Aza*one compound and preparation method thereof

A compound, azaketone technology, applied in the field of tumor treatment drugs, can solve problems such as slow development

Active Publication Date: 2018-10-09
INST OF CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Synthesis of Aza by Asymmetric Cycloaddition Reaction Although the class of compounds has achieved certain success, it still develops slowly and has certain limitations (H.He, W.B.Liu, L.X.Dai, S.L.You, Angew.Chem.Int.Ed.2010, 49, 1496.; L. Wang, S. Li, M. Blümel, A.R. Philipps, A. Wang, R. Puttreddy, K. Rissanen, D. Enders, Angew. Chem. Int. Ed. 2016, 55, 11110.; C. Guo, M. Fleige, D. Janssen-Müller, C.G. Daniliuc, F. Glorius, J. Am. Chem. Soc. 2016, 138, 7840.)

Method used

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  • Aza*one compound and preparation method thereof
  • Aza*one compound and preparation method thereof
  • Aza*one compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] The pre-dried reaction tube was lowered to room temperature under vacuum, and nitrogen heterocyclic carbene VIII-1 (Ar 1 =3,5-(CF 3 ) 2 C 6 h 3 ,R=H,Ar 2 =Ph) (0.01mmol, 10mol%), potassium acetate (0.02mmol, 20mol%), unsaturated imine VII-1 (0.1mmol, 1.0equiv), inject 2-hexenal V-1 (0.2mmol, 2.0 equiv), add 2.0 milliliters of anhydrous 1,4-dioxane under nitrogen protection, move to 40 ° C oil bath and stir, until the thin layer chromatography control shows that the imine disappears (generally 12 hours), the reaction solution is concentrated, and the column After chromatographic separation and purification, the compound shown in I-1 was obtained.

[0088] Its structural formula is:

[0089]

[0090] The experimental data of I-1 are as follows:

[0091] 44mg,>20:1d.r.,94%yield.Yellow oil.R f =0.2(petroleum ether / ethylacetate 10:1) HPLC analysis: 99%ee[Daicel CHIRALPAKIA column, 20°C, 254nm, hexane / i-PrOH=90:10, 1.0mL / min, 13.4min(major), 19.7min(minor)]; 1 H...

Embodiment 2

[0093] The pre-dried reaction tube was lowered to room temperature under vacuum, and nitrogen heterocyclic carbene VIII-2 (Ar 1 =3,5-(CF 3 ) 2 C 6 h 3 ,R=H,Ar 2 =2-iPrC 6 h 4 ) (0.01mmol, 10mol%), potassium acetate (0.02mmol, 20mol%), unsaturated imine VII-1 (0.1mmol, 1.0equiv), injected enaldehyde V-2 (0.2mmol, 2.0equiv), nitrogen protection Add 2.0 ml of anhydrous 1,4-dioxane, move to 40°C oil bath and stir until the thin layer chromatography shows that the imine disappears (generally 12 hours), the reaction solution is concentrated, and after separation and purification by column chromatography The compound shown in I-2 was obtained.

[0094] Its structural formula is:

[0095]

[0096] The experimental data of I-2 are as follows:

[0097] 50.4mg, 9:1d.r., 93% yield. Yellow oil; HPLC analysis: 99%ee[Daicel CHIRALPAK IA column, 20°C, 254nm, hexane / i-PrOH=90:10, 1.0mL / min, 12.3min(major), 16.3min(minor)]; 1 H NMR (400MHz, CDCl 3)δ7.96(d, J=8.4Hz, 3H), 7.56-7.5...

Embodiment 3

[0099] The pre-dried reaction tube was lowered to room temperature under vacuum, and nitrogen heterocyclic carbene VIII-2 (Ar 1 =3,5-(CF 3 ) 2 C 6 h 3 ,R=H,Ar 2 =2-iPrC 6 h 4 ) (0.01mmol, 10mol%), potassium acetate (0.02mmol, 20mol%), unsaturated imine VII-1 (0.1mmol, 1.0equiv), injected enaldehyde V-3 (0.2mmol, 2.0equiv), nitrogen protection Add 2.0 ml of anhydrous 1,4-dioxane, move to 40°C oil bath and stir until the thin layer chromatography shows that the imine disappears (generally 12 hours), the reaction solution is concentrated, and after separation and purification by column chromatography The compound shown in I-3 was obtained.

[0100] Its structural formula is:

[0101]

[0102] The experimental data of I-3 are as follows:

[0103] 40mg, 9:1d.r., 79% yield.Yellow solid, m.p.185-187℃.R f =0.2(petroleumether / ethyl acetate 10:1); HPLC analysis: 98%ee[Daicel CHIRALPAK IA column, 20°C, 254nm, hexane / i-PrOH=90:10, 1.0mL / min, 10.3min(major), 13.9min(minor)];...

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PUM

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Abstract

The invention relates to an azaone compound and a preparation method thereof. Chiral azaone compounds are synthesized by asymmetric cycloaddition reaction of n-heterocyclic carbine catalytic olefine aldehyde and unsaturated imide. The method has the advantages of simple operation, mild reaction conditions and high enantioselectivity. The invention also provides application of the azaone compoundsin treating tumor; a chiral enantiomer has higher tumor suppressive activity than that of raceme of the chiral enantiomer.

Description

technical field [0001] The invention relates to the field of tumor therapy drugs, in particular to an aza The structure, chemical synthesis method, and application in tumor therapy of ketone compounds. Background technique [0002] Aza It is considered as an important structural unit in synthetic chemistry and medicinal chemistry, and many compounds containing this skeleton exhibit significant biological activity (M.Kawase, S.Saito, N.Motohashi, Int.J.Antimicrob.Agents 2000 , 14, 193.; K.Kondo, K.Kan, Y.Tanada, M.Bando, T.Shinohara, M.Kurimura, H.Ogawa, S.Nakamura, T.Hirano, Y.Yamamura, M.Kido, T. Mori, M.Tominaga, J.Med.Chem. 2002, 45, 3805.; S.B.Hoyt, C.London, D.Gorin, M.J.Wyvratt, M.H.Fisher, C.Abbadie, J.P.Felix, M.L.Garcia, X.Li, K.A. Lyons, E. McGowan, D.E. MacIntyre, W.J. Martin, B.T. Priest, A. Ritter, M.M. Smith, V.A. Warren, B.S. Williams, G.J. Kaczorowski, W.H. Parsons, Bioorg. Med. Chem. Lett. 2007, 17, 4630.; A. Palma, A.F. Yépes, S.M. Leal, C.A. Coronado...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/048C07D491/20A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D491/048C07D491/20
Inventor 叶松高中华陈坤泉
Owner INST OF CHEM CHINESE ACAD OF SCI
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