Synthesis method of sartan anti-hypertensive medicament intermediate 2-cyan-4'-methyl diphenyl

A technology of methyl biphenyl and synthesis method, which is applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve the problems of unfavorable production, complex operation of Grignard reagent, high synthesis cost, etc., and achieve less by-products, The effect of low toxicity and easy operation

Inactive Publication Date: 2013-03-13
QILU UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The use of Grignard reagents is complicated to operate, requires anhydrous and oxygen-free operation, and the synthesis cost is high, which is not conducive to industrial production

Method used

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  • Synthesis method of sartan anti-hypertensive medicament intermediate 2-cyan-4'-methyl diphenyl
  • Synthesis method of sartan anti-hypertensive medicament intermediate 2-cyan-4'-methyl diphenyl
  • Synthesis method of sartan anti-hypertensive medicament intermediate 2-cyan-4'-methyl diphenyl

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] The synthetic method of 2-cyano-4'-methylbiphenyl comprises the following steps:

[0037] 1) In a 500ml four-necked bottle, pass N 2 Replace the air in the bottle, repeat 3 times until the air is completely replaced; add p-chlorotoluene (37.95 g, 0.30mol) and 250ml tetrahydrofuran in sequence,

[0038] 2) Add 3 mmol of catalyst, heat to 90°C under stirring, and continue stirring for 10 minutes. The amount of catalyst added is: catalyst: p-chlorotoluene = 0.01:1, molar ratio.

[0039] Described catalyst is Pd complex catalyst, and its structural formula is:

[0040] ;

[0041] in, DBC The structure of Ph- is:

[0042]

[0043] R 1 is benzhydryl; R 2 is chlorine;

[0044] 3) O-chlorobenzonitrile (41.25g, 0.30mol) was slowly dropped into the solution for 0.5~1 hour. The molar ratio of p-chlorotoluene to o-chlorobenzonitrile is: p-chlorotoluene: o-chlorobenzonitrile=1:1; Stir at 90°C for 4h;

[0045] 4) Cool to room temperature, add 1.5mol / L dilute hydrochlori...

Embodiment 2

[0048] 1) In a 500ml four-necked bottle, pass N 2 Replace the air in the bottle, repeat 3 times until the air is completely replaced; add p-chlorotoluene (25.3g, 0.20 mol) and 250ml tetrahydrofuran in sequence;

[0049] 2) Add 4 mmol of catalyst, heat to 60°C under stirring, and continue stirring for 30 minutes. The amount of catalyst added is: catalyst: p-chlorotoluene = 0.02:1, molar ratio.

[0050] Described catalyst is Pd complex catalyst, and its structural formula is:

[0051] Its structural formula is:

[0052] ;

[0053] in, DBC The structure of Ph- is:

[0054]

[0055] R 1 is ethyl; R 2 is methyl;

[0056] 3) O-chlorobenzonitrile (30.25g, 0.22mol) was slowly dropped into the solution for 0.5~1 hour. The molar ratio of p-chlorotoluene to o-chlorobenzonitrile is: p-chlorotoluene: o-chlorobenzonitrile=1:1.1; stir at 60°C for 6 h;

[0057] 4) Cool to room temperature, add 1mol / L dilute hydrochloric acid to adjust to pH=6~7; separate the organic layer,

[0...

Embodiment 3

[0060] 1) In a 500ml four-necked bottle, pass N 2 Replace the air in the bottle, repeat 3 times until the air is completely replaced; add p-chlorotoluene (50.6g, 0.4mol) and 250ml tetrahydrofuran in sequence;

[0061] 2) Add 2 mmol of catalyst, heat to 80°C under stirring, and continue stirring for 20 minutes. The amount of catalyst added is: catalyst: p-chlorotoluene = 0.005:1, molar ratio.

[0062] Described catalyst is Pd complex catalyst, and its structural formula is:

[0063] ;

[0064] in, DBC The structure of Ph- is:

[0065]

[0066] R 1 is propyl; R 2 is chlorine;

[0067] 3) O-chlorobenzonitrile (66g, 0.48mol) was slowly dropped into the solution for 0.5~1 hour. The molar ratio of p-chlorotoluene to o-chlorobenzonitrile is: p-chlorotoluene: o-chlorobenzonitrile=1:1.2; Stir at 80°C for 5 h;

[0068] 4) Cool to room temperature, add 2.5mol / L dilute hydrochloric acid to adjust to pH=6~7; separate the organic layer;

[0069] 5) Extract the aqueous layer wi...

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PUM

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Abstract

The invention provides a synthesis method of sartan anti-hypertensive medicament AIIRA intermediate 2-cyan-4'-methyl diphenyl. O-chlorobenzonitrile and p-chlorotoluene react for one step under the catalytic action of a Pd complex so that high-purity 2-cyan-4'-methyl diphenyl is obtained. The synthesis method has the advantages of fewer reaction steps, easily controlled reaction condition, low price, low raw material price, available raw materials and the like, and is simple to operate.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a synthesis method of 2-cyano-4'-methylbiphenyl. Background technique [0002] 2-cyano-4'-methylbiphenyl (trade name: Sartan biphenyl, Sartanbiphenyl) is a sartan antihypertensive drug (such as losartan, valsartan, ipsartan, irbesartan etc.) key intermediates. Sartan drugs have the characteristics of wide range of effects, significant antihypertensive effect, convenient administration, and small side effects. With a large number of drugs entering the market in recent years, the market usage of 2-cyano-4'-methylbiphenyl intermediates is increasing , it is particularly important to study the synthesis technology of 2-cyano-4'-methylbiphenyl. [0003] The CAS registration number of 2-cyano-4'-methylbiphenyl is: 114772-53-1; English name: 4'-Methyl-2-cyanobiphenyl, aliased as 4'-Methylbiphenyl-2-carbonitrile, 2-Cyano -4'-methylbiphenyl; the molecular structure is: [0004] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/50C07C253/30
Inventor 班青孙斌
Owner QILU UNIV OF TECH
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