Amino acid compound containing diaziridine group and synthesis method thereof

A technology of diaziridine and amino acids, applied in the field of organic synthetic chemistry, can solve the problems of expensive reagents, use, unfriendly environment, etc., and achieve the effects of novel structure and cheap and easy-to-obtain synthetic raw materials.

Pending Publication Date: 2020-05-01
NANJING UNIV OF SCI & TECH
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  • Abstract
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Problems solved by technology

For example, in 2016, Stephan A. Sieber's research group used 1-hydroxyhept-6-yn-3-one as the starting material, and synthesized a class of structures by converting ketones into diaziridine structures, and then oxidizing alcohols into acids Smaller 2-(3-(but-3-yl-1-yl)-3H-diaziridin-3-yl) acetic acid type photocrosslinker, and then associate with other bioactive molecules to form the target structure ( Philipp Kleiner; Wolfgang Heydenreuter; Stephan A.Sieber, Angew.Chem.Int.Ed.2017,56,1396–1401), but the reagents used in the synthesis process are expensive, and some reagents even require additional synthesis, and heavy metals are used in the synthesis process Oxide, not friendly to the environment

Method used

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  • Amino acid compound containing diaziridine group and synthesis method thereof
  • Amino acid compound containing diaziridine group and synthesis method thereof
  • Amino acid compound containing diaziridine group and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The synthesis of intermediate product L2, its synthetic route is as follows:

[0028]

[0029] Put a magnetic stirring bar in a flask with a branched mouth, seal it with a rubber stopper, heat it with a heat gun or a high-temperature flame gun under vacuum, and slowly cool it under vacuum. Charge and discharge argon three times. Under an ice-water bath, add ultra-dry tetrahydrofuran solvent (22ml), diisopropylamine (3ml, 22mmol), and slowly add n-butyllithium (22mmol) dropwise, and stir for 30min under an ice-water bath. Then ethyl acetoacetate (1.27ml, 10mmol) was added dropwise through a syringe, stirred at 0°C for more than 15min, then propyne bromide (0.75ml, 10mmol) was added, and the mixture was slowly raised to room temperature for overnight reaction. Then the reaction solution was poured into saturated ammonium chloride solution to quench, extracted with ethyl acetate, the solvent was evaporated in vacuo, purified by silica gel column chromatography, and cha...

Embodiment 2

[0040] The synthesis of target product L6, its synthetic route is as follows:

[0041]

[0042] Dissolve L-histidine (0.33mmol, 51mg) in water and 1,4-dioxane mixed solvent (1.5ml:1.5ml), add sodium bicarbonate (0.66mmol, 55mg), and then add the intermediate product L5 (0.36mmol, 90mg), stirred overnight at room temperature. The solvent was spinned off in vacuo, filtered, and rinsed several times with methanol. The filtrate was collected, spin-dried in vacuo, and purified by HPLC preparation. 1 H NMR (500MHz, CD 3 OD_SPE)δ8.20(s,1H),7.10(s,1H),4.70(dd,J=9.1,5.0Hz,1H),3.18(dd,J=15.1,5.1Hz,1H),3.00(dd, J=15.1,9.2Hz,1H),2.31(d,J=15.3Hz,1H),2.24(t,J=2.5Hz,1H),2.19(d,J=15.3Hz,1H),1.98(dt, J=7.6,3.7Hz,2H),1.60(dtt,J=22.6,15.1,7.5Hz,2H).ESI-MS Calculated for C 13 h 15 N 5 o 3 :290.13([M+H] + ), Found: 290.04.

Embodiment 3

[0044] The synthesis of target product L7, its synthetic route is as follows:

[0045]

[0046] Dissolve L-isoleucine (0.33mmol, 43mg) in water and 1,4-dioxane mixed solvent (1.5ml:1.5ml), add sodium bicarbonate (0.66mmol, 55mg), and then add the intermediate product L5 (0.36mmol, 90mg), stirred overnight at room temperature. The solvent was spun off in vacuo, extracted with water and ethyl acetate, the organic phase was kept, and the solvent was spun dry. Preparatively purified by HPLC. NMR characterization. 1 HNMR (500MHz, CD 3 OD_SPE) δ4.32(d, J=5.6Hz, 1H), 2.38(d, J=15.2Hz, 1H), 2.28(d, J=15.2Hz, 1H), 2.23(t, J=2.7Hz, 1H ),2.05–1.99(m,2H),1.84(dd,J=12.8,6.4Hz,1H),1.74–1.60(m,2H),1.52–1.42(m,1H),1.27–1.16(m,1H ), 0.91 (dd, J=14.4, 7.1Hz, 6H). ESI-MS Calculated for C 13 h 19 N 3 o 3 :288.13([M+Na] + ), Found: 288.07.

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Abstract

The invention discloses an amino acid compound containing a diaziridine group and a synthesis method thereof. The method comprises the following steps: with ethyl acetoacetate as a raw material, performing a reaction under the action of lithium diisopropylamide; performing a reaction with propargyl bromide to generate 3-oxoheptyl-6-acetylenic acid ethyl ester; then hydrolyzing the reaction productto generate 3-oxoheptyl-6-acetylenic acid, so as to obtain 3-oxoheptyl-6-acetylenic acid; then performing a reaction with hydroxylamine-O-sulfonic acid in an ammonia gas methanol solution; performingiodine elementary substance oxidation to generate 2-(3-(butyl-3-acetylene-1-yl)-3H-diaziridine-3-yl)acetic acid; then carrying out a reaction on 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide to generate 2,5-dioxopyrrolidine-1-yl-2-(3-(butyl-3-yl-1-yl)-3H-diaziridine-3-yl)acetate, and then carrying out a reaction with amino acid molecules to generate the targetproducts. The compound synthesized by the invention contains diaziridine groups and amino acid molecules with biological activity, and can be used in biological activity test and analysis.

Description

technical field [0001] The invention belongs to the technical field of organic synthetic chemistry, and relates to an amino acid compound containing a diaziridine group and a synthesis method thereof, in particular to a (2-(3-(but-3-yn-1-yl)- 3H-diaziridin-3-yl) acetyl) amino acid compound and its synthesis method. Background technique [0002] Amino acid is an important organic compound in biology and the basic unit of protein. The difference in its structure can endow the protein with a specific molecular structure and form, so that the protein molecule has various biochemical activities. Photocrosslinkers are important tools for chemical biology research. Their typical structures usually contain photoreactive groups and responsive groups. Under ultraviolet light, the activation of photoactive groups mediates the irreversible interaction between proteins and ligands. connect. A prominent application of photocrosslinkers is affinity-based protein profiling (AfBPP), where ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D229/02C07D403/12
CPCC07D229/02C07D403/12
Inventor 姜超刘园孩倪梦亭
Owner NANJING UNIV OF SCI & TECH
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