Preparation method of 2-aryl-gamma-aminobutyric acid derivative

An aminobutyric acid and derivative technology, which is applied in the field of preparation of 2-aryl-γ-aminobutyric acid derivatives, can solve the problems of poor compatibility of reaction functional groups, cumbersome steps, harsh reaction conditions, etc., and achieves the universality of substrates. Wide range of properties, good reaction selectivity and mild reaction conditions

Active Publication Date: 2020-08-21
HUAZHONG UNIV OF SCI & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] For the above defects or improvement needs of the prior art, the present invention provides a method for preparing 2-aryl-γ-aminobutyric acid derivatives, which is based on α-aminomethyl silicon, alkene and aryl (or heteroaryl 2-aryl-γ-aminobutyric acid derivatives can be obtained by separation and purification after one-step reaction under the protection of protective gas, light conditions and the synergistic catalysis of photocatalyst / transition metal catalyst. The preparation method is simple, the conditions are mild, the reaction selectivity is good, and the substrate is universal, thereby solving the technical problems of cumbersome steps, harsh reaction conditions, and poor compatibility of reaction functional groups in the preparation methods of such compounds in the prior art.

Method used

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  • Preparation method of 2-aryl-gamma-aminobutyric acid derivative
  • Preparation method of 2-aryl-gamma-aminobutyric acid derivative
  • Preparation method of 2-aryl-gamma-aminobutyric acid derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0060] Add a magnetic stirrer in a 10mL transparent glass reaction tube, photocatalyst Ir(ppy) 2 (bpy)PF 6 (2.4mg, 3.0μmol, 0.010eq), metal catalyst NiCl 2 Glyme (6.6mg, 30μmol, 0.10equivalent), ligand di(OMe)bpy (6.1mg, 30μmol, 0.10equivalent), seal the nozzle with a rubber stopper, protect the reaction system with nitrogen gas (exhaust three times), inject the syringe into Solvent anhydrous DMF (3.0 mL), followed by microsyringe addition of α-aminomethylsilyl 1a (0.12 mL, 0.10 g, 0.60 mmol, 2.0 eq), benzyl acrylate 2a (90 μL, 97 mg, 0.60 mmol, 2.0 eq) , iodobenzene 3a (33μL, 61mg, 0.30mmol, 1.0eq), reacted at room temperature under blue light for 15 hours, then quenched the reaction with water, extracted with ethyl acetate (20mL x 3 times), combined the organic phases, and anhydrous sulfuric acid Sodium-dried, filtered, spin-dried, and column chromatography gave product 4 (78 mg, yield 77%). 1 H NMR (400MHz, CDCl 3)δ:7.34–7.22(m,10H),5.13(d,J=12.5Hz,1H),5.07(d,J=12.5Hz,1...

Embodiment 2

[0062] Add a magnetic stirrer in a 10mL transparent glass reaction tube, photocatalyst Ir(ppy) 2 (bpy)PF 6 (2.4mg, 3.0μmol, 0.010eq), metal catalyst NiCl 2 Glyme (6.6mg, 30μmol, 0.10equivalent), ligand di(OMe)bpy (6.1mg, 30μmol, 0.10equivalent), seal the nozzle with a rubber stopper, protect the reaction system with nitrogen gas (exhaust three times), inject the syringe into Solvent Anhydrous DMF (3.0 mL), followed by microsyringe addition of α-aminomethylsilyl 1b (0.10 g, 0.60 mmol, 0.60 mmol, 2.0 equiv), benzyl acrylate 2a (90 μL, 97 mg, 0.60 mmol, 2.0 equiv) , iodobenzene 3a (33μL, 61mg, 0.30mmol, 1.0eq), reacted at room temperature under blue light for 15 hours, then quenched the reaction with water, extracted with ethyl acetate (20mL x 3 times), combined the organic phases, and anhydrous sulfuric acid Sodium-dried, filtered, spin-dried, and column chromatography gave product 5 (90 mg, yield 88%). 1 H NMR (400MHz, CDCl 3 )δ:7.37–7.22(m,10H),5.14(d,J=12.4Hz,1H),5.06(d,J...

Embodiment 3

[0064] Add a magnetic stirrer in a 10mL transparent glass reaction tube, photocatalyst Ir(ppy) 2 (bpy)PF 6 (2.4mg, 3.0μmol, 0.010eq), metal catalyst NiCl 2 Glyme (6.6mg, 30μmol, 0.10equivalent), ligand di(OMe)bpy (6.1mg, 30μmol, 0.10equivalent), seal the nozzle with a rubber stopper, protect the reaction system with nitrogen gas (exhaust three times), inject the syringe into Solvent anhydrous DMF (3.0 mL), followed by addition of α-aminomethylsilyl 1c (0.11 g, 0.60 mmol, 0.60 mmol, 2.0 equiv), benzyl acrylate 2a (90 μL, 97 mg, 0.60 mmol, 2.0 equiv) with a micro syringe , iodobenzene 3a (33μL, 61mg, 0.30mmol, 1.0eq), reacted at room temperature under blue light for 15 hours, then quenched the reaction with water, extracted with ethyl acetate (20mL x 3 times), combined the organic phases, and anhydrous sulfuric acid Sodium-dried, filtered, spin-dried, and column chromatography gave product 6 (95 mg, yield 90%). 1 H NMR (400MHz, CDCl 3 )δ:7.34–7.27(m,8H),7.26–7.22(m,2H),5.14(...

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Abstract

The invention belongs to the field of organic synthesis, and particularly discloses a preparation method of a 2-aryl-gamma-aminobutyric acid derivative. The method comprises the following steps: by taking alpha-aminomethyl silicon, aryl (or heteroaryl) halide and olefin as substrates, adding catalytic amounts of a photocatalyst and a transition metal catalyst, a ligand and a proper amount of a solvent, reacting at room temperature under the protection of protective gas and blue light irradiation, and separating and purifying to obtain the 2-aryl-gamma-aminobutyric acid derivative. The method has the advantages of simple operation, cheap and easily available raw materials, mild reaction conditions, and realization of synthesis of complex drug active molecules through one-step reaction, andcan be used for rapid construction of a compound library containing the skeleton of the drug active molecules.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and more specifically relates to a preparation method of 2-aryl-γ-aminobutyric acid derivatives. Background technique [0002] 2-Aryl-γ-aminobutyric acid derivatives are a very important class of molecular skeletons, which exist in many biologically active molecules and drugs. For example, certain neurokinin 3 receptor (NK3) antagonists, certain HIV-1 therapeutic agents chemokine receptor CCR5 antagonists, antiallergic drug loperamide, and antiarrhythmic drug bidesolamide all contain Such structural units. For example: the synthesis of such compounds in patent WO 2016083531 A1 requires two-step reactions, and a strong reducing agent is used; patents WO2016144936 A1 and WO 2004041279 A1 require three-step reactions, and require strong bases, oxidants or strong acids, compatibility with functional groups Poor, raw materials are not cheap and easy to get. Documents Org Process Res Dev.2001,5,528-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/145C07C227/10C07C229/34C07D307/33C07D209/48C07J43/00C07D295/155C07C253/30C07C255/42C07D217/04C07D295/104C07D209/20
CPCC07D295/145C07C227/10C07D307/33C07D209/48C07J43/00C07D295/155C07C253/30C07D217/04C07D295/104C07D209/20C07C229/34C07C255/42
Inventor 袁伟明郑松林陈子敏胡媛媛
Owner HUAZHONG UNIV OF SCI & TECH
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