Compound based on benzimidazole substituted phenyl n-butylamide and preparation method of compound

A kind of technology of compound, mixture, be used in the compound based on phenyl n-butyramide substituted by benzimidazole and preparation field thereof

Pending Publication Date: 2021-03-05
TOPHARMAN SHANGHAI +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are still many problems in the synthetic route under this strategy, such as the safety of nitration reaction and the disposal of nitration waste liquid, a large amount of waste acid liquid and waste acid produced by forming the second imidazole ring in polyphosphoric acid or strong acid Disposal of neutralized waste liquid, etc.

Method used

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  • Compound based on benzimidazole substituted phenyl n-butylamide and preparation method of compound
  • Compound based on benzimidazole substituted phenyl n-butylamide and preparation method of compound
  • Compound based on benzimidazole substituted phenyl n-butylamide and preparation method of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0191]The method of preparing intermediate IV is prepared from 3-methyl-4-n-butylamidobenzoic acid (V-1).

[0192]

[0193]1) Preparation of intermediate compound V-5

[0194]3-methyl-4-n-butylaminobenzoic acid (22.1 g, 100 mmol), triameter (10.4 g, 35 mmol, 0.35 eq) and tetrahydrofuran (70 ml) were added to 40 to 45 ° C, which were mixed to 40 to 45 ° C. Then N, N-dimethylformamide (365 mg, 5 mmol, 0.05 eq) was heated for 40 to 45 ° C for 5 to 6 hours, and then transferred to a constant voltage funnel after cooling. Another three-bottle was added to the addition of phytine (11.9 g, 110 mmol, 1.1 eq), acetonitrile (95 mL) and aqueous sodium hydroxide (8 g, 200 mmol, 2 eq in 200ml water), stirred under an ice bath at 0 ~ 5 ° C. Uniform. The prepared anchlor chloride was slowly added dropwise from the constant pressure funnel at 0 ~ 5 ° C to the reaction, and the drip was added to room temperature after 1 hour. The reaction was heated to remove an organic solvent of about half of the volume, a...

Embodiment 2

[0204]The method of preparing intermediate compound Vi-1 is prepared from the intermediate compound V-8.

[0205]

[0206]Compound V-8 (10 g, 55.2 mmol) is illegulated in dried 50 mL acetonitrile, DMF (400 mg, 5.5 mmol), three-yield (6.5 g, 22 mmol), N2Protection, acetonitrile reflux 2H, soluned, TLC showed the feedstock reaction. In another round of foil, nitrobenzamine (8.4 g, 55.2 mmol) is dissolved in 50 ml of dried acetonitrile, potassium carbonate (22.9 g, 165.6 mmol), an ice bath, and the acid chloride reaction droplets is added to the o-nitro. In the reaction solution of benzamine 2, N2Protection, acetonitrile refluxing 2H, concentrated reaction liquid, residual liquid plus 150 ml of water, 150 ml EA extraction, organic phase saturated sodium chloride washing, drying, cycles, column chromatography, gave compound Vi-1, pale yellow solid 14.5g, received Rate 83.3%.

[0207]Compound VI-1 characterization data:

[0208]1H NMR (400MHz, MeOD): 7.92 (DD, J = 8.3, 1.5 Hz, 1H), 7.64-7.76 (m, 3H)...

Embodiment 3

[0211]

[0212]1) Preparation of Compound V-12:

[0213]Compound V-8 (5 g, 27.6 mmol) was added to 25 mL of acetonitrile, and DMF (200 mg, 2.76 mmol) was added sequentially, and three photomics (3.27 g, 11.0 mmol), N2Protecting, acetonitrile refluxing 2 h, another round of methanol solution, add additional chloride solution under an ice bath, and 100 ml of EA, organic saturated saline was washed twice, dried, carried, to obtain Compound V-12, Yellow solid 5 g, yield 93.3%. Compound V-12 characterization data:

[0214]1H NMR (400MHz, CDCL3: Δ7.94 (DD, J = 8.4, 1.7 Hz, 1H), 7.75 (D, J = 1.9 Hz, 1H), 7.67 (DD, J = 8.4, 1.9 Hz, 1H), 6.62 (s, 1h) 3.00 (D, J = 4.8 Hz, 3H), 2.59 (S, 3H).

[0215]LR-MS (ESI) M / Z: 195.4 (M + H)+.

[0216]2) Preparation of Compound Vi-1

[0217]Compound V-12 (388 mg, 2 mmol), orthoxonitrobenzene (347 mg, 2.2 mmol), Pd (DPPF) Cl2(73mg, 0.1mmol), CS2CO3(1.95g, 6mmol) Add 10 mL of toluene, N2Protecting, 10 hours of heating, filtration, 20 mlea was diluted, and the organic phase...

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Abstract

The invention relates to a compound based on benzimidazole substituted phenyl n-butylamide and a preparation method of the compound. According to the method disclosed by the invention, nitrification and polyphosphoric acid cyclization reactions are avoided, and the generation of a large amount of waste acid reaction liquid is avoided from the source. The synthesis method disclosed by the inventionhas the advantages of simplicity, high efficiency, mild conditions, less pollutants and the like, and is suitable for being developed into a green sustainable production process.

Description

[0001]The present disclosure requests the priority of the patent application filed in 2019108072922, filed on August 29, 2019.Technical field[0002]The present disclosure relates to a pharmaceutical compound and a method of preparation thereof. Specifically, the present disclosure relates to a compound of phenylbutamide based on benzimidazole and a preparation method thereof.Background technique[0003]Telmisartan is a novel non-peptide angiotensin II (ATII) receptor antagonist, which is a new type of blood pressure reduction drug for clinical treatment. The Mishatan was first developed by Boehringeringer, and in March 1999, first listed in the United States, then listed in many other countries around the world. The chemical name of Timishatan is 4 '- [(1,4'-dimethyl-2'-propyl [2,6'-1H-benzimidazole] -1'-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid, the structure is as follows:[0004][0005]The Misassarted molecular structure contains two coupled benzimidazole rings, the construction...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/18C07C237/34
CPCC07D235/18C07C237/34
Inventor 沈敬山孙长亮朱富强张骏驰李锐
Owner TOPHARMAN SHANGHAI
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