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Synthesis process of (R,S)-2-[[5-(9- fluorenylmethyloxycarbonylamino)dibenzo[A,D]cycloheptane-2-yl]oxyl]acetic acid

A synthesis process and methoxyphenethyl technology are applied in the field of reagents for solid-phase synthesis of polypeptides, which can solve problems such as unfavorable large-scale application and low yield, and achieve the effects of improving yield and reducing cost.

Active Publication Date: 2016-01-06
上海泰坦科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although the above prior art discloses a (R,S)-2-[[5-(9-fluorenylmethoxycarbonylamino)dibenzo[A,D]cycloheptan-2-yl]oxy]acetic acid The preparation method can meet certain needs, but in the process of realizing the present invention, the inventor found that there are still some shortcomings and shortcomings in the above technical solution, such as the single yield of the last step is only about 75%, and the yield is low, which is not conducive to Large-scale application in industry

Method used

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  • Synthesis process of (R,S)-2-[[5-(9- fluorenylmethyloxycarbonylamino)dibenzo[A,D]cycloheptane-2-yl]oxyl]acetic acid
  • Synthesis process of (R,S)-2-[[5-(9- fluorenylmethyloxycarbonylamino)dibenzo[A,D]cycloheptane-2-yl]oxyl]acetic acid
  • Synthesis process of (R,S)-2-[[5-(9- fluorenylmethyloxycarbonylamino)dibenzo[A,D]cycloheptane-2-yl]oxyl]acetic acid

Examples

Experimental program
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Embodiment 1

[0035] This example relates to a preparation method of (R,S)-2-[[5-(9-fluorenylmethoxycarbonylamino)dibenzo[A,D]cycloheptan-2-yl]oxy]acetic acid, Consists of the following steps:

[0036] Step 1, mix 1mol o-carboxybenzaldehyde with 1mol m-methoxyphenylacetic acid, add sodium acetate, the mol ratio of o-carboxybenzaldehyde, m-methoxyphenylacetic acid, anhydrous sodium acetate is 1:1:0.1, in Stir in a 1L three-necked flask, heat up to 200°C and react for 12 hours, cool down, dissolve the reactant in water, acidify with 5% HCl to obtain 2-(3-methoxystyryl)benzoic acid, extract with ethyl acetate, reduce Evaporate the solvent under pressure, dissolve the reactant with 1L methanol, add Pd-C (the weight ratio of o-carboxybenzaldehyde to Pd-C is 15:1, and the weight loading of Pd in ​​Pd-C is 5%), and flow hydrogen, 28 Stir at ℃ for 2 hours, remove Pd-C by suction filtration, evaporate the solvent under reduced pressure, dissolve with 300ml ethyl acetate, add 1L petroleum ether for ...

Embodiment 2

[0041] This example relates to a preparation method of (R,S)-2-[[5-(9-fluorenylmethoxycarbonylamino)dibenzo[A,D]cycloheptan-2-yl]oxy]acetic acid, Consists of the following steps:

[0042] Step 1, mix 1mol o-carboxybenzaldehyde with 1mol m-methoxyphenylacetic acid, add sodium acetate, the mol ratio of o-carboxybenzaldehyde, m-methoxyphenylacetic acid, anhydrous sodium acetate is 1:1:1, in Stir in a 1L three-necked flask, heat up to 250°C and react for 5 hours, cool down, dissolve the reactant in water, acidify with 5% HCl to obtain 2-(3-methoxystyryl)benzoic acid, extract with ethyl acetate, reduce Evaporate the solvent under pressure, dissolve the reactant with 1L methanol, add Pd-C (the weight ratio of o-carboxybenzaldehyde to Pd-C is 15:1, and the weight loading of Pd in ​​Pd-C is 5%), and pass hydrogen, 33 Stir at ℃ for 2 hours, remove Pd-C by suction filtration, evaporate the solvent under reduced pressure, dissolve with 300ml ethyl acetate, add 1L petroleum ether for rec...

