WO2023157026A1 - A novel process for the preparation of 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile - Google Patents

A novel process for the preparation of 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile Download PDF

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WO2023157026A1
WO2023157026A1 PCT/IN2023/050162 IN2023050162W WO2023157026A1 WO 2023157026 A1 WO2023157026 A1 WO 2023157026A1 IN 2023050162 W IN2023050162 W IN 2023050162W WO 2023157026 A1 WO2023157026 A1 WO 2023157026A1
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formula
carbonitrile
biphenyl
bromomethyl
preparation
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PCT/IN2023/050162
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French (fr)
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Prashant POTNIS
Surender Kumar Dhingra
Sandip Appaji PUJARI
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Aarti Industries Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups

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  • the present invention relates to a novel process for the preparation of 4'-(bromomethyl)[l,l'- biphenyl]-2-carbonitrile. More particularly, the present invention relates to a process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I from 4'-methyl-2- cyanobiphenyl of formula
  • Sarian antihypertensives are a class of new blood pressure lowering drugs that are widely used in clinical practice. They are a class of angiotensin II receptor antagonists (ARB) and are mostly used for the treatment of essential hypertension.
  • ARB angiotensin II receptor antagonists
  • This type of antihypertensive drug has the advantages of obvious antihypertensive effect, good tolerance, small side effects, etc., and also has a certain therapeutic effect on heart failure, myocardial infarction, diabetes and other cardiovascular and cerebrovascular diseases.
  • antihypertensive drugs of the sartan family includes Azilsartan, Azilsartan medoxomil, Candesartan cilexetil, Irbesartan, Losartan, Milfasartan, Olmesartan medoxomil, Pratosartan, Ripisartan, Tasosartan, Telmisartan, and Valsartan. These drugs can be prepared using 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I.
  • CN111960967 discloses a process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2- carbonitrile of formula I by using the continuous flow reactor which consists of dissolving 4'- methyl-2-cyanobiphenyl of formula II in 10 volume of dichloromethane and stored in one of the storage tanks.
  • aq. hydrobromic acid solution used as a brominating agent, 1.1 equivalent of aqueous hydrogen peroxide solution, and the aqueous solution of the sodium bicarbonate used as a quencher are stored.
  • CN’967 process employs the use of the continuous flow reactor which requires the specific setup requiring capital expenditure. Further, due to use of the continuous flow reactor, volume of the dichloromethane solvent required for bromination is high. CN’967 process involves the use of a high equivalents of hydrogen peroxide and involves the use of ethanol-water for purification. The use of high volume of solvent, high equivalents of hydrogen peroxide and use of ethanol makes the process expensive and industrially not feasible. Further the yield obtained from the bromination reaction is low.
  • CN101768035 discloses a process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2- carbonitrile of formula I by addition of 4'-methyl-2-cyanobiphenyl of formula II and 6 volume of dichloromethane in four necked flask. The reaction is carried out at 35-40°C by addition of bromine and 1 equivalent of hydrogen peroxide solution in the presence of light. After completion of the reaction the organic layer is separated and distilled out The obtained reaction mass is further purified with toluene to obtain 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I with yield of 76.4% and purity of 97.8%.
  • CN’035 process involves the use of 6 volumes of dichloromethane and 1 equivalent of hydrogen peroxide solution. Further the yield obtained from the bromination reaction is low. Further CN’035 process involves use of toluene for purification which provides 4'-(bromomethyl)[l,l'-biphenyl]- 2-carbonitrile of formula I having only 97.8% purity. Org. Process Res. Dev. 2007, 11, 892-898 by Beutler et.
  • Beutler et. al., process involves the use of expensive reagents such as N-bromosuccinimide and 2,2'-azobisisobutyronitrile. Further, the said process provides 4'-(bromomethyl)[l,l'-biphenyl]-2- carbonitrile of formula I with less purity.
