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A three-membered ring derivative containing β-amino ester and its synthesis method and application

A kind of synthetic method, technology of three-membered ring

Inactive Publication Date: 2016-08-17
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in view of the important biological uses of three-membered ring derivatives, three-membered ring derivatives with structural diversity are in great demand, and the above methods are far from meeting this demand

Method used

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  • A three-membered ring derivative containing β-amino ester and its synthesis method and application
  • A three-membered ring derivative containing β-amino ester and its synthesis method and application
  • A three-membered ring derivative containing β-amino ester and its synthesis method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078]

[0079] Benzyl alcohol (0.2mmol), imine (0.2mmol), rhodium acetate (0.002mmol), The mixture of molecular sieves (100mg) and (R)-TIRP-BINOL (0.01mmol) was dissolved in 1mL of dichloromethane solvent to prepare mixed solution A, which was stirred at -40°C for 10 minutes. Then, benzyl cyclopropyldiazoacetate (0.2 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at -40°C within 1 hour. After stirring for 3 hours, the reaction mixture was purified by column chromatography to obtain a pure product whose structure was shown in formula (4a), which was (2R, 3S)-2-cyclopropyl-2-benzyloxy-3-(4 -Benzyl-methoxyphenyl)amino-3-phenylpropanoate in 30% yield, with a dr value equal to 98:2 and an ee value equal to 98%. of the product 1 H NMR schematic as figure 1 As shown, its 13 C NMR schematic as figure 2 As shown, the liquid phase diagram of the racemic product is shown in image 3...

Embodiment 2

[0082]

[0083] Benzyl alcohol (0.2mmol), imine (0.2mmol), rhodium acetate (0.002mmol), The mixture of molecular sieves (100mg) and (R)-TIRP-BINOL (0.01mmol) was dissolved in 1mL of dichloromethane solvent to prepare mixed solution A, which was stirred at -40°C for 10 minutes. Then, benzyl cyclopropyldiazoacetate (0.2 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at -40°C within 1 hour. After stirring for 3 hours, the reaction mixture was purified by column chromatography to obtain a pure product whose structure was shown in formula (4b), which was (2R, 3S)-2-cyclopropyl-2-benzyloxy-3-(4 -Benzyl methoxyphenyl)amino-3-(4-chlorophenyl)propanoate in 30% yield, dr equal to 98:2, ee equal to 90%. of the product 1 H NMR schematic as Figure 5 As shown, its 13 C NMR schematic as Image 6 As shown, the liquid phase diagram of the racemic product is shown in Figure 7 As shown, the...

Embodiment 3

[0086]

[0087]Benzyl alcohol (0.2mmol), imine (0.2mmol), rhodium acetate (0.002mmol), The mixture of molecular sieves (100mg) and (R)-TIRP-BINOL (0.01mmol) was dissolved in 1mL of dichloromethane solvent to prepare mixed solution A, which was stirred at -40°C for 10 minutes. Then, benzyl cyclopropyldiazoacetate (0.2 mmol) was dissolved in 1.0 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at -40°C within 1 hour. After stirring for 3 hours, the reaction mixture was purified by column chromatography to obtain a pure product whose structure was shown in formula (4c), which was (2R, 3S)-2-cyclopropyl-2-benzyloxy-3-(4 -Benzyl methoxyphenyl)amino-3-(4-methylphenyl)propanoate in 33% yield, with a dr value equal to 98:2 and an ee value equal to 96%. of the product 1 H NMR schematic as Figure 9 As shown, its 13 C NMR schematic as Figure 10 As shown, the liquid phase diagram of the racemic product is shown i...

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Abstract

The invention relates to a ternary cyclobutane derivative containing beta-amino acid and a chemical synthesis method thereof. Cyclopropyl diazo compound, benzyl alcohol and imine are taken as raw materials, a 4A molecular sieve is taken as water absorbent, chirality BINOL phosphoric acid and rhodium acetate are taken as co-catalyst, organic solvent is taken as solvent, and the product is obtained through further reaction. The synthesis method disclosed by the invention has the advantages of high atom economy and high selectivity, besides the reaction condition is mild, and the operation is safe and simple. The prepared ternary cyclobutane derivative containing beta-amino acid disclosed by the invention is important chemical and medical intermediate, has bioactivity, and is applicable to preparation of antitumour drugs.

Description

technical field [0001] The invention relates to the field of synthetic medicine and chemical industry, and mainly relates to a rapid and highly selective three-membered ring derivative containing β-amino ester and its chemical synthesis method and application. Background technique [0002] A large number of literatures have reported that three-membered ring derivatives have biological activities such as antibacterial, antiviral, and enzyme inhibition in vivo. Therefore, the research on their synthesis methods has always been a hot topic in the field of natural heat product research and medicinal chemistry. The traditional method of synthesizing three-membered ring derivatives is generally through asymmetric cyclopropanation of alkenes, Simmons-Smith cyclopropanation (J.Org.Chem.2010,75,1244), cyclopropanation based on Michael addition (Tetrahedron, 2008,64,7041) and other methods to achieve. However, in view of the important biological uses of three-membered ring derivative...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/32C07C229/34A61P35/00A61P19/08
Inventor 胡文浩李明凤郑庆金伟峰刘顺英
Owner EAST CHINA NORMAL UNIV