Embodiment 3

[0047] This example relates to a preparation method of (R,S)-2-[[5-(9-fluorenylmethoxycarbonylamino)dibenzo[A,D]cycloheptan-2-yl]oxy]acetic acid, Consists of the following steps:

[0048] Step 1, mix 1mol o-carboxybenzaldehyde with 1mol m-methoxyphenylacetic acid, add sodium acetate, the mol ratio of o-carboxybenzaldehyde, m-methoxyphenylacetic acid, anhydrous sodium acetate is 1:1:2, in Stir in a 1L three-necked flask, raise the temperature to 160°C and react for 9 hours, cool down, dissolve the reactant in water, acidify with 5% HCl to obtain 2-(3-methoxystyryl)benzoic acid, extract with ethyl acetate, reduce Evaporate the solvent under pressure, dissolve the reactant with 1L methanol, add Pd-C (the weight ratio of o-carboxybenzaldehyde to Pd-C is 15:1, and the weight loading of Pd in ​​Pd-C is 5%), and flow hydrogen, 40 Stir at ℃ for 2 hours, remove Pd-C by suction filtration, evaporate the solvent under reduced pressure, dissolve with 300ml ethyl acetate, add 1L petroleum...

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Abstract

The invention relates to a synthesis process of (R,S)-2-[[5-(9- fluorenylmethyloxycarbonylamino)dibenzo[A,D]cycloheptane-2-yl]oxyl]acetic acid. The synthesis process comprises the following steps of firstly, reacting o-phthalalde-hydic acid and m-methoxyphenylacetic acid under the catalysis of anhydrous sodium acetate to obtain 2-(3-methoxyphenylethenyl)benzoic acid, and carrying out a reduction reaction through introducing hydrogen under the catalysis of Pd-C; secondly, reacting the product and SOCl2 to obtain 2-methoxy-10,11-dehydro-5H-dibenzo[a,d]cycloheptene-5-ketone, and carrying out reflux reaction under the catalysis of anhydrous AlCl3; thirdly, reacting an intermediate product obtained through the reflux reaction and bromo-acetic acid phenylmethyl ester; and fourthly, carrying out reduction reaction through introducing hydrogen, then, reacting the product and Fmoc-NH2 to obtain (R,S)-2-[[5-(9- fluorenylmethyloxycarbonylamino)dibenzo[A,D]cycloheptane-2-yl]oxyl]acetic acid. According to the synthesis process, a catalyst is optimized, so that the total yield is remarkably increased, and the cost is reduced effectively; and the synthesis process is suitable for large-scale industrial synthesis application.

Description

technical field [0001] The invention relates to a reagent for solid-phase synthesis of polypeptides, in particular to a Ramage linker (R,S)-2-[[5-(9-fluorenylmethoxycarbonylamino)dibenzo[A,D] Synthesis process of cycloheptan-2-yl]oxy]acetic acid. Background technique [0002] (R,S)-2-[[5-(9-Fmoxycarbonylamino)dibenzo[A,D]cycloheptan-2-yl]oxy]acetic acid is an effective solid-phase synthesis of C- End linker is widely used in solid-phase synthesis of polypeptides due to the mild conditions for polypeptide link cleavage. Therefore, the synthetic method and process improvement of researching (R, S)-2-[[5-(9-fluorenylmethoxycarbonylamino) dibenzo[A, D] cycloheptan-2-yl] oxygen] acetic acid have great significance Significance and application value. [0003] CN104761470A (publication date 2015.07.08) discloses a (R,S)-2-[[5-(9-fluorenylmethoxycarbonylamino)dibenzo[A,D]cycloheptan-2-yl]oxy ] the preparation method of acetic acid, comprises the following steps: step (1), o-carb...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/24
Inventor 谢应波张庆张华徐肖冰罗桂云
Owner 上海泰坦科技股份有限公司
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