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Synthesis of alpha-hydroxyl-beta-aminophenol with optical activity

A technology of optical activity and synthetic method, which is applied in organic chemical methods, chemical instruments and methods, organic chemistry, etc., can solve the problems of cumbersome operation, high cost, and low yield, and achieve simple and safe operation, high selectivity, high Yield effect

Inactive Publication Date: 2009-04-08
EAST CHINA NORMAL UNIVERSITY
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  • Abstract
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  • Claims
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Problems solved by technology

The traditional chemical synthesis method for the preparation of optically active α-hydroxy-β-amino acids is a multi-step synthesis method (with (1R)-8-phenylmenthol glyoxylate and 1-nitro-2-phenylethanediol alkane as the starting material, or (2S, 3R)-2,3-epoxy-4-phenylbutyric acid methyl ester as the multi-step reaction of the starting material), or natural product separation method (J.Org.Chem ., 2004, 69, 2844-2850; Tetrahedron Lett., 2003, 44, 6999-7002; Tetrahedron Lett., 2003, 44, 8685-8687), these methods for preparing optically active α-hydroxyl-β-amino acids are all It has the disadvantages of high cost, low yield and cumbersome operation

Method used

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  • Synthesis of alpha-hydroxyl-beta-aminophenol with optical activity
  • Synthesis of alpha-hydroxyl-beta-aminophenol with optical activity
  • Synthesis of alpha-hydroxyl-beta-aminophenol with optical activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Dissolve p-methoxyaniline (0.25mmol), benzaldehyde (0.3mmol), and chiral phosphoric acid catalyst A (Ar=9-phenanthrenyl) (0.005mmol) shown in the structural formula on the right in CH 2 Cl 2 (1.5ml), then add MgSO 4 (0.1g) and Molecular sieve (0.1g) forms reaction system, stirs at room temperature 12 hours, after that Rh 2 (OAc) 4 (0.005mmol), anthracenylmethanol (0.25mmol) was added to the reaction system, cooled to -20°C, and methyl p-methoxyphenyldiazoacetate (0.275mmol) was dissolved in 1mL CH 2 Cl 2 To form a solution in CH 2 Cl 2 The solution was added dropwise to the reaction system within 1 hour. At the end of the injection, stir at -20°C for 3 hours, 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=1:5...

Embodiment 2

[0040] Dissolve p-methoxyaniline (0.25mmol), p-bromobenzaldehyde (0.3mmol), and the same chiral phosphoric acid A as in Example 1: Ar=9-phenanthrenyl (0.005mmol) in chloroform (1.5ml ), then add solid MgSO 4 (0.1g) and Molecular sieves (0.1 g) formed a reaction system, stirred at room temperature for 12 hours, then Cu(OTf) (0.005 mmol) and anthracenylmethanol (0.25 mmol) were added to the reaction system and cooled to 20°C. Methyl-p-methoxyphenyldiazoacetate (0.275 mmol) was dissolved in 1 mL of chloroform to form a solution, and the solution was added dropwise to the reaction system within 1 hour using an auto-sampling pump. At the end of the injection, stir at 20°C for 3 hours, 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 et...

Embodiment 3

[0042] P-methoxyaniline (0.25mmol), o-bromobenzaldehyde (0.3mmol), and the same chiral phosphoric acid A as in Example 1: Ar=9-phenanthrenyl (0.005mmol) were dissolved in toluene (1.5ml), Add solid MgSO 4 (0.1g) and Molecular sieve (0.1g) forms reaction system, stirs at room temperature 12 hours, Rh 2 (OAc) 4 (0.005mmol), anthracenylmethanol (0.25mmol) were added to the reaction system and cooled to 10°C. Methyl p-methoxyphenyldiazoacetate (0.275 mmol) was dissolved in 1 mL of toluene, and this solution was added dropwise into the reaction system within 1 hour using an auto-sampling pump. At the end of the injection, stir at 10°C for 3 hours, 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 pro...

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Abstract

The invention relates to a synthesis method of alpha-hydroxy-beta-amino acid. The method comprises the flowing steps: using four components of diazo compounds, alcohol, amine and aldehyde as raw materials; using chiral phosphoric acid and rhodium carboxylate, or chiral phosphoric acid and cuprous metal complex as catalysts; using an organic solvent as a solvent; using 4 molecular sieve and MgSO4 as a water absorber; after one-step reaction, removing the solvent to obtain a crude product; carrying out column chromatography for the crude product by a solution in which the volume ratio of ethyl acetate to petroleum ether is between 1 to 50 and 1 to 20, so as to obtain a pure product of the alpha-hydroxy-beta-amino acid with optical activity, wherein the molar ratio of the feeding amount of diazo compounds to alcohol to amine to aldehyde to chiral phosphoric acid to rhodium carboxylate or cuprous metal complex is 1.1 to 1 to 1 to 1.2 to 0.02 to 4; and the feeding amounts of the 4 molecular sieve and the MgSO4 is 2 to 5 g / mmol diazo compounds. The synthesis method has the advantages of high atom economy, high selectivity, high yield, and simple and safe operation. The alpha-hydroxy-beta-amino acid with optical activity is widely applied to the field of pharmaceutical chemicals.

Description

technical field [0001] The invention relates to a method for synthesizing an optically active α-hydroxy-β-amino acid. It belongs to the technical field of pharmaceutical synthesis and chemical engineering. Background technique [0002] The optically active α-hydroxy-β-amino acid is an important skeleton structure for the construction of natural products, and there are such skeleton structures in the peptidase inhibitors amastatin (almetadine) and bestatin (ubenimex) , It can also be used to synthesize many antitumor drugs, antibiotics, and antifungal drugs. The traditional chemical synthesis method for the preparation of optically active α-hydroxy-β-amino acids is a multi-step synthesis method (with (1R)-8-phenylmenthol glyoxylate and 1-nitro-2-phenylethane alkane as the starting material, or (2S, 3R)-2,3-epoxy-4-phenylbutyric acid methyl ester as the multi-step reaction of the starting material), or natural product separation method (J.Org.Chem ., 2004, 69, 2844-2850; Te...

Claims

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Application Information

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IPC IPC(8): C07C227/18C07C227/32C07C229/34B01J31/24C07B53/00
Inventor 胡文浩徐新芳周静杨琍苹
Owner EAST CHINA NORMAL UNIVERSITY
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