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Pyrrolo or indolo azacycloalkane structure containing chiral spiro oxyindole compound as well as racemate and preparation method thereof

A technology of azacycloalkanes and compounds is applied in the fields of chiral oxospirocyclic indole compounds and their racemates and preparations, and can solve the problems of achiral synthesis, high price of rhodium, low reaction yield and the like

Active Publication Date: 2018-08-17
SUN YAT SEN UNIV
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

But this reaction has the following problems: 1) the reaction yield is not high, and by-products are numerous; 2) achiral synthesis; 3) the rhodium used is expensive, and requires anhydrous and oxygen-free operation
[0013] To sum up, in the current literature cases of synthesizing oxospirocyclic indole compounds, only [3+2] or [4+1] cycloaddition synthesis strategies are reported, and the use of related cases is affected by the reaction conditions or their own Substrate limitation, and failure to obtain good enantioselectivity or the existence of diastereomers, this paper reports a new class of [5+1] or [6+1] or [7+1] ring Addition Synthesis of Chiral Oxospirocyclic Indoles and Their Racemates with Pyrrole or Indoloazacycloalane Structure

Method used

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  • Pyrrolo or indolo azacycloalkane structure containing chiral spiro oxyindole compound as well as racemate and preparation method thereof
  • Pyrrolo or indolo azacycloalkane structure containing chiral spiro oxyindole compound as well as racemate and preparation method thereof
  • Pyrrolo or indolo azacycloalkane structure containing chiral spiro oxyindole compound as well as racemate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: (-)-1-Benzyl-3',4'-dihydro-2'H-spiro[indoline-3,1'-pyrrolo[1,2-a]pyrazine] Synthesis of -2-one:

[0054] The structural formula of this example is as follows:

[0055]

[0056] To 2-(1H-pyrrol-1-yl)ethylamine (0.24mmol) and N-benzyl isatin (0.2mmol) in dichloromethane solution (2mL), add chiral phosphoric acid catalyst IV-12 (10mol% )and Molecular sieves can be reacted overnight at 25°C. The reaction solution was directly purified by column chromatography to obtain the target product (-)-1-benzyl-3',4'-dihydro-2'H-spiro[indoline-3,1'-pyrrolo[1, 2-a]pyrazine]-2-one: 55.7mg, yield: 85%, enantiomeric excess value (ee value): 88%, yellow solid, [α] 25 D =–82.13 (c=0.88, CH 2 Cl 2 ), mp: 119-121°C; 1 H NMR (400MHz, CDCl 3 )δ7.38–7.30(m,4H),7.30–7.26(m,2H),7.22(td,J=7.8,1.3Hz,1H),7.03(td,J=7.5,1.0Hz,1H),6.75 (d,J=7.8Hz,1H),6.69(dd,J=2.7,1.7Hz,1H),6.13(dd,J=3.6,2.7Hz,1H),5.53(dd,J=3.6,1.6Hz, 1H), 5.04(d, J=15.7Hz, 1H), 4.77(d, J=15.7Hz, 1H), 4.30(ddd,...

Embodiment 2

[0058] Example 2: (-)-1-methyl-3',4'-dihydro-2'H-spiro[indoline-3,1'-pyrrolo[1,2-a]pyrazine] Synthesis of -2-one:

[0059] The molecular structure of this example is as follows:

[0060]

[0061] To 2-(1H-pyrrol-1-yl)ethylamine (0.24mmol) and N-methylisatin (0.2mmol) in dichloromethane solution (2mL), add chiral phosphoric acid catalyst IV-12 (10mol% )and Molecular sieves can be reacted overnight at 25°C. The reaction solution was directly purified by column chromatography to obtain the target product (-)-1-methyl-3',4'-dihydro-2'H-spiro[indoline-3,1'-pyrrolo[1, 2-a]pyrazine]-2-one, yellow solid, 34.3 mg, yield: 68%, enantiomeric excess value (ee value): 68%, [α] 25 D =–89.52 (c=0.83, CH 2 Cl 2 ), mp: 122.7-125.4°C. [α] 25 D =–89.52 (c=0.83, CH 2 Cl 2 ). 1 HNMR (400MHz, CDCl 3 )δ7.33(tt, J=7.7,1.0Hz,1H),7.24(s,1H),7.05(t,J=7.5Hz,1H),6.86(d,J=7.8Hz,1H),6.64( t,J=2.2Hz,1H),6.07(t,J=3.2Hz,1H),5.47(dd,J=3.7,1.6Hz,1H),4.20(dtd,J=11.3,8.0,7.1,4.2Hz ,1H), 4.12(dt,...

