Benzimidazole chiral heterocyclic compound as well as preparation method and application thereof

A technology of benzimidazoles and heterocycles is applied in the field of chiral compound synthesis to achieve the effect of high enantioselectivity

Active Publication Date: 2019-02-15
SUN YAT SEN UNIV
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  • Abstract
  • Description
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Problems solved by technology

However, there are not many reports on the synthesis of chiral benzimidazole compounds using asymmetric catalysis. For asymmetric catalytic conversion, only the use of latent chiral benzimidazole substrates for direct functionalization reactions to synthesize chiral benzimidazole compounds Reports on compounds with sexual chains [(a) Stanley, L.M.; Hartwig, J.F.J.Am.Chem. Soc.2009, 131, 8971. (b) Zhang, D.; He, Y.; Tang, J.Dalton Trans.2016 ,45,11699.(c) Xia,Y.;Lin,L.;Chang,F.;Liao,Y.;Liu,X.Feng,X.Angew.Chem.Int.Ed.2016, 55,12228. ], there is no precedent for introducing a chiral center into a benzimidazol chiral heterocycle through a direct asymmetric catalytic reaction

Method used

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  • Benzimidazole chiral heterocyclic compound as well as preparation method and application thereof
  • Benzimidazole chiral heterocyclic compound as well as preparation method and application thereof
  • Benzimidazole chiral heterocyclic compound as well as preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0117]Example 1.O,O'-[(R)-(1,1'-binaphthyl-2,2'-diphenolyl)]-N-[(R)-2-methyl-1,2, Preparation of 3,4-tetrahydroquinolinyl] phosphoramidite (L5):

[0118] Under nitrogen protection, in a dry 250mL three-neck flask, add 50mL of toluene and phosphorus trichloride (0.67mL, 7.7mmol), and cool to 0°C; in another dry 50mL eggplant-shaped bottle, add (R) -2-Methyl-1,2,3,4-tetrahydroquinoline (1.13g, 7.7mmol), toluene (8mL), and triethylamine (1.8mL, 12.9 mmol), then gradually added dropwise to the above 250mL in the three-necked flask. After the dropwise addition, the temperature was raised to 80°C for 6 hours, and then gradually cooled to -78°C. A solution of (R)-binaphthalene (7.7 mmol) and triethylamine (3.5 mL, 25.2 mmol) in toluene (30 mL) and tetrahydrofuran (6 mL) was slowly added to the system. The system was stirred overnight at room temperature, filtered through celite, and the solvent was removed under reduced pressure. The crude product was separated and purified by col...

Embodiment 2

[0122] Example 2. (S)-[6,6'-((R,R)-2,4-pentanedioloxy)]-2,2'-N,N-bis[(1R)-1-benzene Preparation of ethyl ethyl] phosphoramidite (L12):

[0123] Under nitrogen protection, phosphorus trichloride (32.30 μ L, 0.37 mmol), triethylamine (257.90 μ L, 1.85 mmol), bis[(1R)-1-phenylethyl]amine ( 83.70μL, 0.37mmol), anhydrous toluene (20mL), and then stirred at 50°C for 4h. Cool to room temperature, add (S)-[6,6'-((2R,4R)-2,4-pentanedioloxy)]-2,2'-dihydroxybiphenyl (105.86mg, 0.37mmol) Tetrahydrofuran solution (20 mL) was stirred at room temperature for 16 h. The crude product was purified by column chromatography to obtain the target compound.

[0124] (S)-[6,6-(2R,4R-Pentadioxy)]-(1,1')-biphenyl-(3,5-dioxa-4-phosphacyclohepta[e,g] [1,4])-bis ((R)-1-phenylethyl)amine (L12)

[0125]

[0126] White solid, yield: 84%; melting point: 109.6–110.3°C; [α] D 27 =+59 (c=0.1, CHCl 3 ). 1 H NMR (400MHz, CDCl 3 )δ7.31–7.25(m,2H),7.16–7.10(m,2H),6.98(dd,J=13.6,8.2Hz,2H),6.89(t,J=7.5Hz,...

Embodiment 3

[0127] Example 3. (R)-[6,6'-((S,S)-2,3-butanedioloxy)]-2,2'-N-[(R)-2-methyl-1 , Preparation of 2,3,4-tetrahydroquinolinyl] phosphoramidite (L13):

[0128] In a dry 250mL three-necked flask, add (R)-[6,6'-((S,S)-2,3-butanedioloxy)]-2,2'-dihydroxybiphenyl ( 2.00g, 7.3mmol) and toluene (50mL), phosphorus trichloride (9.60mL, 110.00mmol) and N-methylpyrrolidone (21.00μL, 0.22mmol) were added under nitrogen protection respectively, reacted at 50°C for 30min, and then The reaction liquid was cooled to room temperature, and then the phosphorus trichloride was distilled off under reduced pressure, and then the concentrated phosphorous oxychloride solid was dissolved with 50 mL of tetrahydrofuran; in another dry 250 mL round bottom flask, add (R)-2- Methyl-1,2,3,4-tetrahydroquinoline hydrochloride (1.20g, 6.60mmol) and 30 mL of tetrahydrofuran were cooled to -78°C, and then n-butyl lithium ( 2.5mol / L, 5.30mL), after the dropwise addition, continue to stir and react for 1h; finally, s...

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Abstract

The invention discloses a benzimidazole chiral heterocyclic compound as well as a preparation method and application thereof. The structure formula of the benzimidazole chiral heterocyclic compound isshown in formula I, formula II or formula III in the description. The benzimidazole chiral heterocyclic compound is prepared by treating an iridium complex which is prepared through a metal iridium compound and a phosphoramidite ligand as a catalyst, performing intra-molecular allyl amination on allyl substrate, and then synthesizing with high efficiency and high enantioselectivity. The method has the advantages of being high in catalytic reaction activity, mild in reaction conditions, high in enantioselectivity, wide in substrate applicable scope, and environmentally friendly; the primary in-vitro enzyme inhibition activity test shows that the compound is high in alpha-glucosidase inhibiting activity and can be used as an alpha-glucosidase inhibiting agent, and the compound can also be used as a further modified drug intermediate; the compound has a potential application value in preventing or treating II-diabetes, obesity and complication medicines thereof and pilot compounds thereof.

Description

technical field [0001] The invention belongs to the field of chiral compound synthesis, and relates to a benzimidazolo chiral heterocyclic compound and a preparation method and application thereof. Background technique [0002] Compounds with good α-glucosidase inhibitory activity are of great value to the preparation of drugs for the prevention or treatment of diabetes and its complications. The existing α-glucosidase inhibitors are limited and difficult to meet people's needs , Therefore, there is an urgent need to develop more compounds with α-glucosidase inhibitory activity. [0003] In addition, regarding the synthesis method of the compound, the prior art discloses the following content. [0004] Carbon-heteroatom bonding reactions and their molecular framework construction strategies are one of the main research areas of organic synthetic chemistry, which play a vital role in the rapid and efficient synthesis of complex natural product molecules or the preparation of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D487/06C07D235/14C07D235/24C07D235/08C07D409/04C07D235/18A61P3/10A61P3/04A61P31/12A61P35/00A61P1/16A61P29/00A61P5/50
CPCA61P1/16A61P3/04A61P3/10A61P5/50A61P29/00A61P31/12A61P35/00C07D235/08C07D235/14C07D235/18C07D235/24C07D409/04C07D487/04C07D487/06
Inventor 邱立勤蒋晓丁
Owner SUN YAT SEN UNIV
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