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Method for synthesizing N-fluorene methoxycarbonyl-N-trityl-D-glutamine

A technology of fluorene methoxycarbonyl and trityl, which is applied in the synthesis field of N-fluorene methoxycarbonyl-N-trityl-D-glutamine-OH), and can solve the problem of D-glutamine synthesis The problem of high cost, to achieve the effect of reducing production costs

Active Publication Date: 2008-07-16
GL BIOCHEM SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Solve the problem of high cost of D-glutamine synthesis

Method used

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  • Method for synthesizing N-fluorene methoxycarbonyl-N-trityl-D-glutamine
  • Method for synthesizing N-fluorene methoxycarbonyl-N-trityl-D-glutamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1, referring to the synthetic route, react glutamic acid and Z-Cl in sodium hydroxide solution at 0-15°C to obtain Z-D-Glu-OH. Z-D-Glu-OH was dissolved in DMF, and triethylamine and benzyl bromide were added to react for 24 hours to obtain Z-D-Glu-OBzl. Dissolve 10mmol Z-D-Glu-OBzl in 100mlTHF, add 10mmolET 3 N, add 10mmol of ClCOOEt at -10~-20°C, add 60mmol of ammonia water after 15-30min, react at room temperature for 6hr, and post-process to obtain product 3 with a yield of 62%. Dissolve 10 mmol of compound 3 and 20 mmol of trityl alcohol in 300 ml of HAc, add 1 mmol of sulfuric acid and 20 mmol of acetic anhydride, react at 60° C. for 8 hours, and post-process to obtain product 4 with a yield of 50%. 10 mmol of compound 4 was dissolved in methanol, 0.3 g of 10% Pd / C was added, and reacted with hydrogen gas for 24 hrs to obtain product 5 with a yield of 92%. Dissolve 10 mmol of compound 5 in saturated sodium bicarbonate and dioxane, add 10 mmol of Fmoc-Osu,...

Embodiment 2

[0037] Example 2, dissolve 10mmol Z-D-Glu-OBzl in 100mlTHF, add 10mmolET 3 N, add 10mmol ClCOOEt at -10~-20°C, add 40mmol ammonia water after 15-30min, react at room temperature for 16hr, and post-process to obtain product 3 with a yield of 60.5%. Dissolve 10 mmol of compound 3 and 20 mmol of trityl alcohol in 300 ml of HAc, add 1 mmol of sulfuric acid and 20 mmol of acetic anhydride, react at 50° C. for 24 hours, and post-process to obtain product 4 with a yield of 48%. 10 mmol of compound 4 was dissolved in methanol, 0.6 g of 5% Pd / C was added, and reacted with hydrogen gas for 36 hrs to obtain product 5 with a yield of 91.5%. All the other are identical with embodiment 1.

Embodiment 3

[0038] Example 3, dissolve 10mmol Z-D-Glu-OBzl in 100ml ethyl acetate, add 10mmolET 3 N, add 10mmol ClCOOEt at -10~-20°C, add 20mmol ammonia water after 15-30min, react at room temperature for 24hr, and post-process to obtain product 3 with a yield of 60%. Dissolve 10 mmol of compound 3 and 20 mmol of trityl alcohol in 300 ml of HAc, add 1 mmol of sulfuric acid and 20 mmol of acetic anhydride, react at 45°C for 24 hrs, and post-process to obtain product 4 with a yield of 47%. 10 mmol of compound 4 was dissolved in methanol, 0.6 g of 10% Pd / C was added, 10 ml of cyclohexene was added and refluxed for 8 hours, and post-treatment was performed to obtain product 5 with a yield of 90%. Dissolve 10 mmol of compound 5 in saturated sodium bicarbonate and dioxane, add 10 mmol of Fmoc-Cl, react for 4 hours, and post-process to obtain product 6. All the other are identical with embodiment 1.

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Abstract

The invention relates to a synthetic method of N-fluorenylmethoxycarbonyl-N- triphenylmethyl-D-glutamine to solve the current problems of the shortage of D-Gln raw materials and high cost of synthesizing products from the D-Gln. The synthesis includes the following steps: a. D-glutamate and a carbobenzoxy chloride are reacted to get the N-carbobenzoxy-D-glutamate; in an organic solvent N and N-dimethylformamide with the existence of a triethylamine and bromomethyl-benzene, the N-carbobenzoxy-D-glutamate selectively protects an Alpha-carboxyl to get an N-benzyloxycarbonyl-D-benzyl L-glutamate; b. the triethylamine, ethyl chloroformate and ammonia are added to N- benzyloxycarbonyl-D- benzyl L-glutamate organic solvent with a molar ratio of 1:1:2 to 6; after reacted for 6 to 24 hours under a temperature of -20 to 20 DEG C, an N- benzyloxycarbonyl-D-glutaminebenzylester is gotten; c. the product of b, acetate liquor is reacted with a triphenylmethanol under a catalysis of concentrated sulfuric acid, and N- benzyloxycarbonyl-N-triphenylmethyl-D-glutaminebenzylester can be gotten after reacted for 8 to 24 hours under a temperature of 40 to 60 DEG C; d. benzyloxycarbonyl and benzyl are detracted from the product of c to get the N-triphenylmethyl-D-glutamine; e. the product of d is protected by an Fmoc group to get the N-fluorenylmethoxycarbonyl-N-triphenylmethyl-D- glutamine.

Description

Technical field: [0001] The invention relates to a synthesis method of N-fluorenylmethoxycarbonyl-N-trityl-D-glutamine (Fmoc-D-Gln(Trt)-OH). Background technique: [0002] N-fluorenylmethoxycarbonyl-N-trityl-D-glutamine is a commonly used reagent in solid-phase peptide grafting, and we can synthesize it using D-glutamine as a starting material by a relatively simple method (ref: Tetrahedron Lett; EN; 32; 6; 1991; 739-742), that is, Z-D-Gln-OH obtains the product through a three-step reaction, but due to the relatively low yield and the high market price of D-Gln raw materials, the price of D-Glu is It is relatively cheap, so we developed this synthesis method from this perspective. The structural formula of Fmoc-Gln (Trt)-OH is: [0003] Invention content: [0004] The purpose of the present invention is to provide a synthetic method of N-fluorenylmethoxycarbonyl-N-trityl-D-glutamine. The method solves the problem of high synthesis cost of D-glutamine at present. Th...

Claims

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Application Information

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IPC IPC(8): C07C269/04C07C271/22
CPCY02P20/55
Inventor 徐红岩朱琦
Owner GL BIOCHEM SHANGHAI
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