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Benzimidazole compound and preparation method and application thereof

A technology of benzimidazoles and compounds, applied in the field of medicinal chemistry, can solve problems such as low yield, high preparation cost, and difficult removal of impurities

Inactive Publication Date: 2017-05-10
SUZHOU VIGONVITA LIFE SCIENCES CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In order to solve the deficiencies such as high preparation cost, low yield, and difficult removal of impurities of flibanserin in the prior art, the present invention provides a benzimidazole compound with a structural formula as shown in the following formula (I), and adopts the formula (I) The compound shown can synthesize flibanserin or its pharmaceutically acceptable salt economically, conveniently and with high yield

Method used

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  • Benzimidazole compound and preparation method and application thereof
  • Benzimidazole compound and preparation method and application thereof
  • Benzimidazole compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] Example 1 2-Ethoxy-1H-benzimidazole

[0114]

[0115] Add o-phenylenediamine (20g, 185mmol) and tetraethyl orthoformate (37.3g, 194mmol) into acetic acid (11.1g, 185mmol) and heat at 80°C for 1.5h. TLC showed the reaction was complete. Concentrate the reaction solution to a small volume, then pour it into 200ml of water, stir for 10 minutes, filter with suction, wash the filter cake once with water, and dry at 65°C to obtain 27g of the product with a yield of 90%.

[0116] 1 H NMR(400MHz,DMSO)δ11.78(s,1H),7.35(s,1H),7.21(s,1H),7.07–6.96(m,2H),4.47(q,J=7.1Hz,2H) ,1.37(t,J=7.1Hz,3H).

[0117] ESI-[M+H] + =162.99

Embodiment 2

[0118] Example 2 2-Ethoxy-1H-benzimidazole

[0119]

[0120] Add o-phenylenediamine (0.8kg, 7.39mol) and tetraethyl orthoformate (1.49kg, 7.76mol) into acetic acid (444g) and react at 70°C for 2h. TLC showed the reaction was complete. The reaction solution was cooled to room temperature, and 5% potassium hydroxide aqueous solution (6.4 L) was slowly added, and the reaction system was stirred for 1 h. The precipitated solid was filtered, the filter cake was washed with water, and dried to obtain the target compound as a white solid (1.13kg, 94%). 1 H NMR (400MHz, DMSO-d 6 )δ11.80(brs,1H),7.29(m,2H),7.03(m,2H),4.48(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H).ESI- MS(m / z):163.5[M+H] + ,161.2[M-H] - ; HPLC: the retention time is 12.2min, and the purity is 96.3%.

Embodiment 3

[0121] Example 3 1-(2-chloroethyl)-2-ethoxy-1H-benzimidazole

[0122]

[0123] The product of Example 1 (2g, 12.3mmol), potassium carbonate (6.8g, 49.4mmol), 1,2-dichloroethane (6.1g, 61.5mmol) was added to acetonitrile (10ml) and refluxed for 15h, TLC showed a reaction completely. After suction filtration, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to dryness to obtain 2.77 g, and the crude product yield was 99.8%.

[0124] 1H NMR (400MHz, DMSO) δ7.46–7.38(m,2H),7.14–7.05(m,2H),4.55(q,J=7.1Hz,2H),4.37(t,J=5.9Hz,2H) ,3.96(t,J=5.9Hz,2H),1.41(t,J=7.1Hz,3H).

[0125] ESI-[M+H] + =225.04

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Abstract

The invention discloses a benzimidazole compound as shown in a formula (I), a preparation method of the benzimidazole compound, and application of the benzimidazole compound used for preparing flibaserin or pharmaceutically acceptable salts of flibaserin. The benzimidazole compound as shown in the formula (I) is used for preparing flibaserin, and the defects of high cost, low yield, impurity removal difficulty and the like in the prior art are overcome. The structural formula is as shown in the specification.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular, the invention relates to a benzimidazole compound, a preparation method thereof and an application for preparing flibanserin or a pharmaceutically acceptable salt of flibanserin. Background technique [0002] Flibanserin is a 5-HT1A receptor agonist, a 5-HT2A receptor antagonist, and has partial agonistic activity on the dopamine D4 receptor. It was approved by the FDA in August 2015 for the treatment of low libido in women. Its chemical name is: 1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-2,3-dihydro-1H-benzimidazole-2 -ketone, structural formula is shown in formula (III): [0003] [0004] European patent EP526434 reports that flibanserin is synthesized by 1-(2-chloroethyl)-1H-benzimidazol-2(3H)-one and 1-(3-(trifluoromethyl)phenyl) Condensation of piperazine. As shown in Reaction Formula 1: [0005] Reaction 1: [0006] [0007] Patent US2007 / 0032655 re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/26
CPCC07D235/26
Inventor 吴春晖何洋张健杨飞瀑田广辉
Owner SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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