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3-site substituted (1-iso-indoxoline-2-base)piperidine-2,6-thiazolidinedione and synthetic method thereof

A technology of oxoisoindoline and synthesis method, which is applied in the field of compound and synthesis, and can solve the problems of difficulty in synthesizing new compounds and many reaction steps

Active Publication Date: 2018-02-27
EAST CHINA NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0025] Among the compounds reported above, the parent structures of (1-oxoisoindolin-2-yl)piperidine-2,6-diones were constructed from simple chemicals through multi-step reactions. The method has many reaction steps, and it is very difficult to synthesize a large number of new compounds

Method used

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  • 3-site substituted (1-iso-indoxoline-2-base)piperidine-2,6-thiazolidinedione and synthetic method thereof
  • 3-site substituted (1-iso-indoxoline-2-base)piperidine-2,6-thiazolidinedione and synthetic method thereof
  • 3-site substituted (1-iso-indoxoline-2-base)piperidine-2,6-thiazolidinedione and synthetic method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] 1.1 Synthesis of Compound 1

[0118]

[0119] Compound a (5.0g, 19.3mmol) and biboronic acid pinacol ester (5.4g, 21.26mmol) were added to a 250ml flask, 100ml of acetonitrile was added and stirred, then tert-butyl nitrite (3.44ml, 28.95mmol) was added , The reaction system was reacted at room temperature for 4 hours. The completion of the reaction was monitored by TLC, and the solvent was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=100:1) to obtain compound 1 as a white solid (3.86g, yield 54.1%) ).

[0120] 1 H-NMR (400MHz, DMSO) δ11.01 (s, 1H), 7.91 (d, J = 7.3Hz, 1H), 7.86 (d, J = 7.5Hz, 1H), 7.55 (t, J = 7.4Hz, 1H), 5.14(dd, J=13.3, 5.0Hz, 1H), 4.51(d, J=18.1Hz, 1H), 4.42(d, J= 18.1Hz, 1H), 2.98-2.82(m, 1H), 2.60 (d, J = 16.7Hz, 1H), 2.48-2.38 (m, 1H), 2.09-1.95 (m, 1H), 1.32 (s, 12H).

Embodiment 2

[0122] 1.2 Synthesis of Compound 2

[0123]

[0124] Compound 1 (1g, 2.7mmol) was added to a 100ml flask filled with tetrahydrofuran (20ml) and water (5ml), fully stirred, then slowly added sodium periodate (1.55g, 8.12mmol), and the system was stirred at room temperature for 2 Hour. 1M hydrochloric acid solution (1.89ml, 1.89mmol) was added to the reaction system, and stirred at room temperature for 12 hours. The organic solvent was removed from the reaction system under reduced pressure, then 30 ml of dichloromethane and 10 ml of water were added thereto, and the reaction system was fully stirred for one hour at room temperature. Compound 2 was collected by filtration and washed with water as a solid (523 mg, yield 67.3%).

[0125] 1 H NMR (400MHz, DMSO) δ10.98(s, 1H), 8.02(t, J=7.0Hz, 1H), 7.76(d, J=6.9Hz, 1H), 7.50 (t, J=7.5Hz, 1H ),5.13(dd,J=13.3,5.0Hz,1H),4.50(dd,J=36.4,18.1Hz,2H),3.17(s,2H),2.96–2.82(m,1H),2.59(d, J=17.1Hz, 1H), 2.45–2.36(m, 1H), 2.08–1.95(m, 1H...

Embodiment 3

[0127] 1.3 Synthesis of compound 9

[0128]

[0129] Compound 1 (200mg, 0.43mmol), compound 8 (115mg, 0.43mmol), potassium carbonate (176mg) was added in the flask of 100ml, the mixed solvent of the ethylene glycol dimethyl ether of 8ml and 1ml water was added thereto, then Add tetrakistriphenylphosphine palladium catalyst (25 mg), stir well, replace the reaction system with nitrogen several times, heat to 85 degrees, and react for 8 hours. Water was added to the reaction system, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Filter and spin the filtrate to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=80:1) to obtain compound 9 as a solid (100mg, yield 45%)

[0130] 1 H NMR(400MHz,DMSO)δ10.98(s,1H),7.59(d,J=6.5Hz,1H),7.47(d,J=6.8Hz,2H),7.21 (q,J=8.0Hz,4H ),5.11(dd,J=13.2,5.0Hz,1H),4.39(d,J=17.2Hz,1H),4...

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Abstract

The invention discloses a 3-site substituted (1-iso-indoxoline-2-base)piperidine-2,6-thiazolidinedione and a synthetic method thereof, and belongs to the technical field of medicine synthesis. In a formula I, Y can be Z, R1, R2, -(CH2)n-R3, wherein Z is a boric acid ester group or a boric acid group, R1 is hydroxyl, cyanogroup or trifluoromethyl, R2 is morpholinyl, piperidyl and methyl piperazinegroup; in the formula -(CH2)n-R3, R3 is alkylene, tert-butyl acetate, phenyl group and heterocyclic aromatic group, and n is 0 or 1. The compound can be used for preparing medicines capable of treating or preventing multiple myeloma, leukemia and lymphoma. The formula is shown in the description.

Description

technical field [0001] The present invention relates to compounds and their synthesis, in particular to a class of 3-substituted (1-oxoisoindoline-2-yl) piperidine-2,6-dione compounds and their synthesis methods, and such derivatives Application in the preparation of drugs for treating tumors. Background technique [0002] (1-oxoisoindoline-2-yl)piperidine-2,6-dione (structural formula 1) has good biological activity, and extensive research has been carried out on its derivatives, especially the 3-substituted compound of. [0003] [0004] 3-Amino-(1-oxoisoindoline-2-yl)piperidine-2,6-dione, also known as lenalidomide (trade name: REVLIMID), is produced by Celgene Corporation of the United States through Approved by the FDA and launched in the United States in December 2005, it was first used to treat myelodysplastic syndrome with deletion of the long arm of chromosome 5 (5q). Then its indications were expanded to: mantle cell lymphoma, multiple myeloma, peripheral T c...

Claims

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Application Information

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IPC IPC(8): C07F5/02C07D401/14C07D401/04A61P35/00A61P35/02
CPCC07D401/04C07D401/14C07F5/025
Inventor 吕伟肖栋槐金嵇煜
Owner EAST CHINA NORMAL UNIVERSITY
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