Method for synthesizing optically active alpha-hydroxyl-beta-phenmethyl-beta-amino acid derivative

Abstract

The invention relates to a method for synthesizing optically active alpha-hydroxyl-beta-phenmethyl-beta-amino acid derivative, relating to a process for synthesizing the alpha-hydroxyl-beta-phenmethyl-beta-amino acid derivative. The method adopts ethyl diazoacetate, alcohol and styrylamine or benzyl imine as raw materials, chiral phosphoric acid and rhodium carboxylic acid or chiral phosphoric acid and copper (I) metal complex as catalyst, organic solvent as solvent, and 4molecular sieve, or 3 molecular sieve, or 5 molecular sieve as activating agent; and after one step of reaction, the dissolvent is removed to obtain a crude product. The crude product is processed by the operation of column chromatography by a solution in which the volume ratio of ethyl acetate to sherwood oil ranges from 1:50 to 1:20 to obtain the optically active alpha-hydroxyl-beta-phenmethyl-beta-amino acid derivative. The mol ratio of the components is as follows: diazocompound to alcohol to styrylamine or benzyl imine to chiral phosphoric acid to rhodium carboxylic acid or copper(I) metal complex is equal to 1.1:1:1.2:0.02:0.02; and the proportion of the activating agent is 2 to 5g per mmol diazocompound. The method has the advantages of high atom economy, selectivity and yield, and easy and safe operation.

Description

technical field

[0001] The present invention relates to a method for synthesizing optically active α-hydroxy-β-benzyl-β-amino acid derivatives. The invention belongs to the technical field of pharmaceutical synthesis chemistry. Background technique

[0002] Optically active α-hydroxy-β-benzyl-β-amino acid derivatives are a class of important skeleton structures of special medicinal compounds, among which the side chain skeleton of the antineoplastic peptidase inhibitor Bestatin (Ubenimex) It is such a structure. The existing techniques for synthesizing optically active α-hydroxy-β-benzyl-β-amino acid derivatives are all multi-step reactions, for example: ring opening by epoxy compounds (Tetrahedron Letters, 2003, 44, 6999-7002), or Use natural chiral sources, such as amino acids or sugars as raw materials for synthesis (Biosci.Biotechnol.Biochem., 1999, 65, 1304-1307; Synthesis, 2003, 6, 829-836), or participate in the control of chirality through chiral auxiliaries Synth...

Examples

Embodiment 1

[0035] With N-tert-butoxycarbonyl styrylamine (0.30mmol), anthracenylmethanol (0.25mmol), rhodium acetate (0.005mmol), chiral phosphoric acid catalyst A (Ar=9-phenanthrenyl) shown in the structural formula on the right )(0.005mmol), Molecular sieves (0.1g) dissolved in CH 2 Cl 2 (1.5ml) to form the reaction system. Ethyl diazoacetate (0.275 mmol) was dissolved in 1 mL CH 2 Cl 2 A solution was formed in , and the solution was added dropwise to the reaction system within 1 hour with an auto-sampling pump at room temperature. After the sample injection, stir at room temperature for 1 hour, remove the solvent, and obtain the crude product; then add saturated NaHCO dropwise to the reaction system 3 Aqueous solution (0.1 ml) was used to quench the reaction. The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:50~1:20) to obtain a pure product o...

Embodiment 2

[0038] N-tert-butoxycarbonyl benzyl imine (0.30mmol), anthracenylmethanol (0.25mmol), rhodium acetate (0.005mmol), the same chiral phosphoric acid A as in Example 1: Ar=9-phenanthrenyl (0.005 mmol), Molecular sieves (0.1g) dissolved in CH 2 Cl 2 (1.5ml) to form the reaction system. Ethyl diazoacetate (0.275mmol) was dissolved in 1mL CH 2 Cl 2 A solution was formed in , and the solution was added dropwise to the reaction system within 1 hour with an auto-sampling pump at room temperature. After the sample injection, stir at room temperature for 1 hour, remove the solvent, and obtain the crude product; then add saturated NaHCO dropwise to the reaction system 3 Aqueous solution (0.1 ml) was used to quench the reaction. The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:50~1:20) to obtain a pure product of optically active α-hydroxy-β-benzy...

