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Preparation method of N-9-fluorenyl methoxycarbonyl-N'-trityl-L-histidine

A technology of fluorenyl methoxycarbonyl and trityl histidine, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of lower quality of downstream products, and achieve the effects of simple operation, high yield, and low overall production cost

Active Publication Date: 2021-09-17
GENCHEM & GENPHARM CHANGZHOU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The synthetic method reported by Zhao Pingping et al. (Chemical World, 2008 (9), 549~552) used trityl as the protecting group of the imidazole ring under the Fmoc strategy, and achieved a total yield of 70% in two steps, but Only products with a purity of 95% can be obtained, and direct use will lead to a decline in the quality of downstream products

Method used

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  • Preparation method of N-9-fluorenyl methoxycarbonyl-N'-trityl-L-histidine
  • Preparation method of N-9-fluorenyl methoxycarbonyl-N'-trityl-L-histidine
  • Preparation method of N-9-fluorenyl methoxycarbonyl-N'-trityl-L-histidine

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Experimental program
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Embodiment 1

[0029] Add 500 g of dichloromethane into a clean 2L four-neck flask, add 50 g of L-histidine (molecular weight 155.2, 0.35 mol) while stirring, and heat up to reflux. 67 g of dichlorodimethylsilane (molecular weight 129.1, 0.52 mol) was added dropwise, and the addition was completed in about 2 hours. After the addition, the reaction was kept under reflux for about 6 hours. After the reaction, add 120g of triethylamine (molecular weight: 101.2, 1.19mol) dropwise, then reflux for about half an hour, cool down to about 15°C, and then add 35g of triethylamine (molecular weight: The mixed solution of 100g of methyl chloride (molecular weight: 278.8, 0.36mol) and 100g of dichloromethane was added dropwise in about 4 hours, and then kept at 15-20°C for about 2 hours. Control until the raw materials disappear, add dropwise a mixed solvent of 50 g of methanol and 100 g of ethyl acetate, and stir for about 2 hours after the addition. Suction filtration, the collected solid was rinsed t...

Embodiment 2

[0033] Add 800 g of dichloromethane into a clean 2L four-neck flask, add 50 g of L-histidine (molecular weight 155.2, 0.35 mol) while stirring, and heat up to reflux. 75 g of dichlorodimethylsilane (molecular weight: 129.1, 0.58 mol) was added dropwise, and the addition was completed in about 2 hours. After the reaction, add 70.8g of triethylamine (molecular weight: 101.2, 0.70mol) dropwise, then reflux for about half an hour, cool down to about 15°C, then add 35g of triethylamine (molecular weight: 101.2, 0.35mol), triphenyl The mixed solution of 117g of methyl chloride (molecular weight: 278.8, 0.42mol) and 100g of dichloromethane was added dropwise in about 4 hours, and the reaction was carried out at 15-20°C for about 2 hours after the addition. Control until the raw materials disappear, add dropwise a mixed solvent of 50 g of methanol and 100 g of ethyl acetate, and stir for about 2 hours after the addition. Suction filtration, collect the solid, rinse twice with about 5...

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Abstract

The invention relates to the technical field of synthesis of medical intermediates, in particular to a synthesis method of N-9-fluorenyl methoxycarbonyl-N'-trityl-L-histidine. The method comprises the following steps: by taking L-histidine as a raw material, firstly protecting a-amino on the histidine by using a silane protective agent; reacting with triphenylchloromethane to obtain a silane protection substance of Nim-triphenylmethyl histidine, and then adding water to remove a silane protecting group; and reacting the silane protection substance of the Nim-triphenylmethyl histidine with a 9-fluorenyl methoxycarbonyl protection reagent to obtain the target product N-9-fluorenyl methoxycarbonyl-N '-trityl-L-histidine. The preparation method of the N-9-fluorenyl methoxycarbonyl-N'-trityl-L-histidine provided by the invention is simple and convenient to operate, the product has high purity and high yield, the comprehensive production cost is low, and the preparation method is suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of N-9-fluorenylmethoxycarbonyl-N'-trityl-L-histidine. Background technique [0002] N-9-Fluorenylmethoxycarbonyl-N'-trityl-L-histidine is a synthetic hepatocyte growth factor (Gly-His-Lys tripeptide), human histone H 2 120~125 fragment of A Ac-Thr-Glu-Ser-His-His-Lys-NH 2 It is an important intermediate of the 102-107 fragment Ac-Glu-Leu-Ala-Lys-His-Ala-amide of human histone H2B. [0003] The synthetic method of existing N-9-fluorenylmethoxycarbonyl-N'-trityl-L-histidine and similar products is as follows: [0004] Zhi Xiaoxia et al. (Synthetic Chemistry, 2013(21), 109~110) reported the synthesis of N-9-fluorenylmethoxycarbonyl-N'-4-methyl-trityl-L-histidine Synthesis, the total yield is 52.2%. [0005] The synthetic method reported by Zhao Pingping et al. (Chemical World, 2008 (9), 549~552) used trityl as the protecting ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/64
CPCC07D233/64Y02P20/55
Inventor 王玉琴詹玉进郑建龙
Owner GENCHEM & GENPHARM CHANGZHOU CO LTD
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