  • 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I can be used as a key starting material or as an intermediate in preparing Active Pharmaceutical Ingredients. If, 4'-(bromomethyl)[l,l'- biphenyl] -2- carbonitrile of formula I contains impurities they may get carried forward to a final Active Pharmaceutical Ingredient (API) or may react to form other by-products. Such impurities may be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products or different isomers. Impurities generated due to any reason in any API are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
  • API Active Pharmaceutical Ingredient
  • the inventors of the present invention have identified a novel process for preparing 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I which controls the formation of impurities or efficiently removes the impurities formed.
  • the process provided for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I requires non-expensive reaction setup which makes the process cost effective and industrially viable.
  • An object of the present invention is to provide a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I with improved yield and purity involving the use of simple brominating reagent in a batch reactor.
  • Another object of the present invention is to provide a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I by involving the use of optimized volume of the organic solvent.
  • Another object of the present invention is to provide a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I involving the use of an optimized equivalent of hydrogen peroxide.
  • the present invention provides a novel, efficient and industrially advantageous process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I.
  • a first aspect of the present invention is to provide a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I comprising brominating 4'-methyl-2- cyanobiphenyl of formula II with bromine as a brominating agent in the presence of hydrogen peroxide, a suitable solvent and a light source at a temperature in the range of -78 °C to 30 °C.
  • Second aspect of the present invention is to provide the process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I comprising the steps of: a) brominating 4'-methyl-2-cyanobiphenyl of formula II with bromine as the brominating agent in the presence of hydrogen peroxide, a suitable solvent and a light source at a temperature in the range of -78 °C to 30 °C to obtain crude 4'-(bromomethyl)[l,l'- biphenyl]-2-carbonitrile of formula I; and b) purifying the crude 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I using mixture of alcohol and non-polar solvent to obtain the pure 4'-(
  • the present invention provides a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I, wherein the yield of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I is in the range from 70 to 90%.
  • the present invention provides a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I, wherein the purity of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I is in the range from 96 to 99.9%.
  • the present invention provides a process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I comprising the step of brominating 4'-methyl-2-cyanobiphenyl of formula II with bromine as the brominating agent in the presence of hydrogen peroxide, a suitable solvent and a light source at a temperature in the range of -78 °C to 30 °C to obtain crude 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I.
  • the process as disclosed in the present invention further comprising the step of purifying the crude 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I using mixture of alcohol and non-polar solvent to obtain the pure 4'-(bromomethyl)[l ,r-biphenyl]-2-carbonitrile of formula I.
  • the present invention provides a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I, wherein the yield of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I is in the range from 70 to 90 %.
  • the present invention provides a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I, wherein the purity of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I is in the range from 96 to 99.9%.
  • the present invention provides a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I, wherein the purity of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I is in the range from 98 to 99.9%.
  • the present invention provides a process for the preparation of 4*-(bromomethyl)[l,l'- biphenyl] -2- carbonitrile of formula I comprises brominating 4'-methyl-2-cyanobiphenyl of formula II with bromine in the presence of hydrogen peroxide, a suitable solvent and a light source at a temperature in the range of -20 °C to 20 °C.
  • the process of the present invention is carried out using the batch type of reactor.
  • the process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention wherein the reaction is carried out at a temperature in the range of -20 °C to 20 °C for the period in the range of 10 hours to 20 hours.
  • the process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I further comprises purification of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I by using mixture of alcohol and non polar solvent
  • suitable alcohol is selected from methanol, ethanol, propanol, isopropyl alcohol, n-butanol, isobutanol, tertiary-butanol or a mixture thereof.
  • non-polar solvent is selected from cyclohexane, hexane, dichloromethane, monochlorobenzene, n-heptane or a mixture thereof.
