Synthesis method of O-[2]-[[tert-Butoxycarbonyl]amino]ethyl]-N-[fluorene methoxycarbonyl]-L-tyrosine

A technology of fluorenylmethoxycarbonyl and tert-butoxycarbonyl, which is applied in the field of organic chemical synthesis, can solve the problem of high cost of scale-up production, and achieve the effect of cheap reagents, simple reaction conditions and simple operation

Active Publication Date: 2019-07-16
KANGHUA SHANGHAI DRUG RES DEV CO LTD
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  • Abstract
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Problems solved by technology

[0003] The purpose of this invention is to provide a kind of synthetic method of O-[2-[[tert-butoxycarbonyl] amino] ethyl]-N-[fluorenylmethoxycarbonyl]-L-tyrosine, which mainly solves the problems existing in the present synthetic method. The scale-up production cost is high and technical problems

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  • Synthesis method of O-[2]-[[tert-Butoxycarbonyl]amino]ethyl]-N-[fluorene methoxycarbonyl]-L-tyrosine

Examples

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Effect test

Embodiment 1

[0012] Example 1: O-[2-[[tert-butoxycarbonyl]amino]ethyl]-N-[fluorenylmethoxycarbonyl]-L-tyrosine.

[0013] step 1:

[0014] L-tyrosine benzyl ester p-toluenesulfonate (500 g, 1.13 mol) was added to 1,4-dioxane (2.5 L) and water (2.5 L), then sodium bicarbonate (285 g, 3.39 mol). Cool in an ice-water bath to 0-5°C, add Cbz-Cl (192 g, 1.13 mol) dropwise therein, and control the temperature not to exceed 5°C. After the addition, the reaction was continued for 4 hours under an ice-water bath. Water (5 L) and ethyl acetate (4 L) were added thereto, stirred, separated, and the organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1 (435 g, 95% yield) as a white solid.

[0015] Step 2:

[0016] Compound 1 (400 g, 0.99 mol), N-Boc bromoethylamine (660 g, 2.96 mol), potassium carbonate (408 g, 2.96 mol) and tetrabutylammonium iodide (36.4 g, 0.099 mol) were mixed in DMF (2L). The rea...

Embodiment 2

[0020] Example 2, Step 2 The reaction temperature is 20° C., and the reaction time is 48 hours; the hydrogenation reaction time of Step 3 is 6 hours, and the Fmoc reaction time is 6 hours. All the other are with embodiment 1.

Embodiment 3

[0021] In Example 3, the coupling reaction temperature in step 2 is 30° C., and the reaction time is 36 hours; the hydrogenation reaction time in step 3 is 10 hours, and the Fmoc reaction time is 8 hours. All the other are with embodiment 1.

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Abstract

The invention relates to a synthesis method of O-[2]-[[tert-Butoxycarbonyl]amino]ethyl]-N-[fluorene methoxycarbonyl]-L-tyrosine. The present invention mainly solves the technical problem of high scale-up production cost existing in the present synthesis method. The synthetic steps of that invention comprise: arranging L-tyrosine alanine benzyl ester p-toluenesulfonate in the mixture of 1,4-dioxaneand water, adding sodium bicarbonate and Cbz-Cl to obtain compound 1, wherein that product does not need to be purified; dissolving the compound 1 and N-Boc bromoethylamine in DMF, adding potassium carbonate and tetrabutylammonium iodide to react to obtain compound 2, which can be purified by beating in ethanol; dissolving the compound 2 in tetrahydrofuran, adding palladium-carbon, hydrogenatingat normal pressure, and then adding directly aqueous sodium bicarbonate and Fmoc-Osu into the mixture to react at room temperature, pulping the crude product in the mixed solvent, and filtering to obtain the target product.

Description

technical field [0001] The present invention relates to the field of organic chemical synthesis, in particular to O-[2-[[tert-butoxycarbonyl]amino]ethyl]-N-[fluorenylmethoxycarbonyl]-L-tyrosine (cas number: 1013883-02 -7) Synthetic method. Background technique [0002] O-substituted tyrosine is an important raw material for drug synthesis and is widely used in the synthesis and screening of peptide drugs. And O-(2-aminoethyl)-L-tyrosine is one of the important types, which has attracted the attention of pharmacologists. For example, the A5B1 antagonist synthesized by AstraZeneca researchers to treat solid tumors contains this structure (WO2007 / 141473). Another example is the tyrosine compound (EP1591440) synthesized by Shanghai Pharmaceuticals, which has good efficacy in treating type II diabetes. And O-[2-[[tert-butoxycarbonyl] amino] ethyl]-N-[fluorenylmethoxycarbonyl]-L-tyrosine as an important intermediate, the current synthetic method only has literature (J. Med. Che...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/04C07C271/34
CPCC07B2200/07C07C269/04C07C2603/18C07C271/34C07C271/22
Inventor 徐红岩王鹏涛
Owner KANGHUA SHANGHAI DRUG RES DEV CO LTD
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