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A kind of preparation method of glutamic acid-1-tert-butyl ester derivative

A technology of tert-butyl acetate and glutamic acid is applied in the preparation of carbamic acid derivatives, the preparation of organic compounds, the preparation of cyanide reactions, etc. The effect of high production time, short steps and high efficiency

Active Publication Date: 2018-06-19
成都郑源生化科技有限公司
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Problems solved by technology

[0003] In the prior art, the preparation method of fluorenylmethoxycarbonyl glutamic acid-tert-butyl ester mainly includes: one is to use Z-Glu, prepare Z-Glu internal anhydride by DCC or acetic anhydride, and in the presence of dicyclohexylamine and Methanol, ethanol, and benzyl alcohol react to produce Glu's 1-position methyl ester, ethyl ester, and benzyl ester; but this method cannot produce 1-position tert-butyl ester
[0004] Method 2, Glu is catalyzed by sulfuric acid and methanol to prepare Glu-5-OMe, and then catalyzed by sulfuric acid to add isobutene, or catalyzed by perchloric acid and transesterified with tert-butyl acetate to obtain Glu(OMe)-OtBu, which is then hydrolyzed to produce To obtain Glu-OtBu, Glu-OtBu is no longer reacted with Fmoc--Cl or Fmoc-OSu to obtain Fmoc-Glu-OtBu. This method has a long line, and the 1-tert-butyl ester is unstable during hydrolysis, and the yield is low and the cost is high.
[0005] Method 3, Glu is catalyzed by sulfuric acid and benzyl alcohol to prepare Glu-5-OBzl, and then catalyzed by sulfuric acid to add isobutene, or catalyzed by perchloric acid and transesterified with tert-butyl acetate to obtain Glu(OBzl)-OtBu, hydrogenolysis Decomposition produces Glu-OtBu. Glu-OtBu is no longer reacted with Fmoc-Cl or Fmoc-OSu to produce Fmoc-Glu-OtBu. This method has a long line and high cost of hydrogenolysis. It also has the disadvantages of high cost and long line.

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  • A kind of preparation method of glutamic acid-1-tert-butyl ester derivative
  • A kind of preparation method of glutamic acid-1-tert-butyl ester derivative
  • A kind of preparation method of glutamic acid-1-tert-butyl ester derivative

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[0027] The invention provides a preparation method of glutamic acid-1-tert-butyl ester derivatives, comprising the following steps:

[0028] (1) Prepare glutamic acid-5-tert-butyl ester (Glu(OtBu)) and glutamic acid-1-tert-butyl ester (Glu-OtBu) mixture from glutamic acid (Glu);

[0029] (2) Mix glutamic acid-5-tert-butyl ester (Glu(OtBu)) and glutamic acid-1-tert-butyl ester (Glu-OtBu) mixture with transition metal M salt to obtain M[Glu(OtBu) ] x and M(Glu-OtBu) x A mixture of , where 1≤x≤2;

[0030] (3) Step (2) gained mixture reacts with protection reagent again, and selective reaction obtains the derivative of glutamate-1-tert-butyl ester; Protection reagent is FmocOSu, Fmoc-Cl, (Boc) 2 O, CbzOSu or Cbz-Cl;

[0031] The selective reaction process is:

[0032] Regulated M[Glu(OtBu)] x and M(Glu-OtBu) x The pH value of the mixture solution is 8 to 9, adding a protective reagent, maintaining the pH value of the reaction solution at 8 to 9, reacting for 7 to 10 hours, ...

