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Chiral α-amino-δ-oxopentanoate derivatives and their synthesis methods and applications

A technology of oxopentanoate and synthesis method, which is applied in the field of optically active α-amino-δ-oxopentanoate derivatives and their synthesis, and can solve the problems of difficult control of selectivity, lack of catalyst, low substrate activity, etc. problem, to achieve efficient atom economy, high selectivity, and good yield

Active Publication Date: 2016-04-06
广东和博制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the low activity of the substrate, the lack of catalysts, and the difficulty in controlling the selectivity, the existing synthetic methods have the disadvantages of high cost, low yield, and complicated operation.

Method used

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  • Chiral α-amino-δ-oxopentanoate derivatives and their synthesis methods and applications
  • Chiral α-amino-δ-oxopentanoate derivatives and their synthesis methods and applications
  • Chiral α-amino-δ-oxopentanoate derivatives and their synthesis methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]

[0038] N-p-bromobenzylideneaniline (0.4mmol),[PdCl(allyl)] 2 (0.05mmol), chiral phosphoric acid and Molecular sieves (0.2g) were dissolved in chloroform (1.5mL), then methyl phenyldiazoacetate (0.8mmol) and enamine (0.8mmol) dissolved in chloroform (1.0ml) were added dropwise to In the reaction system, the reaction system was kept at -20-0°C. After the dropwise addition was completed, the reaction system was stirred for 10 minutes, and the solvent was removed under reduced pressure to obtain a crude product, the structure of which was shown in formula (2-1). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:80~1:40) to obtain a pure product. Yield 58%, dr=95:5, ee=60%. nuclear magnetic resonance 1 HNMR, 13 CNMR spectrum such as figure 1 as shown, 1 HNMR(400MHz,Acetone)δ7.82(dd,J=8.4,1.2Hz,2H),7.70–7.63(m,2H),7.61–7.55(m,1H),7.49–7.42(m,2H),7.37 –7.31(m,5H),7.06(d,J=8.5Hz,2H),7.00(dd,J=8.6,7.4Hz,2H),6.62(M,1H),6.49(dd,J...

Embodiment 2

[0040]

[0041] N-p-Bromobenzylideneaniline (0.4mmol),[PdCl(allyl)] 2 (0.05mmol), chiral phosphoric acid and Molecular sieves (0.2g) were dissolved in chloroform (1.5mL), then, tert-butyl phenyldiazoacetate (0.8mmol) and enamine (0.8mmol) dissolved in chloroform (1.0ml) were added dropwise in 1 hour Into the reaction system, the reaction system is at -20 ~ 0 ° C, after the dropwise addition is completed, stir for 10 minutes, and remove the solvent under reduced pressure to obtain a crude product, the structure of which is shown in formula (2-2). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:80~1:40) to obtain a pure product. Yield 51%, dr=95:5, ee=80%. nuclear magnetic resonance 1 HNMR, 13 CNMR spectrum such as figure 2 as shown, 1 HNMR (400MHz, CDCl 3 )δ7.71-6.67(m,2H),7.64-7.60(m,2H),7.51-7.46(m,1H),7.40–7.25(m,7H),7.15–6.87(m,6H),6.71- 6.66(m,1H),6.42(d,J=7.8Hz,1H),4.90(s,1H),4.63(dd,J=11.3,1.9Hz,1H),3.61(dd,J=17.4,11...

Embodiment 3

[0043]

[0044] N-p-Bromobenzylideneaniline (0.4mmol),[PdCl(allyl)] 2 (0.05mmol), chiral phosphoric acid and Molecular sieves (0.2g) were dissolved in chloroform (1.5mL), then adamantyl phenyldiazoacetate (0.8mmol) and enamine (0.8mmol) dissolved in chloroform (1.0ml) were added dropwise in 1 hour Into the reaction system, the reaction system is at -20 ~ 0 ° C, after the dropwise addition is completed, stir for 10 minutes, and remove the solvent under reduced pressure to obtain a crude product, the structure of which is shown in formula (2-3). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:80~1:40) to obtain a pure product. Yield 69%, dr=95:5, ee=88%. nuclear magnetic resonance 1 HNMR, 13 CNMR spectrum such as image 3 as shown, 1 HNMR (400MHz, CDCl 3 )δ7.75–7.66(m,2H),7.64–7.56(m,2H),7.48(dd,J=10.5,4.3Hz,1H),7.39–7.29(m,7H),7.09-7.02(m, 1H), 6.68(t, J=7.3Hz, 1H), 6.41(d, J=7.8Hz, 1H), 4.88(s, 1H), 4.62(dd, J=11.4, 2.2Hz, ...

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Abstract

The invention discloses a synthesis method of an optically pure alpha-amino-delta-oxopentanoate derivative. The optically pure alpha-amino-delta-oxopentanoate derivative is prepared by carrying out one-step reaction at the temperature of 20 DEGC below zero to 0 DEGC by taking a diazo compound, an imine and an enamine as raw materials, allyl palladium chloride and chiral phosphoric acid as catalysts, an organic solvent as a solvent and a 0.4nm molecular sieve as a water-absorbing agent. The synthesis method of the optically pure alpha-amino-delta-oxopentanoate derivative has the advantages of efficient atom economy, high selectivity and small use amount of catalysts and is easy and safe to operate. The synthesized optically pure alpha-amino-delta-oxopentanoate derivative can function as an important organic synthetic intermediate and an important pharmaceutical intermediate.

Description

technical field [0001] The invention belongs to the fields of synthetic medicine and chemical industry, and mainly relates to an optically active α-amino-δ-oxopentanoic acid ester derivative and its synthesis method and application. Background technique [0002] Optically active α-amino-δ-oxopentanoic acid ester derivatives have good antibacterial activity, are an important skeleton structure for building natural products and drugs, and are important intermediates in organic synthesis and drug synthesis. Optically active α-amino-δ-oxopentanoate derivatives can also be used in the synthesis of numerous antitumor drugs, anti-obesity, antibiotics and antifungal drugs, etc. Due to low substrate activity, lack of catalyst, and difficult control of selectivity, the existing synthetic methods have the disadvantages of high cost, low yield, and cumbersome operation. Contents of the invention [0003] The present invention overcomes the shortcomings existing in the prior art synth...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/36C07C227/32C07C255/58C07C255/30C07D295/145A61P3/04
Inventor 胡文浩张丹周俊康正辉
Owner 广东和博制药有限公司
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