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Preparation method of beta2-amino acid derivative

A technology of derivatives and amino acids, applied in the field of organic synthesis, can solve the problems of poor compatibility of reactive functional groups, harsh reaction conditions, cumbersome steps, etc., and achieve the effects of good functional group compatibility, easy preparation, and good reaction selectivity

Pending Publication Date: 2022-05-06
HUAZHONG UNIV OF SCI & TECH
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Problems solved by technology

[0004] Aiming at the defects of the prior art, the present invention provides a β 2 -A method for preparing amino acid derivatives, which uses α-aminomethyl silicon, olefins and aryl (or heteroaryl) halides as raw materials, under the conditions of the presence of specific ligand structures and solvents, under the protection of protective gas, Under the synergistic catalysis of light and photocatalyst / transition metal catalyst, β can be obtained by separation and purification after one-step reaction 2 -Amino acid derivatives, the preparation method is simple, the reaction selectivity is good and the substrate universality is strong, thereby solving the cumbersome steps, harsh reaction conditions, poor compatibility of reaction functional groups, and problems existing in the preparation methods of such compounds in the prior art. Low yield and other technical problems

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  • Preparation method of beta2-amino acid derivative
  • Preparation method of beta2-amino acid derivative
  • Preparation method of beta2-amino acid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] In a glove box under nitrogen atmosphere, a magnetic stirrer, photocatalyst 4CzIPN (1.2 mg, 1.5 μmol, 0.0050 equiv), and metal catalyst NiBr were added to a 10 mL transparent glass reaction tube. 2 · glyme (9.3 mg, 30 μmol, 0.10 equiv), ligand 6,6'-di(Me)bpy (5.6 mg, 30 μmol, 0.10 equiv), α-aminomethylsilicon 1a (77 mg, 0.45 mmol, 1.5 equiv) , acrylate 2a (49 mg, 0.30 mmol, 1.0 equiv), aryl halide 3-1 (92 mg, 0.45 mmol, 1.5 equiv) anhydrous NMP (1.5 mL), stopper to seal the mouth, place the reaction at room temperature under blue light irradiation After 24 hours, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried, and the product 4 (70 mg, collected by column chromatography) was obtained. rate 69%). 1 H NMR (600MHz, CDCl 3 )δ7.33–7.26(m,3H),7.26–7.16(m,5H),7.13(d,J=7.8Hz,2H),5.06–5.01(m,2H),3.03–2.97(m,1H) ,2.9...

Embodiment 2

[0060] In a glove box under nitrogen atmosphere, a magnetic stirrer, photocatalyst 4CzIPN (1.2 mg, 1.5 μmol, 0.0050 equiv), and metal catalyst NiBr were added to a 10 mL transparent glass reaction tube. 2 · glyme (9.3 mg, 30 μmol, 0.10 equiv), ligand 6,6'-di(Me)bpy (5.6 mg, 30 μmol, 0.10 equiv), α-aminomethylsilicon 1a (77 mg, 0.45 mmol, 1.5 equiv) , acrylate 2a (49 mg, 0.30 mmol, 1.0 equiv), aryl halide 3-2 (98 mg, 0.45 mmol, 1.5 equiv) anhydrous NMP (1.5 mL), stopper to seal the mouth, place the reaction at room temperature under blue light irradiation After 24 hours, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried, and the product 5 (81 mg, collected by column chromatography) was obtained. rate 77%). 1 H NMR (600MHz, CDCl 3 )δ7.29(d,J=7.2Hz,3H),7.20(d,J=6.8Hz,2H),7.04–7.01(m,4H),5.04(s,2H),2.97(dt,J=13.9 ,6.9Hz,...

Embodiment 3

[0062] In a glove box under nitrogen atmosphere, a magnetic stirrer, photocatalyst 4CzIPN (1.2 mg, 1.5 μmol, 0.0050 equiv), and metal catalyst NiBr were added to a 10 mL transparent glass reaction tube. 2 · glyme (9.3 mg, 30 μmol, 0.10 equiv), ligand 6,6'-di(Me)bpy (5.6 mg, 30 μmol, 0.10 equiv), α-aminomethylsilicon 1a (77 mg, 0.45 mmol, 1.5 equiv) , acrylate 2a (49 mg, 0.30 mmol, 1.0 equiv), aryl halide 3-3 (98 mg, 0.45 mmol, 1.5 equiv) anhydrous NMP (1.5 mL), stopper to seal the mouth, place the reaction at room temperature under blue light irradiation After 24 hours, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried, and the product 6 (75 mg, collected by column chromatography) was obtained. rate 71%). 1 H NMR (600MHz, CDCl 3 )δ7.33-7.25(m,3H),7.21-7.17(m,2H),7.12(t,J=7.5Hz,1H),7.00-6.93(m,3H),5.04(s,2H),3.04 –2.9...

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Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a beta2-amino acid derivative. The preparation method comprises the following steps: taking alpha-aminomethyl silicon, olefin and aryl (or heteroaryl) halide as raw materials, in the presence of a specific ligand structure and a solvent, under the protection of a protective gas, illumination and the synergistic catalysis of a photocatalyst / transition metal catalyst, carrying out a one-step reaction, and then separating and purifying to obtain the beta2-amino acid derivative. The reaction selectivity is good, and the substrate universality is high, so that the technical problems of tedious steps, harsh reaction conditions, relatively poor compatibility of reaction functional groups, low yield and the like in the preparation method of the beta2-amino acid derivative in the prior art are solved.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and more particularly, relates to a beta 2 - Process for the preparation of amino acid derivatives. Background technique [0002] beta 2 - Amino acid derivatives are a very important class of molecular backbones that are present in many biologically active molecules and drugs. Such as patent CN 101198606A, WO 2005 / 092858 A2 discloses a beta 2 -The amino acid derivatives have ORL1 receptor antagonist activity, which can be used to relieve and treat various pains and other various central nervous system diseases. In these patent documents, β with ORL1 receptor antagonist activity is synthesized 2 - Amino acid derivatives require at least 4 steps of reaction, and the average yield is only 15%. In these reactions, strong bases are required, functional group compatibility is poor, atom economy and step economy are poor, and raw materials are not cheap readily available. When conducting...

Claims

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Application Information

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IPC IPC(8): C07D295/145
CPCC07D295/145C07D295/155C07F7/1804C07F7/1892C07D295/192C07F5/025C07F7/0812C07D295/26C07D209/86C07D333/76C07D213/64C07D209/08C07D277/62C07D317/60C07D215/12C07D307/79C07D295/182C07D211/62C07D217/04C07D211/22C07D491/107C07D221/20C07C227/10C07C229/34
Inventor 袁伟明郑松林胡媛媛陈子敏
Owner HUAZHONG UNIV OF SCI & TECH
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