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Synthetic method for Fmoc-DOOA.HCl

A synthesis method and ether-forming technology, applied in chemical instruments and methods, preparation of organic compounds, bulk chemical production, etc., can solve problems such as high cost, difficulty in purification, complicated process steps, etc., achieve environmental friendliness, low price, Ease of industrial production

Inactive Publication Date: 2015-10-07
德阳市德氏生物科技有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The purpose of the present invention is to provide a synthetic method of Fmoc-DOOA HCl, which mainly solves the technical problems of high cost, complex process steps and difficult purification in the existing synthetic method, thereby realizing industrialized large-scale production

Method used

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  • Synthetic method for Fmoc-DOOA.HCl
  • Synthetic method for Fmoc-DOOA.HCl
  • Synthetic method for Fmoc-DOOA.HCl

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Dissolve 1 equivalent of diglycolamine in 500 ml of water, add 1.5 equivalents of triethylamine, add a total of 1.2 equivalents of Boc anhydride in batches, monitor the reaction process by TLC, react at room temperature for 4 hours, and the reaction ends. Add 500ml of ethyl acetate for extraction, combine multiple ethyl acetate layers, wash with saturated brine until neutral, dry with 400g of anhydrous sodium sulfate for 12 hours, filter and concentrate to obtain 208g of Boc-diethylene glycol amine, HPLC purity 99.55%, yield The rate is 95%.

[0022] Two, synthetic Fmoc-ethanolamine, reaction is as follows:

[0023]

Embodiment 2

[0025] Dissolve 1 equivalent of ethanolamine in 500 mL of water, add 500 mL of tetrahydrofuran to aid dissolution, add 1.2 equivalents of Fmoc-Osu in batches, monitor the pH change during the reaction and maintain the pH at 7-10 with sodium carbonate, monitor the reaction process by TLC, and react at room temperature for 4 Hour, white solid was separated out after reaction finishes, and this solid is Fmoc-ethanolamine, filter, wash solid twice with 200ml water, filter, dry, obtain 260g product, HPLC purity is 99.76%, yield 92%.

[0026] 3. Activate Fmoc-ethanolamine, the reaction formula is as follows:

[0027]

example 3

[0029] Dissolve 1 equivalent of Fmoc-ethanolamine in 1.5L of ethyl acetate, add 1.2 equivalents of triethylamine, cool down to -5°C, slowly add 1.2 equivalents of methanesulfonyl chloride, and maintain the temperature range at -5°C during the reaction To 5 ℃, TLC monitor the reaction process, react for 6 hours, the reaction is over, add 3N hydrochloric acid to neutralize the pH to neutral, separate the ethyl acetate layer, wash with saturated brine until neutral, add 400g of anhydrous sodium sulfate and dry for 12 hours , filtered and concentrated to obtain 324g of the product, the HPLC purity was 98.37%, and the yield was 90%.

[0030] 4. Synthesis of Fmoc-DOOA (Boc) by docking, the reaction formula is as follows:

[0031]

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Abstract

The invention relates to a synthetic method for Fmoc-DOOAHCl. The synthetic method mainly overcomes the technical problems of low yield and difficult purification of conventional synthetic methods. According to a technical scheme in the invention, the synthetic method for Fmoc-DOOAHCl comprises the following steps: with diglycolamine and ethanolamine as starting raw materials, respectively introducing a Boc protective group and an Fmoc protective group onto diglycolamine and ethanolamine so as to obtain Boc-diglycolamine and Fmoc-ethanolamine; activating a hydroxyl group of Fmoc-ethanolamine and then bonding Fmoc-ethanolamine with Boc-diglycolamine under the action of strong base to form ether so as to produce Fmoc-DOOA(Boc); and finally, removing the Boc protective group with HCl so as to obtain Fmoc-DOOAHCl. Fmoc-DOOAHCl is drug connection and modification agent with excellent performance.

Description

technical field [0001] The invention relates to a method of introducing Boc and Fmoc protecting groups to the amino groups of diglycolamine and ethanolamine respectively, and then reacting the two to form ether to obtain Fmoc-DOOA (Boc), and finally selectively removing the Boc protecting group to obtain Fmoc -DOOA·HCl, belonging to the technical field of chemical synthesis. Background technique [0002] Fmoc-DOOA·HCl (Fmoc-1-amino-3,6-dioxa-8-octylamine hydrochloride) is widely used in the connection and modification of small molecules, polypeptides, and macromolecular drugs, as well as the synthesis of medical and biological materials. In terms of synthesis, for example, the synthesis of the human receptor 5HT4 dimer (Soulier, Jean-Louis; Russo, Olivier. Journal of Medicinal Chemistry (2005), 48(20), 6220-6228). In addition, it is also used in the field of synthesis of conjugated drugs (patent: WO2010126178A1). At present, the main reported synthesis method is to first s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/16C07C269/06
CPCY02P20/55
Inventor 尹彦波尹彦文陈浩
Owner 德阳市德氏生物科技有限公司