  • Example-3 a) Step I: Preparation of 4 , -(bromometiiyl)[l,l’-biph «iyl]-2-carbonitrile of formula I
  • Example-4 a) Step I: Preparation of 4 , -(bromomethyl)[l,l , -biphenyl]-2-carbonitrile of formula I
  • Example-5 a) Step I: Preparation of 4 , -(bromomethyl)[l,l , -biphenyl]-2-carbonitrile of formula I

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  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention discloses a process for the preparation of 4'-(bromomethyl)[1,1'-biphenyl]- 2-carbonitrile of formula I from 4'-methyl-2-cyanobiphenyl of formula II with improved yield and purity involving the use of simple brominating reagent in a batch reactor.

Description

A NOVEL PROCESS FOR THE PREPARATION OF 4’-(BROMOMETHYL)[l,l’- BIPHENYLJ-2-CARBONITRILE
FIELD OF THE INVENTION:
The present invention relates to a novel process for the preparation of 4'-(bromomethyl)[l,l'- biphenyl]-2-carbonitrile. More particularly, the present invention relates to a process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I from 4'-methyl-2- cyanobiphenyl of formula
BACKGROUND OF THE INVENTION:
4'-(bromomethyl)[l,l '-biphenyl]-2-carbonitrile of formula I is a key intermediate for the synthesis of several pharmaceutical drugs from the sartan family.
Figure imgf000002_0001
Sarian antihypertensives are a class of new blood pressure lowering drugs that are widely used in clinical practice. They are a class of angiotensin II receptor antagonists (ARB) and are mostly used for the treatment of essential hypertension. This type of antihypertensive drug has the advantages of obvious antihypertensive effect, good tolerance, small side effects, etc., and also has a certain therapeutic effect on heart failure, myocardial infarction, diabetes and other cardiovascular and cerebrovascular diseases. Examples of antihypertensive drugs of the sartan family includes Azilsartan, Azilsartan medoxomil, Candesartan cilexetil, Irbesartan, Losartan, Milfasartan, Olmesartan medoxomil, Pratosartan, Ripisartan, Tasosartan, Telmisartan, and Valsartan. These drugs can be prepared using 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I.
There are several synthetic methods reported in the literature to prepare 4'-(bromomethyl)[l,l'- biphenyl]-2-carbonitrile of formula I.
CN111960967 discloses a process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2- carbonitrile of formula I by using the continuous flow reactor which consists of dissolving 4'- methyl-2-cyanobiphenyl of formula II in 10 volume of dichloromethane and stored in one of the storage tanks. In another three different storage tanks, aq. hydrobromic acid solution used as a brominating agent, 1.1 equivalent of aqueous hydrogen peroxide solution, and the aqueous solution of the sodium bicarbonate used as a quencher are stored. In the reactor, 4'-methyl-2-cyanobiphenyl of formula n, aqueous hydrobromic acid solution, aqueous hydrogen peroxide solutions are pumped and mixed using a high-efficiency mixer and reacted by using in-built LED light After completion of the reaction, aqueous solution of the quencher is mixed by using a high-efficiency mixer and the reaction mass is allowed to separate the organic and the aqueous layer. The organic layer is concentrated to obtain the crude solid. The crude solid is further purified by using a mixture of ethanol-water to obtain the pure 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I with yield of 75% and purity of 99.1%.
CN’967 process employs the use of the continuous flow reactor which requires the specific setup requiring capital expenditure. Further, due to use of the continuous flow reactor, volume of the dichloromethane solvent required for bromination is high. CN’967 process involves the use of a high equivalents of hydrogen peroxide and involves the use of ethanol-water for purification. The use of high volume of solvent, high equivalents of hydrogen peroxide and use of ethanol makes the process expensive and industrially not feasible. Further the yield obtained from the bromination reaction is low.
CN101768035 discloses a process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2- carbonitrile of formula I by addition of 4'-methyl-2-cyanobiphenyl of formula II and 6 volume of dichloromethane in four necked flask. The reaction is carried out at 35-40°C by addition of bromine and 1 equivalent of hydrogen peroxide solution in the presence of light. After completion of the reaction the organic layer is separated and distilled out The obtained reaction mass is further purified with toluene to obtain 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I with yield of 76.4% and purity of 97.8%.
