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Method for preparing Fmoc-Tyr (tBu)-OH

A fmoc-tyr-or, C1-C4 technology, applied in the field of preparing Fmoc-Tyr-OH, can solve the problems of easy formation of explosive mixture, potential safety hazards, poor safety, etc., and achieve shortened production steps, low cost, and improved production efficiency. and the effect of yield

Active Publication Date: 2020-12-18
成都郑源生化科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the method is simple in steps, it still needs to use isobutene when introducing tert-butyl. Isobutene is a gas at normal temperature and pressure, which is inconvenient to operate, and it is easy to form an explosive mixture if it leaks into the air, which has certain safety hazards. Therefore, this method The method is not safe and needs further improvement

Method used

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  • Method for preparing Fmoc-Tyr (tBu)-OH
  • Method for preparing Fmoc-Tyr (tBu)-OH
  • Method for preparing Fmoc-Tyr (tBu)-OH

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Weigh and add 18 grams of L-Tyr (tyrosine) and 100 ml of methanol into the reaction bottle, and add SOCl dropwise under stirring. 2 (thionyl chloride) 120ml, reflux reaction. When TLC (thin-layer chromatography) detects that there is no L-Tyr (tyrosine) in the reaction system, the reaction is complete. The reaction solution that has completed the above reaction is vacuum concentrated to a volume of 20 ml, and 100 ml of petroleum ether is added to separate out a white solid. After centrifugation and drying, 19.2 g of white solid was obtained, with a yield of 95.3%.

[0054] 19.2 g of Tyr-OCH will be obtained 3 Add HCl to 160ml acetone and 40ml water, adjust pH=8-9 with sodium carbonate, add 33.7 g Fmoc-OSu, react at room temperature for 8 hours, adjust pH=2-3 with 1M dilute hydrochloric acid, and precipitate white solid Fmoc-Tyr- OCH 3 , filtered, and dried to obtain 39.8 grams of white solid, with a yield of 95.4%.

[0055] The resulting 39.8 g of Fmoc-Tyr-OCH 3 , ...

Embodiment 2

[0058] Weigh and add 18g of L-Tyr (tyrosine) and 100ml of ethanol to the reaction flask, and add SOCl dropwise under stirring. 2 (thionyl chloride) 120ml, reflux reaction. When TLC (thin-layer chromatography) detects that there is no L-Tyr (tyrosine) in the reaction system, the reaction is complete. The reaction solution that has completed the above reaction is vacuum concentrated to a volume of 20 ml, and 100 ml of petroleum ether is added to separate out a white solid. After centrifugation and drying, 19.8 g of white solid was obtained, with a yield of 94.7%.

[0059] Add the obtained 19.8 grams of Tyr-OEt·HCl to 160 ml of acetone and 40 ml of water, adjust the pH to 8-9 with sodium carbonate, add 33.7 grams of Fmoc-OSu, react at room temperature for 8 hours, and adjust the pH to 2-3 with 1M dilute hydrochloric acid , precipitated white solid Fmoc-Tyr-OEt, filtered and dried to obtain 40.1 g of white solid with a yield of 93.2%.

[0060] The obtained 40.1 g of Fmoc-Tyr-OEt...

Embodiment 3

[0063] Weigh and add 180g of L-Tyr (tyrosine) and 1000ml of methanol into the reaction flask, add SOCl dropwise under stirring 2 (Thionyl chloride) 1200ml, reflux reaction. When TLC (thin-layer chromatography) detects that there is no L-Tyr (tyrosine) in the reaction system, the reaction is complete. The reaction solution that has completed the above reaction is vacuum concentrated to a volume of 20 ml, and 100 ml of petroleum ether is added to separate out a white solid. Centrifuge and dry to obtain 191 g of white solid, yield 95.0%.

[0064] 191 grams of Tyr-OCH will be obtained 3 Add 1600ml acetone and 400ml water with HCl, adjust pH=8-9 with sodium carbonate, add 337g Fmoc-OSu, react at room temperature for 8 hours, adjust pH=2-3 with 1M dilute hydrochloric acid, precipitate white solid Fmoc-Tyr- OCH 3 , filtered, and dried to obtain 398 grams of white solid, with a yield of 95.4%.

[0065] The resulting 398 g of Fmoc-Tyr-OCH 3 , join in 5000ml tert-butyl acetate and ...

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Abstract

The invention relates to a method for preparing FmocTyr (tBu)-OH, and belongs to the technical field of medical intermediate chemical engineering. The technical problem to be solved by the invention is to provide a method for preparing Fmoc-Tyr (tBu)-OH with good safety. The method comprises the following steps: a, mixing an Fmoc-Tyr-OR solid, tert-butyl acetate, perchloric acid and tert-butyl alcohol to react, adjusting the pH value to 5-6, separating out a solid, filtering, washing and drying to obtain an Fmoc-Tyr (tBu)-OR solid, wherein R is a C1-C4 alkyl; and b, carrying out hydrolysis onthe Fmoc-Tyr (tBu)-OR solid to obtain an Fmoc-Tyr (tBu)-OH product. The method is improved on the basis of the existing synthetic route, isobutene is not added when tert-butyl is introduced, the operation is simple and controllable, the safety is good, the cost is low, the production steps can be effectively shortened, the production efficiency and the yield are improved, and the method is suitable for modern industrial production.

Description

technical field [0001] The invention relates to a method for preparing Fmoc-Tyr(tBu)-OH, which belongs to the technical field of pharmaceutical intermediate chemical industry. Background technique [0002] Fmoc-Tyr(tBu)-OH is fluorenylmethoxycarbonyl-oxy-tert-butyl-tyrosine, a chemical intermediate, commonly used in peptide synthesis, and its structural formula is: [0003] [0004] Patent CN103833593A discloses a preparation method of N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-tyrosine, which first reacts to generate Tyr-OMe HCl, and then reacts with benzyl chloroformate Prepare Z-Tyr-OMe, then react with isobutene to prepare Z-Tyr(tBu)-OMe, then saponify to generate Z-Tyr(tBu), then hydrogenolyze to prepare Tyr(tBu), and finally react to generate Fmoc-Tyr(tBu) -OH. The method has long steps, low yield and low production efficiency, and needs to use explosive gas isobutylene, which has poor safety and is not suitable for modern industrial production. [0005] Li Xi...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/22
CPCC07C269/06C07C2603/18C07C271/22
Inventor 潘俊锋张东海付若彬郑征
Owner 成都郑源生化科技有限公司
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