IL24046A

IL24046A - Substituted biphenylyl acetic acids and their preparation

Info

Publication number: IL24046A
Application number: IL24046A
Authority: IL
Original assignee: Merck & Co Inc
Priority date: 1964-09-10
Filing date: 1965-07-28
Publication date: 1970-03-22
Also published as: NL6511845A; GB1116435A; BR6572746D0; FR7007M; FR1460659A; CH490309A; GB1116433A; GB1116434A; ES317635A1; FR7047M; BE669347A; FR7008M; FR7048M; GB1116432A; US3624142A

Description

acetic preparation A 2 relates to new biphenylyl aliphatic and derivatives thereof and the inventio in acids the esters and amides thereof as well as the corresponding and the salts the wherein and are hydrogen or lower or one of them is hydrogen and the other is lower as and the lower as and the lower lower halo lower as t or and form together a methylene or grou or together with the a and of add f and the othe one alkyl as and the lower amino as and the lower as and the with the proviso that where of and one is hydrogen and the other one is halo lower both independently be hydrogen or have any of the other connotations stated and provided further that where n or other must be 0 or X is COOS wherein is lower lower alkenyl as and the lower alkynyl as lower alkyl as and the lower lower alkoxy lower alkyl and the poly lower alkoxy lower as di hox and the poly hydroxy lower alkyl as and the lower alkyl as and the lower lower alkyl as and the poly hydroxy lower alkyl as and phenyl lower alkyl as phenyle and the lower alkoxy henyl ih as and the 4 as and trifl as h and the alk lover alkyl as h and the alkyl pyrrolidyl as and the alkyl pyrrolidyl lower alkyl as and the or both Y radicals together with the nitrogen atom to which form they are attached la saturated heterocyclic ring whose Y Y apart from said is one of the which is lower alkyl as and the ξ where is alkyl as and the where alkyl as and the and the pharmaceutically salts 5 invention also consists in pharmaceutically salts of the acids of formula the alkali alkaline earth amine and the the preferred aspects of this X is or R is and the but especially is hydrogen or lower alkyl especially compounds of formula A above may be represented by one the X 11 X have the same meaning as in formula and is alkox or and is or lowe alkyl when is lower is hydrogen and is lower lower lower halo lower alkyl or and taken together are ethylene or form with the a cyelopropyl Representa ive compounds encompassed within the scope of the present invention include acetic biphenylylacetic biphenylylacetic acetic and compounds described above have a high of activity and are effective in the prevention and inhibition of granuloma tissue Certain of them possess this activity in a high degree and are of value in the treatment of arthritic and disorders and in like conditions which are responsive to treatment with matory In the compounds of this invention have a useful degree of antipyretic ae 1 analgesic cholesterol and also 2 indicate some fatty acid synthesis For 3 they are normally administered orally in tablets or the optimum dosage of on 5 the particular compound being used and the type and severity 6 of the condition being Although the optimum 7 quantities of these compounds of this invention to be used Θ in such manner will depend on the compound employed and 9 the particular type of disease condition oral 10 dose levels of preferred compounds in the range of 11 per day are useful in control of ic depending on the activity of the specific7 13 compound and the reaction sensitivity of the The acid compounds of the invention possessing an asymmetric carbon atom 16 are ordinarily present in the form of a raceraic 17 The resolution of such racemates can be carried out by a vast number of known some racemic 19 mixtures can be precipitated as eutectics instead of mixed 20 crystal and can thus be quickly separated and in such 21 oases can sometimes be selectively The more 22 common method of chemical resolution greatly By this method diastereomers are formed from the racemic mixture by reaction with an resolving an base can be 26 reacted with the carboxyl The difference in 27 solubilit between the diastereomers formed permits the 28 selective crystallization of one form and regeneration 1 of the opticall acid from the There however 2 a third method of resolving which shows great This is 3 one or the other forms of biochemical procedures using selective l enzymatic the racemic acid can be subjected to an asymmetric oxidase or decarboxylase which by oxidation o destroy one leaving the other form Even more attractive is the use of a hydrolysase on a derivative of the racemic mixture to form preferentially 9 of the esters or amides of the acids can 10 subjected to an esterase which will selectively saponify one 11 enantiomorph and leave the other 12 When the free acid is resolved into and 13 the antiinflammatory activity is found to reside virtually completely in the The desired 15 isomer of the free acid may be prepared by any one of the preceding described resolving preferably working 17 from the free acid as t starting 18 amide or salt diastereomers of the free acid may be formed 19 such as 20 clnehonidine 21 22 basic amino acids 23 such as amino acid and the eater diastereomers of the free acid may be formed with such as and the Especially preferred is the use of 27 cinchonidine to give the readily decomposable diastereomer 1 as and distilling the solvent at 2 pressure until crystals begin to appear and further 3 