CN’035 process involves the use of 6 volumes of dichloromethane and 1 equivalent of hydrogen peroxide solution. Further the yield obtained from the bromination reaction is low. Further CN’035 process involves use of toluene for purification which provides 4'-(bromomethyl)[l,l'-biphenyl]- 2-carbonitrile of formula I having only 97.8% purity. Org. Process Res. Dev. 2007, 11, 892-898 by Beutler et. al., discloses a process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I by bromination of 4'-methyl-2- cyanobiphenyl of formula II using N-bromosuccinimide as a brominating agent, 2,2'- azobisisobutyronitrile as a free radical initiator, hydrogen bromide as a catalyst and cyclohexane as a solvent The reaction was carried out at 67 °C for 1 hour to obtain 4'-(bromomethyl)[l,l'- biphenyl]-2-carbonitrile of formula I with yield of 85 % and purity of 98 %.
Beutler et. al., process involves the use of expensive reagents such as N-bromosuccinimide and 2,2'-azobisisobutyronitrile. Further, the said process provides 4'-(bromomethyl)[l,l'-biphenyl]-2- carbonitrile of formula I with less purity.
The above literature processes fail to provide 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I with 99.5% purity by using simple brominating reagent in the batch reactor. The above process either involves the use of a high volume of solvent, higher moles of hydrogen peroxide or involves the use of free radical initiator which makes the process expensive and industrially not viable.
4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I can be used as a key starting material or as an intermediate in preparing Active Pharmaceutical Ingredients. If, 4'-(bromomethyl)[l,l'- biphenyl] -2- carbonitrile of formula I contains impurities they may get carried forward to a final Active Pharmaceutical Ingredient (API) or may react to form other by-products. Such impurities may be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products or different isomers. Impurities generated due to any reason in any API are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
The American Food and Drug Administration (FDA) as well as European medicament control offices require, according to the Q7A ICH (International Conference on Harmonization) guidance, that Active Pharmaceutical Ingredient (API) is free of impurities to the maximum possible extent The reason being achieving maximum safety of using the drug in clinical practice.
It is always advantageous to use an intermediate of high purity which is free from the undesired impurities, or such impurities should be present in acceptable amounts. The purity of the chemical compounds can be measured by chromatographic techniques such as high pressure liquid chromatography (HPLC) or by gas chromatography (GC). Further it is the most crucial part of the chemical synthesis to use inexpensive industrial methods, use simple reagents to obtain products with desired purity.
Therefore, there is a continuous need to develop a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I which obviates problem associated with prior art processes, such as requirement of specific reaction set-up of flow reactor, use of high volume of solvent and high equivalent of hydrogen peroxide and still provides lower yield and purity.
The inventors of the present invention have identified a novel process for preparing 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I which controls the formation of impurities or efficiently removes the impurities formed. The process provided for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I requires non-expensive reaction setup which makes the process cost effective and industrially viable.
OBJECTS OF THE INVENTION:
The objects of the present invention are described herein below:
An object of the present invention is to provide a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I with improved yield and purity involving the use of simple brominating reagent in a batch reactor.
Another object of the present invention is to provide a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I by involving the use of optimized volume of the organic solvent.
Another object of the present invention is to provide a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I involving the use of an optimized equivalent of hydrogen peroxide.
Yet another object of the present invention is to provide a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I avoiding the use of the free radical initiator. Further object of the present invention is to provide a process for the purification of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I providing the product with >99.5% purity.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a novel, efficient and industrially advantageous process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I.
Figure imgf000006_0001
A first aspect of the present invention is to provide a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I comprising brominating 4'-methyl-2- cyanobiphenyl of formula II with bromine as a brominating agent in the presence of hydrogen peroxide, a suitable solvent and a light source at a temperature in the range of -78 °C to 30 °C.
