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

A technology of aspartic acid and tert-butyl acetate, which is applied in the preparation of carbamic acid derivatives, organic compounds, cyanide reaction, etc., can solve the problems of high cost, expensive hydrogenolysis, and long lines, and achieve production The effect of high timeliness, short steps and high efficiency

Active Publication Date: 2018-06-22
成都郑源生化科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Method 1: Use Z-Asp to prepare Z-Asp internal acid anhydride through DCC or acetic anhydride, react with methanol, ethanol, benzyl alcohol in the presence of dicyclohexylamine, and prepare Asp's 1-position methyl ester, ethyl ester, Benzyl ester; but this method cannot produce 1-tert-butyl ester
[0005] Method 2, Asp is catalyzed with sulfuric acid and benzyl alcohol to prepare Asp(OBzl), and then catalyzed with sulfuric acid to add isobutylene, or catalyzed by perchloric acid and transesterified with tert-butyl acetate to obtain Asp(OBzl)-OtBu, which is hydrolyzed or Asp-OtBu is obtained by hydrogenolysis, and Asp-OtBu is no longer reacted with Fmoc-Cl or Fmoc-OSu to obtain Fmoc-Asp-OtBu. This method has a long line, and the 1-tert-butyl ester is unstable during hydrolysis, and the yield is low; hydrogenolysis expensive, high cost

Method used

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

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preparation example Construction

[0028] The present invention provides a kind of preparation method of aspartic acid-1-tert-butyl ester derivative, comprising the following steps:

[0029] (1) Aspartic acid (Asp) is prepared aspartic acid-4-tert-butyl ester (Asp(OtBu)) and aspartic acid-1-tert-butyl ester (Asp-OtBu) mixture;

[0030] (2) Mix aspartic acid-4-tert-butyl ester (Asp(OtBu)) and aspartic acid-1-tert-butyl ester (Asp-OtBu) mixture with transition metal M salt to obtain M[Asp( OtBu)] x and M(Asp-OtBu) x A mixture of , where 1≤x≤2;

[0031] (3) The mixture obtained in step (2) reacts with a protective reagent again, and selectively reacts to obtain a derivative of aspartic acid-1-tert-butyl ester;

[0032] The selective reaction process is:

[0033] Regulation M[Asp(OtBu)] x and M(Asp-OtBu) x The pH value of the mixture solution is 8-9, adding a protective reagent, maintaining the pH value of the reaction solution at 8-9, reacting for 7-10 hours, and then acidifying, extracting, crystallizing, f...

Embodiment 1

[0060] The preparation of embodiment 1 fluorenyl moxycarbonyl aspartic acid-1-tert-butyl ester

[0061] Specifically include the following steps:

[0062] (1) Prepare aspartic acid-4-tert-butyl ester (Asp(OtBu)) and aspartic acid-1-tert-butyl ester (Asp-OtBu) mixture from aspartic acid (Asp): three ports in 2000mL Add 581g of tert-butyl acetate and 133g of aspartic acid into the bottle, stir, add 100mL of perchloric acid dropwise, react at 20°C for 48 hours, cool down to 0°C, add 600mL of water, and 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;

[0063] (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, and r...

Embodiment 2

[0065] The preparation of embodiment 2 fluorenyl methaneoxycarbonyl aspartic acid-1-tert-butyl ester

[0066] Specifically include the following steps:

[0067] (1) Prepare aspartic acid-4-tert-butyl ester (Asp(OtBu)) and aspartic acid-1-tert-butyl ester (Asp-OtBu) mixture from aspartic acid (Asp): three ports in 3000mL Add 1162g of tert-butyl acetate and 133g of aspartic acid into the bottle, stir, add 130mL of perchloric acid dropwise, react at 15°C for 30 hours, cool down to 0°C, add 600mL of water, and 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;

[0068] (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 100ml of tetrahydrofuran and 67.4g of Fmoc-OSu, maintain the pH at 8-9,...

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Abstract

The invention relates to a preparation method of an aspartic acid-1-tert-butyl ester derivative and the field of polypeptide synthesis. The preparation method includes following steps: (1), preparing aspartic acid into a mixture of aspartic acid-4-tert-butyl ester and aspartic acid-1-tert-butyl ester; (2), mixing the mixture with salt of transition metal M to obtain a mixture of M[Asp(OtBu)]x and M(Asp-OtBu)x, wherein x is greater than or equal to 1 and less than or equal to 2; (3), enabling the mixture to react with a protection agent, and allowing selective reaction to obtain the aspartic acid-1-tert-butyl ester derivative. The preparation method is few in step, low in cost, high in production time efficiency and easy for industrial mass production.

Description

technical field [0001] The invention relates to a preparation method of aspartic acid-1-tert-butyl ester derivatives, belonging to the field of polypeptide synthesis. Background technique [0002] Aspartic acid-1-tert-butyl ester derivatives such as fluorenylmethoxycarbonyl aspartic acid-1-tert-butyl ester is a basic raw material commonly used in polypeptide synthesis, used for the synthesis of thymopentin and thymofasin peptide and many other drug peptides. [0003] In the prior art, the preparation method of fluorenyl methaneoxycarbonyl aspartic acid-tert-butyl ester mainly includes: [0004] Method 1: Use Z-Asp to prepare Z-Asp internal acid anhydride through DCC or acetic anhydride, react with methanol, ethanol, benzyl alcohol in the presence of dicyclohexylamine, and prepare Asp's 1-position methyl ester, ethyl ester, Benzyl ester; but this method cannot produce 1-tert-butyl ester. [0005] Method 2, Asp is catalyzed with sulfuric acid and benzyl alcohol to prepare A...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/22C07C269/04
CPCC07C227/18C07C269/04C07C271/22C07C229/24
Inventor 付若彬郑征彭章勤仲良
Owner 成都郑源生化科技有限公司
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