crystallization produced by allowing the to cool to thereby separating the two The acid may then be recovered its salt by partitioning 6 the salt between an organic such as benzene or 7 and dilute hydrochloric 8 Derivatives of the resolved form the 9 free acid then may be prepared in the usual These 10 derivatives generally are more active than racemates of 11 the same the form of these 12 substantially freejof the is a still 3 further aspect of this For purposes of further the preparation o the compounds of this invention will be discussed under four 16 separate Each area will refer to the structural 17 Formulas or IV previously Structural Formula 19 The compounds of structural Formula wherein X is 20 may be prepared by two separate syntheses 21 as processes A and from the known compounds 22 of the structural V 1 subBtltuent on the ketone compound may be converted 2 to the desired and group by an appropriate series of 3 known This conversion is carried out at various steps of the depending upon the effect upon the substituent during the reactions to the final acetic acid 6 At whatever stage conversion is carried 7 the procedure is For usin the 8 the nitro group may be reduced such the 9 presenco of palladium under an atmosphere of hydrogen to form 10 amino The amino group may be reacted with an organic 11 such as methyl to form the or 12 substituted amino or it may be acylated an 13 halide or to form an The amino group may also be dlazotized and the replaced by a hydroxyl in may be alkylated 16 to form an The salt derived from the 17 amino group may also be treated with ethyl xanthate followed by of the xanthate under alkaline conditions 19 give the mercapto if may then be 20 alkylated with a dialkyl sulfate or halide to the 21 alkyl mercapto The alkyl mercapto group may be 22 for with potassium permanganate 23 alkaline to the alkylsulfonyl In addition the mercapto group may oxidized to a sulfonic acid group which may be treated with thionyl chloride and an amine to 26 obtain the Also the diazonium 27 compound may be reacted with a cuprous halide in the cold under 1 acid conditions to form a halide or it may be reacted 2 with cuprous cyanide to a cyano which may then be 3 subjected to acid hydrolysis to form a The group may be formed from a carboxyl After the formation of the 6 the acid chain is converted to the ester or 7 tertiary This compound is then reacted to obtain a 8 cyano group on the phenyl The cyano is converted to 9 the carboxyl group via an imido which is treated with 10 sulfur tetrafluoride and converted to the tri luoromethyl 11 protected side chain may then be converted to 12 the acid by In the carboxyl group may 13 be converted thionyl subsequently d d t further reduced to the hydroxymethyl which is converted to the chloromethyl which group may then be converted to a methyl If other lower alkyl substituents are formyl 18 the group may be to a lower 19 by means of a reaction using the appropriately 20 substituted triphenylphosphorane and the lower 21 allcene then reduced to the desired lower alkyl 22 This preparation of the lower alkyl group is carried out on 23 the acetic acid ester compound and the ester subsequently hydrolyzed or saponified to the final desired When more than one substituent is to be present 26 and each is to be the same the conversion from the 27 compound is carried out multiple nitro 28 when different substituents are the ketone 1 containing leas than three nitro groups may either be converted 2 to the desired group or groups followed by nitration of the 3 compound obtained and subsequent reaction of the nitro to obtain mixed substituents on the the desired ketone may be prepared from an appropriately substituted benzene and 6 a substituted aniline In this the 7 amino group on the aniline is used to form the biphenyl moiety 8 and the bromo group on the aniline is used to form the ketone 9 For and fluorobenzene 13 inert solvent to obtain the Qrignard This compound is then treated with cadmium chloride to obtain the yl corresponding diphenyl cadmium This compound is then treated with a lower alkyl acid chloride to give the corresponding 17 This procedure can also be used to prepare the starting 18 ketone containing a lower alkyl or a 19 by using the appropriately substituted benzene aniline 20 compound as starting When is to be a phenyl still another 22 procedure is For or an 23 appropriately substituted terphenyl with at least one of the end rings is reacted with acetyl chloride under conditions to form a 26 The appropriately substituted obtained as described may then be converted to the desired acid of Formula by one of two Process A In this the may be reacted with ammonium polysulfide in an inert such as dioxane or at elevated temperatures under sure for at least several hours to obtain the desired it is preferred to carry out this step in an organic amine with sulfur at elevated temperatures and sequent hydrolysis at any suitable temperature of the thioamide formed with an alkali or alkali earth The preferred amines which are used as solvents in this reaction are generally and anhydrous especially morpholine The reaction may be carried out at any suitable elevated preferably at or near the reflux temperature of the low boiling a bomb is The subsequent hydrolysis may preferably be carried out with such bases as sodium hydroxide or potassium hydroxide 1 at elevated 2 When groups which are easily reduced or oxidized 3 are desired such as the and cyano groups the acid