The process for preparation of pure 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention is depicted in scheme-I herein below:
Figure imgf000006_0002
Second aspect of the present invention is to provide the process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I comprising the steps of: a) brominating 4'-methyl-2-cyanobiphenyl of formula II with bromine as the brominating agent in the presence of hydrogen peroxide, a suitable solvent and a light source at a temperature in the range of -78 °C to 30 °C to obtain crude 4'-(bromomethyl)[l,l'- biphenyl]-2-carbonitrile of formula I; and b) purifying the crude 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I using mixture of alcohol and non-polar solvent to obtain the pure 4'-(bromomethyl)[l,l'- biphenyl]-2-carbonitrile of formula I.
The process for preparation of the pure compound of 4'-(bromomethyl)[l,l'-biphenyl]-2- carbonitrile of formula I is depicted in scheme-II herein below:
Figure imgf000007_0001
In another embodiment, the present invention provides a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I, wherein the yield of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I is in the range from 70 to 90%.
In yet another embodiment, the present invention provides a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I, wherein the purity of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I is in the range from 96 to 99.9%. DETAILED DESCRIPTION OF THE INVENTION
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the disclosure to achieve one or more of the desired objects or results.
The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher/lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to the contrary.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art In case of conflict, the present document, including definitions will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.
The terms“comprise(s),”“include(s), "“having, ’’“has, ”“can,”“contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,”“an” and“the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments“comprising, ’’“consisting of and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not
In view of the above defined objectives, the present invention provides a process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I comprising the step of brominating 4'-methyl-2-cyanobiphenyl of formula II with bromine as the brominating agent in the presence of hydrogen peroxide, a suitable solvent and a light source at a temperature in the range of -78 °C to 30 °C to obtain crude 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I.
In one embodiment, the process as disclosed in the present invention further comprising the step of purifying the crude 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I using mixture of alcohol and non-polar solvent to obtain the pure 4'-(bromomethyl)[l ,r-biphenyl]-2-carbonitrile of formula I.
In another embodiment, the present invention provides a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I, wherein the yield of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I is in the range from 70 to 90 %.
In yet another embodiment, the present invention provides a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I, wherein the purity of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I is in the range from 96 to 99.9%.
In yet another embodiment, the present invention provides a process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I, wherein the purity of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I is in the range from 98 to 99.9%.
Preferably, the present invention provides a process for the preparation of 4*-(bromomethyl)[l,l'- biphenyl] -2- carbonitrile of formula I comprises brominating 4'-methyl-2-cyanobiphenyl of formula II with bromine in the presence of hydrogen peroxide, a suitable solvent and a light source at a temperature in the range of -20 °C to 20 °C.
The starting material of the process, 4'-methyl-2-cyanobiphenyl of formula II can be prepared as per the process disclosed in WO9816486.
The process of the present invention is carried out using the batch type of reactor.
The process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention, wherein the molar ratio of 4'-methyl-2-cyanobiphenyl of formula II to bromine ranges from 1 :0.4 to 1 : 1. The process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I, as disclosed in the invention, wherein the molar ratio of 4'-methyl-2-cyanobiphenyl of formula II to hydrogen peroxide ranges from 1:0.1 to 1:0.5.
The process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention, wherein 25 % to 50 % of hydrogen peroxide in an aqueous solution is used.
The process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention, wherein the suitable solvent is selected from cyclohexane, hexane, dichloromethane, ethylene dichloride, monochlorobenzene, chloroform, carbon tetrachloride, n-heptane or a mixture thereof.
The process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I, as disclosed in the present invention, wherein the volume of suitable solvent with respect to 4'- methyl-2-cyanobiphenyl of formula II ranges from 2 volume to 10 volume.
The process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention, wherein the light source is selected from LED or UV lamp.
The process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention, wherein the reaction is carried out at a temperature in the range of -78 °C to 30 °C for the period in the range of 5 hours to 24 hours.
Preferably, the process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention, wherein the reaction is carried out at a temperature in the range of -20 °C to 20 °C for the period in the range of 10 hours to 20 hours.
The process wherein 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I can be isolated by filtration method.
