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Method for synthesizing alpha-alkoxyl-beta-amino ester derivative

A synthesis method and technology of amino esters, applied in chemical instruments and methods, preparation of organic compounds, preparation of cyanide reaction, etc., can solve problems such as insufficient activation ability of chiral protonic acid, achieve short reaction time and wide source of raw materials , high efficiency effect

Inactive Publication Date: 2009-09-16
EAST CHINA NORMAL UNIV
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Problems solved by technology

Its disadvantage is that firstly amines, aldehydes and chiral protonic acids need to be prepared in the presence of magnesium sulfate and 4 Stir for 12 hours under the condition of a dehydrating agent such as molecular sieves, so that the aldehyde and amine react to form an imine, which shows that the activation ability of the chiral protonic acid is not strong enough. Secondly, the reaction should be carried out at a low temperature of -20°C. Thirdly, The aldehydes in the substrates used are aromatic aldehydes

Method used

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  • Method for synthesizing alpha-alkoxyl-beta-amino ester derivative
  • Method for synthesizing alpha-alkoxyl-beta-amino ester derivative

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Embodiment 1

[0028] Rhodium acetate (0.005mmol), o-aminophenol (0.5mmol), benzaldehyde (0.5mmol), titanium tetraisopropoxide (0.55mmol) and 4 Molecular sieves (250mg) were dissolved in 6ml CH 2 Cl 2 , stirred at room temperature for 2 to 3 hours to prepare a reaction system, dissolved methyl phenyldiazoacetate (1.0mmol) in 3ml CH 2 Cl 2 Inject the solution in the above reaction system slowly with the injection pump, and the time is controlled for 1 to 3 hours. After the injection is completed, the reaction is continued for 2 to 3 hours, and then saturated NaHCO is added dropwise to the reaction system. 3 The aqueous solution was used to quench the reaction, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, which was subjected to column chromatography (ethyl acetate:petroleum ether=1:50~1:20) to obtain a pure product. Yield 75%, dr value 79:21. Yellow oil; 1 H NMR (500MHz, CDCl 3 )δ (ppm) 7.25-7.35 (m, 5H), 7.10-7.13 (m, 3H), 6.97-6.9...

Embodiment 2

[0030] Rhodium acetate (0.005mmol), o-aminophenol (0.5mmol), p-chlorobenzaldehyde (0.5mmol), titanium tetraisopropoxide (0.55mmol) and 4 Molecular sieves (250mg) were dissolved in 6ml CH 2 Cl 2 , stirred at room temperature for 2 to 3 hours to prepare a reaction system, methyl phenyldiazoacetate (1.0mmol) was dissolved in 3ml CH 2 Cl 2 In the process, use the injection pump to slowly inject the solution into the above reaction system, and the time is controlled for 1 to 3 hours. After the injection is completed, continue to react for 2 to 3 hours, and then add saturated NaHCO to the reaction system dropwise. 3 The aqueous solution was used to quench the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:50~1:20) to obtain a pure product. The yield was 68%, and the dr value was 74:26. Yellow oil; 1 H NMR (300MHz, CDCl 3 )δ (ppm) 7.25-7.34 (m, 4H), 7....

Embodiment 3

[0032] Rhodium acetate (0.005mmol), o-aminophenol (0.5mmol), p-methoxybenzaldehyde (0.5mmol) and tetraethoxytitanium (0.55mmol)4 Molecular sieves (250mg) were dissolved in 6ml CH 2 Cl 2 , stirred at room temperature for 2 to 3 hours to prepare a reaction system, methyl phenyldiazoacetate (1.0mmol) was dissolved in 3ml CH 2 Cl 2 Inject the solution in the above reaction system slowly with the injection pump, and the time is controlled for 1 to 3 hours. After the injection is completed, the reaction is continued for 2 to 3 hours, and then saturated NaHCO is added dropwise to the reaction system. 3 The aqueous solution was used to quench the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:50~1:20) to obtain a pure product. The yield was 53%, and the dr value was 67:33. Yellow oil; 1 H NMR (300MHz, CDCl 3 )δ (ppm) 7.26-7.38 (m, 5H), 6.89-6.92 (d, 2H)...

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Abstract

The invention provides a method for synthesizing an alpha-alkoxyl-beta-amino ester derivative, and relates to a process for synthesizing an intermediate compound of an anticancer medicament. The method comprises the following steps: weighing rhodium acetate, o-aminophenol, aldehyde, alkoxytitanium and a diazo compound according to molar ratio of 0.01:1.0:1.0:1.1:2.0; dissolving the aldehyde, the o-aminophenol, the alkoxytitanium, the rhodium acetate and a dehydrating agent in an organic solvent; stirring the mixture for 2 to 3 hours at room temperature to prepare a reaction system; dissolving the diazo compound into the solvent consisting of the organic solvent by a sampling pump to be injected into the reaction system; dripping saturated NaHCO3 aqueous solution to perform a quenching reaction after 2 to 3 hours of reaction; removing the solvent by reduced pressure distillation to prepare a crude product of the alpha-alkoxyl-beta-amino ester derivative with two chiral centers; and carrying out column chromatography on the crude product by ethyl acetate and sherwood oil according to the ratio of 1:50-1:20 to obtain a pure product. The method has convenient and safe operation, short reaction time and high efficiency; the reaction condition at room temperature is mild; raw materials have wide resources; and the product can be widely applied to synthesis of intermediate compound of the anticancer medicament.

Description

technical field [0001] The invention discloses a method for synthesizing alpha-alkoxy-beta-amino ester derivatives, relates to a process for synthesizing anticancer drug intermediates, and belongs to the technical field of pharmaceutical chemicals. Background technique [0002] α-Alkoxy-β-amino ester derivatives are an important skeleton structure for building natural products, and there are similar structures in the peptidase inhibitors amastatin (almastatin) and bestatin (ubenimex) Skeleton structure, in addition, there is a similar structural skeleton in the anticancer drug paclitaxel. Paclitaxel is a substance extracted from Taxus plants with high anti-tumor activity. It has good curative effects on breast cancer, ovarian cancer, non-small cell lung cancer, etc., and is currently one of the main drugs for treating this type of disease. The methods for producing paclitaxel include natural extraction, plant cell culture and chemical synthesis. Among them, the parent ring...

Claims

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Application Information

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IPC IPC(8): C07C229/34C07C227/10
Inventor 胡文浩张娜张旭杨琍苹
Owner EAST CHINA NORMAL UNIV
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