Embodiment 3

[0040] N-benzyloxycarbonyl styrylamine (0.30mmol), anthracenylmethanol (0.25mmol), rhodium acetate (0.005mmol), the same chiral phosphoric acid A as in Example 1: Ar=9-phenanthrenyl (0.005mmol ), Molecular sieve (0.1g) was dissolved in toluene (1.5ml) to form a reaction system. Methyl diazoacetate (0.275 mmol) was dissolved in 1 mL of toluene to form a solution, and the solution was added dropwise to the reaction system within 1 hour at room temperature with an automatic sample pump. After the sample injection, stir at room temperature for 1 hour, remove the solvent, and obtain the crude product; then add saturated NaHCO dropwise to the reaction system 3Aqueous solution (0.1 ml) was used to quench the reaction. The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:50~1:20) to obtain a pure product of optically active α-hydroxy-β-benzyl-β-amino...

technical field

[0001] The present invention relates to a method for synthesizing optically active α-hydroxy-β-benzyl-β-amino acid derivatives. The invention belongs to the technical field of pharmaceutical synthesis chemistry. Background technique

[0002] Optically active α-hydroxy-β-benzyl-β-amino acid derivatives are a class of important skeleton structures of special medicinal compounds, among which the side chain skeleton of the antineoplastic peptidase inhibitor Bestatin (Ubenimex) It is such a structure. The existing techniques for synthesizing optically active α-hydroxy-β-benzyl-β-amino acid derivatives are all multi-step reactions, for example: ring opening by epoxy compounds (Tetrahedron Letters, 2003, 44, 6999-7002), or Use natural chiral sources, such as amino acids or sugars as raw materials for synthesis (Biosci.Biotechnol.Biochem., 1999, 65, 1304-1307; Synthesis, 2003, 6, 829-836), or participate in the control of chirality through chiral auxiliaries Synth...

Examples

Embodiment 1

[0035] With N-tert-butoxycarbonyl styrylamine (0.30mmol), anthracenylmethanol (0.25mmol), rhodium acetate (0.005mmol), chiral phosphoric acid catalyst A (Ar=9-phenanthrenyl) shown in the structural formula on the right )(0.005mmol), Molecular sieves (0.1g) dissolved in CH 2 Cl 2 (1.5ml) to form the reaction system. Ethyl diazoacetate (0.275 mmol) was dissolved in 1 mL CH 2 Cl 2 A solution was formed in , and the solution was added dropwise to the reaction system within 1 hour with an auto-sampling pump at room temperature. After the sample injection, stir at room temperature for 1 hour, remove the solvent, and obtain the crude product; then add saturated NaHCO dropwise to the reaction system 3 Aqueous solution (0.1 ml) was used to quench the reaction. The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:50~1:20) to obtain a pure product o...

Embodiment 2

[0038] N-tert-butoxycarbonyl benzyl imine (0.30mmol), anthracenylmethanol (0.25mmol), rhodium acetate (0.005mmol), the same chiral phosphoric acid A as in Example 1: Ar=9-phenanthrenyl (0.005 mmol), Molecular sieves (0.1g) dissolved in CH 2 Cl 2 (1.5ml) to form the reaction system. Ethyl diazoacetate (0.275mmol) was dissolved in 1mL CH 2 Cl 2 A solution was formed in , and the solution was added dropwise to the reaction system within 1 hour with an auto-sampling pump at room temperature. After the sample injection, stir at room temperature for 1 hour, remove the solvent, and obtain the crude product; then add saturated NaHCO dropwise to the reaction system 3 Aqueous solution (0.1 ml) was used to quench the reaction. The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:50~1:20) to obtain a pure product of optically active α-hydroxy-β-benzy...

Embodiment 3

[0040] N-benzyloxycarbonyl styrylamine (0.30mmol), anthracenylmethanol (0.25mmol), rhodium acetate (0.005mmol), the same chiral phosphoric acid A as in Example 1: Ar=9-phenanthrenyl (0.005mmol ), Molecular sieve (0.1g) was dissolved in toluene (1.5ml) to form a reaction system. Methyl diazoacetate (0.275 mmol) was dissolved in 1 mL of toluene to form a solution, and the solution was added dropwise to the reaction system within 1 hour at room temperature with an automatic sample pump. After the sample injection, stir at room temperature for 1 hour, remove the solvent, and obtain the crude product; then add saturated NaHCO dropwise to the reaction system 3Aqueous solution (0.1 ml) was used to quench the reaction. The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:50~1:20) to obtain a pure product of optically active α-hydroxy-β-benzyl-β-amino...

Images