In one embodiment of the present invention, the process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I further comprises purification of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I by using mixture of alcohol and non polar solvent The process of the purification of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention, wherein suitable alcohol is selected from methanol, ethanol, propanol, isopropyl alcohol, n-butanol, isobutanol, tertiary-butanol or a mixture thereof.
The process of the purification of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention, wherein non-polar solvent is selected from cyclohexane, hexane, dichloromethane, monochlorobenzene, n-heptane or a mixture thereof.
The process of the purification of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention, wherein the volume of alcohol solvent with respect to 4'-methyl- 2-cyanobiphenyl of formula II ranges from 2 volume to 4 volume.
The process of the purification of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention, wherein the volume of non-polar solvent with respect to 4'- methyl-2-cyanobiphenyl of formula II ranges from 6 volume to 10 volume.
The process of the purification of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention, wherein ratio of alcohol: non polar solvent used ranges from 1 : 1 to 1: 5.
The process of the purification of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention, wherein 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I is dissolved in the mixture of alcohol/non polar solvent by heating the reaction mixture at a temperature in the range of 50 °C to 90 °C.
The process of the purification of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I as disclosed in the present invention, wherein 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I can be isolated by cooling the reaction mixture and filtering the solid.
Various features and embodiments of the present invention are illustrated in the following representative examples, which are intended to be illustrative and non-limiting. EXAMPLES:
Example-1: a) Step I: Preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I
In a IL flask, dichloromethane (300 mL) and 4'-methyl-2-cyanobiphenyl (100 g) were added. The LED light source was switched on. To this reaction mixture, bromine (49.6 g) and hydrogen peroxide (23.5 g) were added below 30 °C. After completion of the reaction, the reaction mixture was quenched with sodium thiosulphate solution (200 mL). The reaction mixture was extracted with dichloromethane (200 mL) and the organic layer was washed with water and subjected to distillation. After partial distillation, n-heptane (600 mL) was added and solvent further distilled out to obtain slurry mass. The slurry mass was filtered, washed with n-heptane (100 mL) to obtain the crude mass of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I. b) Step II: Purification of 4,-(bromometiiyi)[l,l’-biphenyl]-2-carbonitrile of formula I
In a 2L flask, wet cake of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I obtained in step I, butanol (800 mL) and dichloromethane (200 mL) were charged. The resulting mixture was heated, stirred for 1 hour and cooled to obtain solid. The obtained solid was filtered, washed with butanol (50 mL) and dried to obtain pure 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I. (Purity: >99%).
Example-2: a) Step I: Preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I
In a IL flask, dichloromethane (75 mL), n-heptane (450 mL) and 4'-methyl-2-cyanobiphenyl (50 g) were added. The LED light source was switched on. To this reaction mixture, bromine (29 g) and hydrogen peroxide (12 g) were added below 30 °C. After completion of the reaction, the reaction mixture was quenched with sodium thiosulphate solution (100 mL) to obtain the slurry mass. The slurry mass was filtered, washed with n-heptane (100 mL) to obtain the crude mass of 4'-(bromomethyl)[l,l '-biphenyl]-2-carbonitrile of formula I. b) Step II: Purification of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I
In a 2L flask, wet cake of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I obtained in step I, butanol (800 mL) and dichloromethane (200 mL) were charged. The resulting mixture was heated, stirred for 1 hour and cooled to obtain solid. The obtained solid was filtered, washed with butanol (50 mL) and dried to obtain pure 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I. (Purity: >99%, Yield: 72%).
