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Method for synthesizing optically active derivative of omega - aryl - (2S) - N - boc -alpha amino acid

A tert-butoxycarbonyl and optically active technology, which is applied in the field of synthesis of ω-aryl--N-tert-butoxycarbonyl-α-amino acid derivatives, can solve the problems of unsuitable industrial production, long synthesis time, short reaction time, etc. problems, to achieve the effect of reasonable reaction process selection and shortened synthesis time

Active Publication Date: 2012-01-18
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved in the present invention is to adopt a brand-new optically active ω-aryl-(S)-N-tert-butoxycarbonyl-α- The synthesis method of amino acid derivatives solves the problem that the synthesis time of ω-aryl-(S)-N-tert-butoxycarbonyl-α-amino acid derivatives in the existing literature process is long and cannot be industrialized; The use of expensive palladium reagent in the medium reduces the synthesis cost

Method used

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  • Method for synthesizing optically active derivative of omega - aryl - (2S) - N - boc -alpha amino acid
  • Method for synthesizing optically active derivative of omega - aryl - (2S) - N - boc -alpha amino acid
  • Method for synthesizing optically active derivative of omega - aryl - (2S) - N - boc -alpha amino acid

Examples

Experimental program
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Effect test

Embodiment 1

[0021] 6-Phenyl-(S)-2-N-tert-butoxycarbonyl-aminocaproic acid ethyl ester

[0022] The first step: the synthesis of 6-phenyl-5-ketone-(S)-N-tert-butoxycarbonyl-α-aminocaproic acid ethyl ester:

[0023]

[0024] First prepare the Grignard reagent: equip a three-neck flask with a dropping funnel and an internal thermometer, put magnesium (0.48g, 20mmol) and dried tetrahydrofuran (30mL), replace it with a nitrogen atmosphere, and prepare the benzyl Bromine (3.4 g, 20 mmol) in dry tetrahydrofuran (10 mL). Initially drop 2 mL of this solution to initiate the reaction, then slowly drop the remainder, maintaining the internal temperature at 60-70°C. N-tert-butoxycarbonylpyroglutamic acid ethyl ester (4.6g, 18mmol) in dry tetrahydrofuran solution (100mL) was cooled to between minus 50°C and minus 40°C with dry ice, acetone and water system, and dropped into the form of benzyl bromide Reagent (40mL, 20mmol) was added dropwise, and the reaction solution was stirred at this tempe...

Embodiment 2

[0029] Synthesis of 7-phenyl-(S)-N-tert-butoxycarbonyl-α-aminoheptanoic acid ethyl ester

[0030] The first step: the synthesis of 7-phenyl-5-ketone-(S)-N-tert-butoxycarbonyl-α-aminoheptanoic acid ethyl ester:

[0031]

[0032] First prepare the Grignard reagent: a three-necked flask equipped with a dropping funnel and an internal thermometer, put magnesium (0.48g, 20mmol) and dried tetrahydrofuran (30mL), replace the inside with a nitrogen atmosphere, and prepare the bromine in the dropping funnel. Ethylbenzene (3.7g, 20mmol) in dry tetrahydrofuran (10mL). Initially drop 2mL of this solution to initiate the reaction, then slowly drop the rest, maintaining the internal temperature at 60-70°C. A dry tetrahydrofuran solution (100 mL) of ethyl N-tert-butoxycarbonyl pyroglutamate (4.6 g, 18 mmol) was cooled to between minus 50°C and minus 40°C with dry ice, acetone and water, and the above-mentioned ethyl bromide was added dropwise Benzene Grignard reagent (40 mL, 20 mmol)...

Embodiment 3

[0037] Synthesis of 8-phenyl-(S)-N-tert-butoxycarbonyl-α-aminocaprylic acid ethyl ester

[0038] The first step: the synthesis of 8-phenyl-5-ketone-(S)-N-tert-butoxycarbonyl-α-aminocaprylic acid ethyl ester:

[0039]

[0040] First prepare the Grignard reagent: a three-necked flask equipped with a dropping funnel and an internal thermometer, put magnesium (0.48g, 20mmol) and dried tetrahydrofuran (30mL), replace the inside with a nitrogen atmosphere, and prepare the bromine in the dropping funnel. Propylbenzene (4.0 g, 20 mmol) in dry tetrahydrofuran (10 mL). Initially drop 2 mL of this solution to initiate the reaction, then slowly drop the rest, maintaining the internal temperature at 60-70°C. N-tert-butoxycarbonyl pyroglutamic acid ethyl ester (4.6g, 18mmol) in dry tetrahydrofuran (100mL) was cooled to between minus 50°C and minus 40°C with dry ice, acetone and water, and the above-mentioned Grignard reagent was added dropwise (40mL, 20mmol), the dropwise addition w...

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Abstract

This invention relates to a process for synthesizing optically active omega-aryl-(2S)-N-tert-butyloxycarbonyl-alpha-amino acid derivative, more specifically, omega-aryl-(2S)-N-tert-butyloxycarbonyl-alpha-amino acid ester. The process comprises: preparing omega-arylalkyl bromide into Grignard reagent, reacting with ethyl N-tert-butyloxycarbonyl-L-pyroglutamate to obtain omega-aryl-5-one-(S)-N-tert-butyloxycarbonyl-alpha-amino acid ethyl ester, and reducing to obtain omega-aryl-(2S)-N-tert-butyloxycarbonyl-alpha-amino acid ethyl ester. The process has such advantages as reasonable reaction process, abundant raw materials, short synthesis time, and no need for expensive enzyme reagents, and is suitable for mass production.

Description

Technical field: [0001] The present invention relates to the synthesis method of optically active ω-aryl-(2S)-N-tert-butoxycarbonyl-α-amino acid derivatives, in particular to ω-aryl-(2S)-N-tert-butoxycarbonyl- Synthetic method of α-amino acid ester. Background technique: [0002] Derivatives of aromatic amino acids play an exciting role in biological neuron cells. ω-Phenyl-(S)-N-tert-butoxycarbonyl-α-amino acid belongs to aromatic amino acid, and this series of amino acids have good biological activity, such as 5-phenyl-(S)-2-N -tert-butoxycarbonyl-amino acid, this series of structural amino acids all show a strong inhibitory effect on Cathepsin K, which is a biological enzyme on osteoclasts and plays a vital role in bone resorption. [0003] ω-aromatic amino acids are not only important pharmaceutical intermediates, but also have many applications in drug molecules, and ω-aromatic amino acids have other biochemical properties, which play an important role in regulating th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/36C07C227/18
Inventor 张治柳丁传勇马汝建陈曙辉李革
Owner 上海药明康德新药开发有限公司
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