Embodiment 1

[0059] The preparation of embodiment 1 fluorenyl methaneoxycarbonyl glutamic acid-1-tert-butyl ester

[0060] Specifically include the following steps:

[0061] (1) Prepare glutamic acid-5-tert-butyl ester (Glu(OtBu)) and glutamic acid-1-tert-butyl ester (Glu-OtBu) mixture from glutamic acid (Glu): add 581g of tert-butyl acetate and 147g of glutamic acid were stirred, and 100mL of perchloric acid was added dropwise, reacted at 20°C for 48 hours, cooled to 0°C, and then added with 600mL of water, washed with Na 2 CO 3 Neutralize to pH=8~9, separate liquid, then use 100mL 1% Na 2 CO 3 The aqueous solution was washed three times, the aqueous phase was combined, and extracted three times with 200 ml of petroleum ether;

[0062] (2) Transfer the aqueous phase obtained in step (1) into a 2L three-necked flask, and then add 187.5g CuSO 4 ·5H 2 O, stir, and adjust the pH to 8-9 with sodium carbonate. Add 100ml of tetrahydrofuran, add 33.7g of Fmoc-OSu, maintain the pH at 8-9, a...

Embodiment 2

[0064] The preparation of embodiment 2 fluorenyl methaneoxycarbonyl glutamate-1-tert-butyl ester

[0065] Specifically include the following steps:

[0066] (1) Prepare glutamic acid-5-tert-butyl ester (Glu(OtBu)) and glutamic acid-1-tert-butyl ester (Glu-OtBu) mixture from glutamic acid (Glu): add 1162g tert-butyl acetate and 147g glutamic acid, stir, add dropwise 130mL perchloric acid, react at 15°C for 30 hours, cool down to 0°C, add 600mL water, use Na 2 CO 3 Neutralize to pH=8~9, separate liquid, then use 100mL 1% Na 2 CO 3 The aqueous solution was washed three times, the aqueous phase was combined, and extracted three times with 200 ml of petroleum ether;

[0067] (2) Transfer the aqueous phase obtained in step (1) into a 2L three-necked flask, and then add 93.75g CuSO 4 ·5H 2 O, stir, and adjust the pH to 8-9 with sodium carbonate. Add 100 ml of tetrahydrofuran, 67.4 g of Fmoc-OSu, maintain the pH at 8-9, and react for 8 hours to obtain the crude product fluoreny...

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Abstract

The invention relates to a preparation method of a 1-tert-butyl glutamate derivative, and belongs to the field of peptide synthesis. The preparation method of the 1-tert-butyl glutamate derivative comprises the following steps: 1, processing glutamic acid to prepare a 5-tert-butyl glutamate and 1-tert-butyl glutamate mixture; 2, mixing the 5-tert-butyl glutamate and 1-tert-butyl glutamate mixture with salt of transition metal M to obtain an M[Glu(OtBu)]x and M(Glu-OtBu)x mixture, wherein x is not smaller than 1 and not greater than 2; and 3, reacting the mixture obtained in step 2 with a protection reagent, and carrying out a selective reaction to obtain the 1-tert-butyl glutamate derivative. The method has the advantages of short steps, low cost, high production time efficiency, and easy realization of industrial large-scale production.

Description

technical field [0001] The invention relates to a preparation method of glutamic acid-1-tert-butyl ester derivatives, belonging to the field of polypeptide synthesis. Background technique [0002] Glutamic acid-1-tert-butyl ester derivatives such as fluorenylmethoxycarbonyl glutamic acid-1-tert-butyl ester is a basic raw material commonly used in peptide synthesis, used to synthesize liraglutide, thymosin peptide, etc. Multiple drug peptides. [0003] In the prior art, the preparation method of fluorenylmethoxycarbonyl glutamic acid-tert-butyl ester is mainly as follows: one is to use Z-Glu to prepare Z-Glu internal anhydride by DCC or acetic anhydride, and in the presence of dicyclohexylamine and Methanol, ethanol, and benzyl alcohol react to produce the 1-position methyl ester, ethyl ester, and benzyl ester of Glu; but this method cannot produce the 1-position tert-butyl ester. [0004] Method 2, Glu is catalyzed by sulfuric acid and methanol to prepare Glu-5-OMe, and th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C269/04C07C271/22
CPCC07C227/18C07C269/04C07C271/22C07C229/24
Inventor 付若彬郑征杨再宽王震
Owner 成都郑源生化科技有限公司
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