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Preparation method of Nalpha-fluorenylmethoxycarbonyl-glutamine tert-butyl ester

A fluorene methoxycarbonyl and glutamine technology, applied in the field of peptide synthesis, can solve the problems of long cycle, low cost and high cost, and achieve the effects of improving quality, shortening cycle and simplifying process

Inactive Publication Date: 2016-01-20
上海吉尔多肽有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The technical purpose of the present invention is to overcome the technical problems of complexity, long period, high cost and low yield in the original process, and provide a preparation method of Nα-fluorenylmethoxycarbonyl-glutamine tert-butyl ester and its intermediate , the method is simple and easy to control, the two-step reaction cycle is short, the cost is low, and it is suitable for large-scale production

Method used

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  • Preparation method of Nalpha-fluorenylmethoxycarbonyl-glutamine tert-butyl ester
  • Preparation method of Nalpha-fluorenylmethoxycarbonyl-glutamine tert-butyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Add 795g of tert-butyl acetate to a 2000ml three-necked flask, then add 100ggln, stir, cool down to below 5°C, add 103.1g of perchloric acid dropwise, react at 20°C for 36 hours, then add 400ml of water, use sodium hydroxide Adjust the pH value of the system to about 8, and extract the water phase product once with 500ml tert-butyl acetate, combine the product phases and wash twice with saturated brine, and then concentrate to dryness to obtain 35g of oil, which is h-gln-otbu, the yield : 22.8%.

[0039] Add 35gh-gln-otbu to a 2000ml three-necked flask, then add 58.3g of fmoc-osu and 250ml of acetone, adjust the pH of the system to 8-9 with aqueous sodium carbonate, react at 15°C for 6 hours, and monitor the reaction by TLC process, after the reaction is completed, wash the system 4 times with a mixed solvent of 500ml of ethyl acetate and petroleum ether, then extract with 1L of ethyl acetate, acidify with 100g of citric acid and wash with acid water 3 times, and then w...

Embodiment 2

[0042] Add 298.2g tert-butyl acetate into a 2000ml three-necked flask, then add 75ggln, stir, cool down to below 5°C, add 67.04g perchloric acid dropwise, react at 15°C for 24 hours, then add 400ml of water, and oxidize with hydrogen The pH value of the sodium-adjusted system is about 8, and the aqueous phase product is extracted once again with 500ml tert-butyl acetate, and the combined product phase is washed twice with saturated brine, and then concentrated to dryness to obtain 30g of oil, which is h-gln-otbu, which is collected Rate: 26.2%.

[0043] Add 30gh-gln-otbu into a 2000ml three-necked flask, then add 62.6g of fmoc-osu and 250ml of THF, adjust the pH value of the system to 8-9 with aqueous sodium carbonate solution, react for 8 hours, and track and monitor the reaction process by TLC. After completion, the system was washed 3 times with a mixed solvent of 500ml of ethyl acetate and petroleum ether, then extracted with 1L of ethyl acetate, acidified with 80g of citr...

Embodiment 3

[0046] Add 788.6g tert-butyl acetate into a 2000ml three-necked flask, then add 66.1ggln, stir, cool down to below 5°C, add 81.8g perchloric acid dropwise, react at 25°C for 36 hours, then add 400ml of water, use Sodium hydroxide adjusts the pH value of the system to about 8, and then extracts the water phase product once with 500ml tert-butyl acetate, combines the product phase and washes it twice with saturated brine, and then concentrates to dryness to obtain 31g of oil, which is h-gln-otbu , Yield: 30.6%.

[0047] Add 31gh-gln-otbu to a 2000ml three-necked flask, then add 77.56g of fmoc-osu and 290ml of dioxane, adjust the pH of the system to 8-9 with aqueous sodium carbonate solution, react for 10 hours, and track and monitor the reaction by TLC process, after the reaction is completed, wash the system 4 times with a mixed solvent of 500ml of ethyl acetate and petroleum ether, then extract with 1L of ethyl acetate, acidify with 90g of citric acid and wash with acid water ...

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Abstract

The invention discloses a preparation method of Nalpha-fluorenylmethoxycarbonyl-glutamine tert-butyl ester and mainly solves the technical problems of complexity, long period, low yield, high cost and the like of an original technology. The preparation method comprises steps as follows: step one, gln and tert-butyl acetate are mixed, and h-gln-otbu is prepared under the action of perchloric acid; or, gln and z-cl are mixed, z-gln-oh is prepared and mixed with tert-butyl acetate, z-gln-otbu is prepared and subjected to catalytic hydrogenation in methyl alcohol, and h-gln-otbu is prepared; step two, h-gln-otbu and a fmoc-group protective agent are mixed, pH value is regulated to 8-9 by an alkali compound sodium carbonate aqueous solution in the presence of an organic solvent, fmoc-gln-otbu is prepared through reaction, and a pure product of fmoc-gln-otbu is prepared through processing. With the adoption of setting of a reasonable process route, Nalpha-fluorenylmethoxycarbonyl-glutamine tert-butyl ester and an intermediate thereof are prepared, and Nalpha-fluorenylmethoxycarbonyl-glutamine tert-butyl ester is applicable to mass production.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a preparation method of Nα-fluorenylmethoxycarbonyl-glutamine tert-butyl ester and its intermediate. Background technique [0002] In the current prior art, the preparation route of Nα-fluorenylmethoxycarbonyl-glutamine tert-butyl ester and its intermediates is to first synthesize z-gln-oh, then pass through isobutylene to make z-gln-otbu, and then undergo hydrogenation Remove the z-group to obtain h-gln-otbu, and then mix it with the fmoc-group to obtain fmoc-gln-otbu. The operation steps of this method are cumbersome and require pressurized catalytic hydrogenation, and the control conditions are relatively harsh , and the yield is low, the cycle is long, the cost is high, there is certain danger, and it is not suitable for commercial production. Contents of the invention [0003] The technical purpose of the present invention is to overcome the technical problems of comp...

Claims

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Application Information

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IPC IPC(8): C07C271/22C07C269/04
Inventor 徐红岩张家宝
Owner 上海吉尔多肽有限公司
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