Method for synthesizing optically active derivative of 5 - aryl - (S) - N - boc - alpha amino pentanoic acid

A tert-butoxycarbonyl, optically active technology, applied in the field of synthesis of 5-aryl--N-tert-butoxycarbonyl-α-aminovaleric acid derivatives, can solve the problem of reducing synthesis cost, incapable of industrialized production, and synthesis time. Long and other problems, to achieve the effect of shortening the synthesis time and selecting a reasonable reaction process

Active Publication Date: 2007-12-26
上海药明康德新药开发有限公司
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Problems solved by technology

[0011] The technical problem to be solved in the present invention is: the adoption of a brand-new optically active 5-aryl-(S)-N-tert-butoxycarbonyl-alpha- The synthesis method of aminovaleric acid derivatives solves the problem that the synthesis time of 5-aryl-(S)-N-tert-butoxycarbonyl-α-aminovaleric acid derivatives is long and cannot be industrialized in the existing literature process; and avoids Eliminates the use of expensive palladium reagents or enzyme reagents in existing processes, reducing synthesis costs

Method used

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  • Method for synthesizing optically active derivative of 5 - aryl - (S) - N - boc - alpha amino pentanoic acid
  • Method for synthesizing optically active derivative of 5 - aryl - (S) - N - boc - alpha amino pentanoic acid
  • Method for synthesizing optically active derivative of 5 - aryl - (S) - N - boc - alpha amino pentanoic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0026] 【5-Phenyl-5-keto-(S)-N-tert-butoxycarbonyl-α-aminovalerate ethyl ester (3a)】Synthesis:

[0027]

[0028] First prepare the Grignard reagent (2a) of bromobenzene, equipped with a dropping funnel and a three-necked flask with an internal thermometer, put Mg (0.77g, 32mmol) and dried tetrahydrofuran (30mL), and replace it with nitrogen, A solution of bromobenzene (5.1 g, 32 mmol) in dry tetrahydrofuran (10 mL) was prepared in a dropping funnel. Start to drop 2mL of this solution to initiate the reaction, then slowly drop the rest, maintaining the internal temperature at 60-70°C.

[0029] N-tert-butoxycarbonyl-L-pyroglutamic acid ethyl ester (1) (7g, 27mmol) in dry tetrahydrofuran (100mL) was cooled to between minus 50°C and minus 40°C with dry ice, acetone and water system, drop Add the above-mentioned Grignard reagent 2a (40mL, 32mmol), after the addition is completed, the reaction solution is stirred at this temperature for 60 minutes, rises to minus 10°C, and is the...

Embodiment 2

[0034] Synthesis of [5-p-methoxyphenyl-5-one-(S)-N-tert-butoxycarbonyl-α-aminovaleric acid ethyl ester (3b)]:

[0035]

[0036]N-tert-butoxycarbonyl-L-pyroglutamic acid ethyl ester (1) (4.6g, 18mmol) in dry tetrahydrofuran (100mL) was cooled to between minus 50°C and minus 40°C with dry ice, acetone and water, Grignard reagent (2b) (40mL, 20mmol) of p-methoxybromobenzene was added dropwise, and the dropwise addition was completed. The reaction solution was stirred at this temperature for 60 minutes, raised to minus 10°C, and then washed with 10% saturated NH 4 Cl aqueous solution was quenched, the organic layer was separated, the aqueous layer was extracted three times with 50 mL of diethyl ether, the combined organic layer was washed with water and saturated brine, and then washed with anhydrous Na 2 SO 4 Drying, filtration, rotary evaporation, column chromatography (petroleum ether / ethyl acetate=20:1) to obtain the target product 5-p-methoxyphenyl-5-one-(S)-N-tert-butoxy...

Embodiment 3

[0041] Synthesis of [5-p-methoxyphenyl-5-one-(S)-N-tert-butoxycarbonyl-α-aminovaleric acid ethyl ester (3b)]:

[0042]

[0043] N-tert-butoxycarbonyl-L-pyroglutamic acid ethyl ester (1) (4.6g, 18mmol) in dry tetrahydrofuran (100mL) was cooled to between minus 50°C and minus 40°C with dry ice, acetone and water, Grignard reagent (2b) (40mL, 20mmol) of p-methoxybromobenzene was added dropwise, and the dropwise addition was completed. The reaction solution was stirred at this temperature for 60 minutes, raised to minus 10°C, and then washed with 10% saturated NH 4 Cl aqueous solution was quenched, the organic layer was separated, the aqueous layer was extracted three times with 50 mL of diethyl ether, the combined organic layer was washed with water and saturated brine, and then washed with anhydrous Na 2 SO 4 Drying, filtration, rotary evaporation, column chromatography (petroleum ether / ethyl acetate=20:1) to obtain the target product 5-p-methoxyphenyl-5-one-(S)-N-tert-butox...

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Abstract

This invention relates to a method for synthesizing optically active 5-aryl-(S)-N-tert-butyloxycarbonyl-alpha-aminopentanoic acid derivative. The method comprises: preparing conventional and abundant phenyl bromide into Grignard reagent, reacting with ethyl N-tert-butyloxycarbonyl-L-pyroglutamate to obtain ethyl 5-aryl-5-one-(S)-N-tert-butyloxycarbonyl-alpha-pentanoate, and reducing to obtain ethyl 5-aryl-(S)-N-tert-butyloxycarbonyl-alpha-pentanoate. The method has such advantages as short reaction time and low cost, and is suitable for mass production. The method solves the problems of long synthesis time, unable industrial production, expensive Pd reagent or enzyme reagent, and high synthesis cost faced by the present technique.

Description

Technical field: [0001] The present invention relates to the synthesis of optically active 5-aryl-(S)-N-tert-butoxycarbonyl-α-aminovaleric acid derivatives, in particular to 5-aryl-(S)-N-tert-butoxycarbonyl - Synthesis of α-aminovalerate. Background technique: [0002] Amino acids can be divided into three categories according to the chemical properties of their side chain R-groups: aromatic amino acids, aliphatic amino acids, and heterocyclic amino acids. [0003] Aromatic amino acids are not only important pharmaceutical intermediates, but also have many applications in drug molecules, and aromatic amino acids have other biochemical properties, which play an important role in the regulation of physiological functions of organisms, such as derivatives of aromatic amino acids It can excite neurons. [0004] 5-aryl-(S)-N-tert-butoxycarbonyl-α-aminovaleric acid belongs to aromatic amino acid. In the regulation of some enzyme activities, this type of amino acid and its deriva...

Claims

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Application Information

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