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Method for catalytically asymmetrically synthesizing chiral beta-aminoketone derivative

An aminoketone and asymmetric technology, which is applied in the field of catalytic asymmetric synthesis of chiral β-aminoketone derivatives, can solve the problems of narrow application range of substrates and nucleophiles, expensive metal catalysts, and high requirements for substrate structures. , achieve good application prospects and social value, reduce reaction cost, high yield and high enantioselectivity

Active Publication Date: 2019-05-14
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most methods use metal catalysts, which are expensive and require high substrate structure, which greatly limits their practicality.
In the existing reports of organocatalytic asymmetric synthesis of chiral β-amino ketone derivatives, the scope of application of substrates and nucleophiles is narrow, and the reactivity is general

Method used

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  • Method for catalytically asymmetrically synthesizing chiral beta-aminoketone derivative
  • Method for catalytically asymmetrically synthesizing chiral beta-aminoketone derivative
  • Method for catalytically asymmetrically synthesizing chiral beta-aminoketone derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: (R)-3,3'-bis(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-6,6'-bis(trifluoromethyl) -[1,1'-Binaphthyl]-2,4-2'-diol preparation

[0026] N 2 Under protection, sequentially add (R)-2,2'-bis(methoxymethyl ether)-6,6'-bis(trifluoromethyl)-1,1'-bibi in a 100mL two-necked bottle Naphthalene (2.96 mmol, 1.51 g) and THF (24 mL). The temperature of the system was cooled to 0°C, a 2.5M n-butyllithium n-hexane solution (8.88 mmol, 3.6 mL) was added, and the mixture was stirred at this temperature for 2 hours. The temperature of the system was then cooled to -78°C, and perfluorotoluene (20.72 mmol, 2.9 mL) was added dropwise. After the dropping, the system was slowly raised to room temperature and stirred at room temperature for 12 hours. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) in an ice bath, and then extracted three times with ether (3×10 mL). The combined extract phase was washed with brin...

Embodiment 2

[0027] Example 2: (S,E)-2-(5-oxo-1,5-diphenylpentene-1-en-3-yl)isoindole-1,3-dione (1a) preparation

[0028] N 2 Under protection, add additives, β-phthalimide propylene ketone substrate (0.1 mmol, 1.0 equiv), and chiral binaphthol catalyst (L3 or L6) (0.05 to 0.5 equiv) in a 25 mL reaction flask. ), potassium styryl trifluoroborate (1 to 5 equiv) and anhydrous trifluorotoluene (1 mL), the reaction system is sealed and heated (reaction temperature 25 to 90°C). The reaction was monitored by TLC analysis until the reaction was completed, the reaction system was filtered through celite and concentrated, and the concentrated crude product obtained was separated and purified by column chromatography to obtain the target compound 1a.

[0029] The characterization data of the target compound 1a are as follows:

[0030] White solid, [α] D 20 = +29.6(c1.0,CHCl 3 ). MP: 100.0-103.9°C. 1 H NMR(600MHz, CDCl 3 )δ7.96(d,J=7.8Hz,2H), 7.83(dd,J=5.1,3Hz,2H), 7.69(dd,J=5.4,3Hz,2H), 7.55(t,J=7.8Hz, ...

Embodiment 3

[0037] Example 3: Binaphthol-catalyzed reaction method expansion of β-phthalimide acrylone and aromatic substituted potassium trifluoroborate

[0038] N 2 Under protection, add additives, β-phthalimide propylene ketone (0.1 mmol, 1.0 equiv), chiral binaphthol catalyst L6 (0.01 mmol, 0.1 equiv), aryl or Heterocyclic aryl substituted styryl trifluoroborate potassium salt (0.2 mmol, 2 equiv) and anhydrous trifluorotoluene (2 mL). The reaction system was sealed and heated to 60°C. After monitoring the reaction by TLC until the reaction is complete, the reaction system is filtered through celite and concentrated, and the concentrated crude product is separated and purified by column chromatography to obtain the corresponding target compound 1a-1l. The reaction formula of the reaction process is as follows:

[0039]

[0040] In Example 3, the reaction conditions were changed as follows: the type and amount of additives, the type and reaction time of styryl trifluoroborate potassium salt...

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Abstract

The invention discloses a method for catalytically asymmetrically synthesizing a chiral beta-aminoketone derivative. The method includes taking a chiral binaphthol derivative shown in a formula (3) asa catalyst; and in the presence of an organic solvent and an additive, preforming, by potassium trifluoroborate shown in a formula (2), an asymmetric 1,4-addition reaction on a beta-phthalimide acrylone compound shown in a formula (1) to generate the beta-aminoketone derivative containing one chiral center shown in a formula (4), wherein the reaction formula is shown in the specification. The invention discloses a new chiral catalyst of a polyfluoroaphthol skeleton, adopts nonmetallic catalysis, avoids the use of metal catalysts from the source, and reduces the reaction cost. The yield and enantioselectivity of the target product are high, the reaction conditions are simple and mild, and a method for preparing multiple chiral beta-aminoketone derivatives is provided, so that the method has better application prospect and social value.

Description

Technical field [0001] The present invention relates to a method for catalyzing asymmetric synthesis of chiral β-amino ketone derivatives. Background technique [0002] Chiral β-amino ketone derivatives are a class of chemical substances with important activities, which have important uses in the fields of medicine, pesticides and dyes. Such structures are also widely found in natural biologically active peptide chains, such as the cyclic peptide structure of the protein phosphatase inhibitor Motuporin, the side chain of the anticancer drug Taxol and the immune response modifier Bestatin. The synthesis methods of chiral β-aminoketone derivatives reported in the literature are limited, so the development of an efficient and green method to prepare chiral β-aminoketones has greater challenges and good application prospects. [0003] In 1991, the Noyori group passed Ru(O 2 CCH 3 ) 2 And (R)-BINAP realizes the asymmetric hydrogenation of N-acyl-β-(amino)acrylate, and provides> 99% ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48C07D409/06C07D405/06C07D403/06C07D405/14B01J31/02
Inventor 毛斌童梦楠王建飞柏详陈祉威朱兴一陈志卫俞传明
Owner ZHEJIANG UNIV OF TECH
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