Example-3: a) Step I: Preparation of 4,-(bromometiiyl)[l,l’-biph«iyl]-2-carbonitrile of formula I
In a IL flask, dichloromethane (300 mL) and 4'-methyl-2-cyanobiphenyl (100 g) were added. The UV lamp was switched on. To this reaction mixture bromine (49.6 g) and hydrogen peroxide (29.3 g) solution were added at below 30 °C. After completion of the reaction, the reaction mixture was quenched with sodium thiosulphate solution (200 mL). The reaction mixture was extracted with dichloromethane (200 mL), the organic layer was washed with water and subjected to distillation. After partial distillation, n-heptane (400 mL) was added and solvent further distilled out to obtain slurry mass. The slurry mass was filtered, washed with n-heptane (100 mL) to obtain the crude mass of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I. b) Step II: Purification of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I
In a 2L flask, wet cake of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I obtained in step I, butanol (800 mL) and dichloromethane (200 mL) were charged. The resulting mixture was heated, stirred for 1 hour and cooled to obtain solid. The obtained solid was filtered, washed with butanol (50 mL) and dried to obtain pure 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I. (Purity: >99%).
Example-4: a) Step I: Preparation of 4,-(bromomethyl)[l,l,-biphenyl]-2-carbonitrile of formula I
In a 5L reaction flask, dichloromethane (600 mL) and 4'-methyl-2-cyanobiphenyl (200 g) were added. The UV lamp was switched on. To this reaction mixture, bromine (99.2 g) and hydrogen peroxide (52.8 g) solution were added slowly at below 30 °C. After the completion of the reaction, the reaction mixture was quenched with aq. sodium thiosulphate solution (400 mL). The reaction mixture was extracted with dichloromethane (400 mL) and the organic layer was washed with water and subjected to distillation. After partial distillation, IP A (400 mL) was added and solvent further distilled out to obtain slurry mass. The slurry mass was filtered, washed with IP A (200 mL) and dried under vacuum to obtain the crude mass of 4'-(bromomethyl)[l,l'-biphenyl]-2- carbonitrile of formula I. b) Step II: Purification of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I
In a 2L flask, wet cake of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I obtained in step I, butanol (800 mL) and dichloromethane (200 mL) were charged. The resulting mixture was heated, stirred for 1 hour and cooled to obtain solid. The obtained solid was filtered, washed with butanol (50 mL) and dried to obtain pure 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I. (Purity: >99%).
Example-5: a) Step I: Preparation of 4,-(bromomethyl)[l,l,-biphenyl]-2-carbonitrile of formula I
In a 5L photochemical reactor, dichloromethane (1600 mL) and 4'-methyl-2-cyanobiphenyl (200 g) were added. The UV lamp was switched on. To the reaction mixture, bromine (99.2 g) and hydrogen peroxide (52.8 g) solution were slowly added at below 30 °C. After completion of the reaction, the reaction mixture was quenched with aq. sodium thiosulphate solution (400 mL). The reaction mixture was extracted with dichloromethane (400 mL) and the organic layer was washed with water (200 mL) and subjected to distillation. After partial distillation IP A (400 mL) was added and solvent further distilled out to obtain slurry mass. The slurry mass was filtered, washed with IP A (200 mL) and dried under vacuum to obtain the crude mass of 4'-(bromomethyl)[l,l'- biphenyl] -2- carbonitrile of formula I. b) Step II: Purification of 4*-(bromometiiyl)[l,l,-biphenyl]-2-carbonitrile of formula I
In a 2L flask, wet cake of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I obtained in step I, butanol (800 mL) and dichloromethane (200 mL) were charged. The resulting mixture was heated, stirred for 1 hour and cooled to obtain solid. The obtained solid was filtered, washed with butanol (50 mL) and dried to obtain pure 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I. (Purity: >99%).
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
The description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
While considerable emphasis has been placed herein on the particular features of this invention, it will be appreciated that various modifications can be made, and that many changes can be made in the preferred embodiments without departing from the principles of the invention. These and other modifications in the nature of the invention or the preferred embodiments will be apparent to those skilled in the art from the invention herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

Claims

Claims:
1. A process for the preparation of 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I comprising the step of brominating 4'-methyl-2-cyanobiphenyl of formula II with bromine as the brominating agent in the presence of hydrogen peroxide, a suitable solvent and a light source at a temperature in the range of -78 °C to 30 °C to obtain crude 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I.