Embodiment 3

[0063] Example 3: (-)-1-isopropyl-3',4'-dihydro-2'H-spiro[indoline-3,1'-pyrrolo[1,2-a]pyrazine Synthesis of ]-2-one:

[0064] The molecular structure of this example is as follows:

[0065]

[0066] To 2-(1H-pyrrol-1-yl)ethylamine (0.24mmol) and N-isopropyl isatin (0.2mmol) in dichloromethane solution (2mL), add chiral phosphoric acid catalyst IV-12 (10mol %)and Molecular sieves can be reacted overnight at 25°C. The reaction solution was directly purified by column chromatography to obtain the target product (-)-1-isopropyl-3',4'-dihydro-2'H-spiro[indoline-3,1'-pyrrolo[1 ,2-a]pyrazine]-2-one, yellow solid, 54.2mg, yield: 97%, enantiomeric excess value (ee value): 74%, [α] 25 D =–80.15 (c=0.85, CH 2 Cl 2 ), mp: 144-147°C. [α] 25 D =–80.15 (c=0.85, CH 2 Cl 2 ). 1 H NMR (400MHz, CDCl 3 )δ7.34–7.29(m,1H),7.27(s,1H),7.05(d,J=7.8Hz,2H),6.69–6.60(m,1H),6.09(t,J=3.2Hz,1H ),5.48(dd,J=3.7,1.7Hz,1H),4.58(p,J=7.0Hz,1H),4.21(td,J=8.5,4.7Hz,1H),4.18–4.08(m,2H) ,3.30(dt,J...

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Abstract

The invention relates to the field of chemocatalysis and discloses a pyrrolo or indolo azacycloalkane structure containing chiral spiro oxyindole compound as well as a racemate and a preparation method thereof. The method comprises the following steps of by taking N-substituted isatin or benzene ring substituted isatin (1) and N-alkylamino group substituted pyrrole or indole (2) as reaction substrates and using chiral phosphoric acid or an enantiomer or a racemate thereof as a catalyst, directly preparing the pyrrolo or indolo azacycloalkane structure containing chiral spiro oxyindole compoundby one step by a way of catalyzing [m+1] cycloaddition in the environment of a solvent and an additive. Through a method of [5+1], [6+1] or [7+1] cycloaddition, by taking the chiral phosphoric acid as the catalyst, asymmetric synthesis is realized; and by using isatin which is not modified, a 3',4'-dihydro-2'H-spiro[indoline-3,1'-pyrrolo[1,2-a]pyrazine]-2-ketone compound is obtained for the firsttime through one-step reaction only, and the reaction can be extended to the cycloaddition process of a larger ring system. By adopting the method provided by the invention, an activity test is performed on the obtained compound, and a lead compound with very good physiological activity is obtained.

Description

technical field [0001] The invention belongs to the field of chemical catalysis, and relates to a chiral oxo-spirocyclic indole compound containing a pyrrole or indoloazacycloalkane structure, a racemate and a preparation method thereof. Background technique [0002] Oxospirocyclic indoles are an important class of natural product core structures [(a) Kitajima, M.; Nakamura, T.; Kogure, N.; Ogawa, M.; Mitsuno, Y.; Ono, K .; Yano, S.; Aimi, N.; Takayama, H.J. Nat. Prod. 2006, 69, 715-718. (b) Zhao, Y.; Liu, L.; Sun, W.; Lu, J.; D.; Li, X.; Yu, S.; Bernard, D.; Ochsenbein, P.; Ferey, V.; .2013,135,7223-7234.], among them, the compounds obtained by structurally modifying and transforming the core of this type of natural products have obvious anti-tumor activity, and related compounds have entered clinical phase I trials and have attracted much attention [(a) Zhao, Y.; Aguilar, A.; Bernard, D.; Wang, S.J. Med. Chem.2015, 58, 1038-1052. (b) Aguilar, A.; Lu, J.; .; Du, D.; Bern...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/20C07D471/22A61P35/00
CPCA61P35/00C07D471/22C07D487/20
Inventor 邱立勤陈晖旋张雅琪何雪峰
Owner SUN YAT SEN UNIV
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