Synthesis method of chiral gamma-amine methylene-gamma-butylene lactone compound

A technology of aminomethylene and butenolactone, which is applied in the field of organic synthesis, can solve the problems of unfavorable development of new drugs and other products, complex raw material structure, heavy metal residues, etc., and achieve a wide range of substrates, simple steps, and no heavy metal residues Effect

Inactive Publication Date: 2018-11-30
JILIN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Through the analysis and summary of the existing synthesis methods, the current methods generally have disadvantages such as complex raw material structures and cumbersome steps, while the use of heavy metals such as silver and copper causes high costs and is prone to heavy metal residues, which is harmful to the development of new drugs and other products. unfavorable

Method used

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  • Synthesis method of chiral gamma-amine methylene-gamma-butylene lactone compound
  • Synthesis method of chiral gamma-amine methylene-gamma-butylene lactone compound
  • Synthesis method of chiral gamma-amine methylene-gamma-butylene lactone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: Synthesis of (S)-5-((R)-phenyl(phenylamino)methyl)furan-2(5H)-one

[0025]

[0026] Dissolve 18g (0.1mol) of benzaldehyde aniline, 6g (5mmol) of (R,R)-phosphorimidic acid and 4g of hydroxypropyl-β-cyclodextrin in 1L of anhydrous toluene, stir for 15min, and cool down to -40°C, add 48 g (0.3 mol) of 2-(trimethylsilyloxy) furan under nitrogen protection, react for 10 hours and then perform silica gel column chromatography (eluent ethyl acetate:petroleum ether volume ratio=1:2) The product was purified to obtain 25.7 g of a colorless oily liquid with a yield of 97%, 80% ee, 93:7dr. Chiral OJ-H column, n-hexane:ethanol=80:20, flow rate 1.0mL / min, wavelength λ=254nm, retention time: t(primary)=27.865min, t(secondary)=32.746min; 1 H NMR (400MHz, DMSO-d 6 )δ7.81(d, J=8.0Hz,1H), 7.43(d,J=4.0Hz,2H), 7.30(t,J=8.0Hz,2H), 7.24–7.21(m,1H), 7.02( t,J=8.0Hz,2H), 6.68(d,J=8.0Hz,2H), 6.53(t,J=8.0Hz,1H), 6.40(d,J=8.0Hz,1H), 6.17–6.15( m,1H), 5.50(d,J=4.0Hz,1H), 4.90–4.8...

Embodiment 2

[0027] Example 2: Synthesis of (S)-5-((R)-phenyl(phenylamino)methyl)furan-2(5H)-one

[0028] Dissolve 18g (0.1mol) of benzaldehyde aniline, 6.7g (8mmol) of (R,R)-phosphorimidic acid and 4g of hydroxypropyl-β-cyclodextrin in 1L of anhydrous toluene, and stir for 15 minutes. Cool down to -40°C, add 48 g (0.3 mol) of 2-(trimethylsiloxy)furan under nitrogen protection, react for 10 hours and then perform silica gel column chromatography (eluent ethyl acetate:petroleum ether volume ratio=1: 2) The product was purified to obtain a colorless oily liquid (23.1 g, 91% yield, 72%ee, 91:9dr). The product structure is the same as in Example 1.

Embodiment 3

[0029] Example 3: Synthesis of (S)-5-((R)-phenyl(phenylamino)methyl)furan-2(5H)-one

[0030] Dissolve 18g (0.1mol) of benzaldehyde aniline, 3g (2.5mmol) of (R,R)-phosphorimidic acid and 4g of hydroxypropyl-β-cyclodextrin in 1L of anhydrous toluene, and stir for 15 minutes. Cool down to -40°C, add 48 g (0.3 mol) of 2-(trimethylsiloxy)furan under nitrogen protection, react for 10 hours and then perform silica gel column chromatography (eluent ethyl acetate:petroleum ether volume ratio=1: 2) The product was purified to obtain a colorless oily liquid (23.6 g, yield 92%, 75% ee, 89:11dr). The product structure is the same as in Example 1.

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Abstract

The invention discloses a synthesis method of chiral gamma-amine methylene-gamma-butylene lactone compound, and belongs to the technical field of organic synthesis. According to the synthesis method,Schiff base, a chiral organic small molecular catalyst, and an auxiliary agent are dissolved in anhydrous toluene, an obtained mixture is stirred for 10 to 20min; under nitrogen protection, 2-(trimethyl siloxy)furan is added into an obtained reaction system, an obtained reaction mixture is subjected to column chromatography purification so as to obtain the chiral gamma-amine methylene-gamma-butylene lactone compound. In the synthesis method, Schiff base and 2-(trimethyl siloxy)furan are subjected to asymmetric vinylogy Mannich, product yield is 90% or higher, the highest enantioselectivity is97%, the highest diastereoselectivity is 93:7, and the synthesis method is capable of realizing high efficiency of synthesis of chiral gamma-butylene lactone containing gamma site amine methylene.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for catalytically synthesizing chiral γ-amine methylene-γ-butene lactone compounds by using a chiral organic small molecule catalyst. Background technique [0002] As the core skeleton structure of many natural products, chiral γ-butenolactone and its derivatives have important biological activities and are widely used in the field of new drug development. The synthesis of such compounds has been reported, mainly through multi-step reactions such as metal salt-catalyzed esterification and cyclization. For example, Ma Shengming and Wu Shulin described a kind of salt produced by 2,3-dienoic acid and chiral organic base in the mixed solvent of water-organic solvent, 20-80°C, and copper halide catalysis in the patent CN1102587C A cyclization reaction occurs to obtain optically active β-halogenated-γ-butenolides; Aso Shengming, Duan Dehui and others des...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/58
CPCC07D307/58
Inventor 张广良周天云张锁秦高纪罡刘国峰
Owner JILIN UNIV
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