 3 )δ9.09(s,1H),7.21(m,1H),6.98(ddt,1H),6.87(dd,1H),4.44(t,1H),4.30(d,2H),2.58(qt,2H ), 2.07(m,2H).

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Abstract

The invention relates to a preparation method of 3-(7-hydroxy-1-oxoisoindole-2-yl) piperidine-2, 6-dione. According to the synthetic method, in the presence of hydrochloric acid, a copper catalyst andsodium nitrite, a compound shown in formula (I) is reacted at 60 to 80 DEG C to obtain a compound represented by formula (II); wherein the structural formula of the compound in the formula (I) is shown in the invention specification, and in the formula (II), R is used for representing CH2, C=O, O=S=O, NH, N-CH3, N-CH2-CH3, N-CH2-CH3, N-(CH2)2-CH3 or N-(CH2)3-CH3. The method has the advantages ofmild reaction conditions, easiness in operation, stability in synthesis, difficulty in ring opening, simple raw materials and the like, and convenience is provided for synthesis of new drugs of pomalidomide and lenalidomide.

Description

technical field [0001] The invention belongs to the field of organic compound synthesis, and in particular relates to a synthesis method of 3-(7-hydroxyl-1-oxoisoindol-2-yl)piperidine-2,6-dione. Background technique [0002] 3-(7-Hydroxy-1-oxoisoindol-2-yl)piperidine-2,6-dione compounds are a class of important pharmaceutical precursors, they are widely used in synthesis and medicinal chemistry Fields, such as the synthesis of amine drugs. Methamides, an immunomodulator with antitumor activity, have attracted widespread attention. [0003] As an immunomodulatory drug, lenalidomide, a kind of idomide, has multiple mechanisms of action. In vitro studies, lenalidomide has three main effects: 1) direct anti-tumor effect 2) inhibition Angiogenesis 3) Immunomodulation. In vivo, lenalidomide directly or indirectly induces tumor cell apoptosis by inhibiting bone marrow stromal cell support, antiangiogenic and antiosteoclastic effects, and immunomodulatory activities. At the mole...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 汪明中朱明新苏道李金金
Owner 苏州爱玛特生物科技有限公司
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