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Synthetic method of 2-cyano-4'-methylbiphenyl

A technology of sartan biphenyl and its synthesis method, which is applied in the direction of condensation preparation of carbonyl compounds, carboxylic acid amide dehydration preparation, organic chemistry, etc., which can solve the problems of inability to carry out large-scale industrial production, increase the difficulty of separation and purification, and low total reaction yield and other issues, to achieve the effect of improving the utilization rate of atoms, facilitating production management, and easily obtaining raw materials

Active Publication Date: 2014-08-27
启东东岳药业有限公司
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Problems solved by technology

[0003] At present, there are many commonly used methods for synthesizing and preparing sartan biphenyl, which mainly contain the following: (1) Meyer o-anisic acid method, using salicylic acid or o-anisic acid as raw material, applying Meyer reaction, and synthesizing sartan biphenyl through oxazoline Tanbiphenyl, but its synthetic route is too long, and the total reaction yield is low
(2) Suzuki coupling method, 4-methylphenylboronic acid and 2-bromoxynil are coupled under the catalysis of palladium to synthesize sartan biphenyl. Due to the high price of raw materials, this synthetic route can only stay in the laboratory stage , it is not yet possible to carry out industrialized large-scale production
(3) Negishi coupling method, first prepare p-tolyl magnesium halide by Grignard reaction, then react with ZnCl to prepare organozinc reagent, finally cross-coupling with o-bromoxynil to synthesize sartan biphenyl, this synthetic method needs to prepare a large amount of Organic zinc reagent, and anhydrous ZnCl2 is very easy to absorb water, which makes the operation more difficult, and the addition of a large amount of metal reagents will also increase the difficulty of separation and purification
(4) Catalytic reduction method, preparing sartan biphenyl by catalytic hydrodebromination of 4'-dibromomethyl-2-cyanobiphenyl or 4'-bromomethyl-2-cyanobiphenyl, the raw material of this method It is synthesized by bromination after the synthesis of sartan biphenyl, and the reverse synthesis is obviously unreasonable

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  • Synthetic method of 2-cyano-4'-methylbiphenyl

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Embodiment Construction

[0017] Preparation of 2-amino-5-methylbenzophenone (Ⅳ)

[0018] Put benzoyl chloride (133.6mL, 1.15mol) in a reaction flask, stir, heat up to 120°C, slowly add p-toluidine (50.00g, 0.46mol), heat up to 140°C after the addition, and add no Water ZnCl2 (79.06 g, 0.58 mol), the temperature was raised to 160 ° C for 3 hours, the temperature was lowered to 100 ° C, 200 mL of water was added, stirred, and the water layer was poured out after cooling. Add 150mL of 70% sulfuric acid to the residue in the reaction bottle, stir at 140°C for 2 hours, pour the reaction solution into a large amount of water after cooling, neutralize the reaction solution with ammonia water, extract with ethyl acetate, and remove the ethyl acetate by rotary evaporation. The solid was recrystallized from 95% ethanol to obtain a yellow solid (79.70 g, yield 82.2%).

[0019] 1H NMR (400MHz, CDCl3, ppm) δ: 7.64(d,1H),7.54(t,1H),7.47(t,2H),7.23(s,1H),7.13(d,1H),5.91(s, 2H), 2.18(s, 3H).

[0020] Preparation o...

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Abstract

The invention discloses a synthetic method of 2-cyano-4'-methylbiphenyl, which adopts paratoluidine and benzoyl chloride as raw materials; a Friedel-Crafts acylation reaction is carried out under a Lewis acid catalysis condition; then a ring-closure reaction of a diazonium salt and a benzene ring is carried out in the presence of sodium nitrite; ring opening is carried out under an alkaline condition to generate a main product as shown in formula VI and a byproduct as shown in formula VII, and the ring-opening products are prepared into salts which are then subjected to separation; and finally, carboxyl groups are converted into cyan groups to obtain 2-cyano-4'-methylbiphenyl. The synthetic method of the invention has the advantages of easily available raw materials, safety, convenience for production management, low cost, reduction in 'three wastes' pollution, byproduct recyclability, and improved atom utilization rate.

Description

technical field [0001] The invention relates to a synthesis method of sartan biphenyl. Background technique [0002] 2-cyano-4'-methylbiphenyl (sartan biphenyl, Ⅰ) is a key intermediate in the synthesis of angiotensin Ⅱ antagonist drugs, such as losartan, telmisartan, valsartan, ibe Shatan et al. This type of drug has the characteristics of high efficiency, safety, good tolerance, and target organ protection, and has a strong development momentum and broad prospects. Therefore, the improvement of the synthesis process of sartan biphenyl is of great significance to the synthesis research and production of the whole beach drugs. [0003] At present, there are many commonly used methods for synthesizing and preparing sartan biphenyl, which mainly contain the following: (1) Meyer o-anisic acid method, using salicylic acid or o-anisic acid as raw material, applying Meyer reaction, and synthesizing sartan biphenyl through oxazoline Tanbiphenyl, but its synthetic route is too lo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/20C07C255/50C07C45/45C07C49/675
Inventor 王巧纯汪家宏吕心渊龙中柱蔡水洪
Owner 启东东岳药业有限公司
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