Method for preparing 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl) glutaric acid-5-benzyl ester

Abstract

The invention discloses a method for preparing 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl) glutaric acid-5-benzyl ester, which comprises the following steps of: a. with glutamic acid and phthalic anhydride as raw materials, carrying out reflux reaction for 4-10h in a solvent azeotropic with water under the action of using tertiary amine as a catalyst, cooling and distilling for removing the solvent to obtain a crude product of an intermediate 1, and then washing and purifying the crude product of the intermediate 1; b. with the intermediate 1 obtained in the step a and benzyl alcohol as raw materials, carrying out reflux reaction for 1-36h in the solvent in presence of the catalyst, cooling and distilling for removing the solvent to obtain a crude product of the target product; and washing and purifying the obtained crude product of the target product. The method has novel synthesis route and process, and the process is easy to operate and industrialize; the raw materials are cheap and can be obtained easily; and the method has the advantages of low comprehensive cost and good chirality.

Description

technical field [0001] The invention belongs to the field of compound synthesis, and relates to a preparation method of glutamic acid derivatives, in particular to the compound 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)glutaric acid -5-benzyl ester, has another name called the synthetic method of N-phthaloyl glutamic acid-γ-benzyl ester. Background technique [0002] 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)glutarate-5-benzyl ester, also known as N-phthaloylglutamic acid-γ-benzyl Ester (MW: 367.35), is the synthetic intermediate of long-acting antihypertensive drug cilazapril (WO2001083458) and other angiotensin-converting enzyme inhibitors (EP0629627A2) and other protease inhibitors (WO99 / 46248), and can also be used as Synthesis of theanine in health care products and dietary flavoring agents. There are mainly two kinds of synthesis methods involved in the literature, both of which are prepared by the reaction of glutamic acid-γ-benzyl ester. [0003] One method is prepared by...

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Problems solved by technology

[0012] The compound N-ethoxycarbonylphthalimide used in the first method is more expensive and unstable, making its preparation and use especially industrialized, which is neither economical nor easy to control; in the second method, the use of amino During the acylation of phthalic anhydride, the temperature is high, and the benzyl ester is easily partially decomposed, and the yield of the benzyl glutamate used in the two methods is not high during preparation, so the cost is relatively high

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