2. The process as claimed in claim 1, wherein said process further comprising the step of purifying the crude 4'-(bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I using mixture of alcohol and non-polar solvent to obtain the pure 4'-(bromomethyl)[l,l'- biphenyl]-2-carbonitrile of formula I.
3. The process as claimed in claim 1, wherein the molar ratio of 4'-methyl-2-cyanobiphenyl of formula II to bromine is in the range from 1 : 0.4 to 1 : 1.
4. The process as claimed in claim 1, wherein the molar ratio of 4'-methyl-2-cyanobiphenyl of formula II to hydrogen peroxide is in the range from 1 : 0.1 to 1 : 0.5.
5. The process as claimed in claim 1, wherein said process for the preparation of 4'- (bromomethyl)[l,l'-biphenyl]-2-carbonitrile of formula I is carried out at temperature in the range of - 20 to 20 °C.
6. The process as claimed in claim 1, wherein said suitable solvent is selected from cyclohexane, hexane, dichloromethane, ethylene dichloride, monochlorobenzene, chloroform, carbon tetrachloride, n-heptane or a mixture thereof.
7. The process as claimed in claim 1 , wherein the volume of solvent with respect to 4-methy 1- 2-cyanobiphenyl of formula II ranges from 2 volume to 10 volume.
8. The process as claimed in claim 1, wherein said light source is selected from LED or UV lamp.
9. The process as claimed in claim 1, wherein said process is carried out for the period in the range from 5 hours to 24 hours.
10. The process as claimed in claim 2, wherein said alcohol used in the purification is selected from methanol, ethanol, propanol, isopropyl alcohol, n-butanol, isobutanol, tertiary- butanol, or mixture thereof.
11. The process as claimed in claim 2, wherein said non-polar solvent used in the purification is selected from cyclohexane, hexane, dichloromethane, monochlorobenzene, n-heptane or a mixture thereof.
12. The process as claimed in claim 2, wherein the ratio of alcohol: non polar solvent used ranges from 1: 1 to 1: 5.
13. The process as claimed in claim 1, wherein the yield of 4'-(bromomethyl)[l,l'-biphenyl]- 2-carbonitrile of formula I is in the range from 70 to 90 %.
14. The process as claimed in claim 1, wherein the purity of 4'-(bromomethyl)[l,l'-biphenyl]- 2-carbonitrile of formula I is in the range from 96 to 99.9 %.
15. The process as claimed in claim 1, wherein said process is carried out in a batch reactor.
PCT/IN2023/050162 2022-02-21 2023-02-20 A novel process for the preparation of 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile WO2023157026A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006103068A1 (en) * 2005-04-01 2006-10-05 Lek Pharmaceuticals D.D. A synthesis of 4-bromomethyl-2'-formylbiphenyl and 4-bromomethyl-2'- hydroxymethylbiphenyl and its use in preparation of angiotensin ii antagonists
WO2011073703A2 (en) * 2009-12-16 2011-06-23 Sanofi-Aventis Process for the preparation of 4-bromomethyl-[1,1'-biphenyl]-2'-carbonitrile
CN111960967A (en) * 2020-08-13 2020-11-20 浙江金立源药业有限公司 Continuous flow method for synthesizing p-bromomethyl biphenyl carbonitrile and reaction device thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006103068A1 (en) * 2005-04-01 2006-10-05 Lek Pharmaceuticals D.D. A synthesis of 4-bromomethyl-2'-formylbiphenyl and 4-bromomethyl-2'- hydroxymethylbiphenyl and its use in preparation of angiotensin ii antagonists
WO2011073703A2 (en) * 2009-12-16 2011-06-23 Sanofi-Aventis Process for the preparation of 4-bromomethyl-[1,1'-biphenyl]-2'-carbonitrile
CN111960967A (en) * 2020-08-13 2020-11-20 浙江金立源药业有限公司 Continuous flow method for synthesizing p-bromomethyl biphenyl carbonitrile and reaction device thereof

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