is prepared followed by appropriate reactions on the acid For 6 the or cyano 7 acetic acid compound may be prepared by nitration of the yl 8 unsubstltuted blphenylacetic and subsequent reaction 9 to the desired amino or cyano nitration may 0 be carried out in sulfuric acid fuming nitric acid 1 at low such as to preferably at 2 or around or with fuming nitric acid alone or with 3 concentrated nitric acid at low temperatures preferably to or with fuming nitric acid in acetic acid at low or by any other 6 known conditions which will afford the appropriate 7 The nitro compound may then be catalytically 8 reduced to the amino Such catalysts as platinum 9 and palladium and the like are representative of this 0 catalytic The amine may be diazotlzed by 1 known methods and the diazo compound reacted with a 2 cyanide such as cuprous to form the 3 ired cyano Process B The alternative preparation of these acids of Formula I be illustrated as follows 1 1 In this the acetophenone 1 2 reacted with an alkali hypohalite followed by 3 of the reaction mixture sulfur dioxide and acidification of the solution to precipitate a acid In Step the acid is converted to its acid halide by reaction with a thionyl halide in 7 inert The acid halide is subsequently 8 with a solution of ethereal diazomethane to form the 9 corresponding This diazo compound 10 then reacted with silver oxide in alcohol to form the corresponding acid The 12 then converted by any means to the desired 13 acetic acid compound the diazoketone may be reacted with silver oxide in to form the free compound 16 In this only the acetophenone compounds 17 containing the triflu l or di may be ths starting material and maintained throughout the 20 subsequent When it is desired to obtain any 21 other or the nltro acetophenone compounds may 22 be used as the starting material and the substituent 23 converted to the desired group at the acetic acid stage of the synthesis or employing the appropriate as previously such groups 2 as or lower alkylthlo also be placed 27 on the by appropriate conversion of the nltro group 28 at any of the the benzoic acid compound 1 to the final acetic acid 2 Reactions and Conditions of Process B 3 Step 1 Reaction with an alkali or alkali earth such as sodium potassium and the especially sodium 6 with or without an inert solvent 7 at any suitable temperature to 8 preferably at or near the temperature of the consumption of the excess 0 halite with any suitable reducing 1 erably sulfur followed by 2 tion of the reaction mixture with any suitable 3 such as a mineral acid sulfuric and the preferably dilute hydrochloric the reaction is preferably 6 carried out in an inert suitable 7 vents are ethers 8 tetrahydrof and the 9 erably 0 Step 2 Reaction by any known such as reaction 1 with an acid halide of an inorganic such as thionyl phosphorus 3 phosphorus phosphorus the preferably thionyl chloride in an inert solvent aromatic 6 vents and the 7 ably chloroform or ethers at any suitable 8 erature preferably at elevated 9 but especially at or near the 0 reflux temperature of the Step Reaction with diazomethane in an inert 2 such aromatic solvents 3 and the preferably tetrahydrofuran or but especially ether at any suitable temperature or 6 preferably 0 to 7 Reaction with an alcohol and a such as 8 silver or preferably silver 9 either in the alcohol as solvent also or in 0 an inert such as aromatic 1 and the preferably using the alcohol as 2 at any suitable temperature to 3 preferably at elevated but especially at elevated but especially at or the reflux temperature of the Saponification or hydrolysis by any 7 such as reaction with a base and subsequent 8 trallzation of the mixture with a mineral Ste Same as Step except an inert such as 0 is used and water is used in place of the 1 1 In Reaction Step 1 the hypohalite is 2 consumed prior to acidification of reaction 3 this is not and acidification may be carried out The amount of hypohalite used is not critical only the yield of tho desired 6 acid be affected by changing amount of either of 7 Reaction Step 2 is a common reaction of converting 8 an acid to an acid and although a method has been 9 many other methods well known in the art may 10 be 11 Step 3 in the above illustration is carried out 12 reacting the acid preferably the acid in 13 an inert solvent with a solution of an excess of in an inert The inert solvent used not any solvent inert to the such as aromatic solvents or various may be 17 It is to use ether or In order 18 to avoid side reactions and loss of the acid 19 inert solvent mixture is generally added to an excess of 20 diazomethane solution at reduced 21 any molar ratio of diazomethane and the acid low 22 temperatures to slightly elevated are within 23 the contemplation of this This reaction step is preferably carried out at 0 to the acid to at least 3 moles of a solution 26 of diazomethane In 27 In Reaction Step it is preferred 28 as a safety precaution to first remove the excess 1 Preparation of of Structural 2 The compounds of Structural Formula wherein X I and a lower alkyl is desired other than lower acid halide other than an acetyl described in the reacted with the biphenyl 17 under conditions to obtain the desired ketone 18 as described in the known biphenyl 19 ketones may be nitrated the appropriate positions to 20 obtain other nitro substituted biphenyl lower ketones 21 In the first process A the appropriately 22 substituted ketone is converted to a which is 23 treated with a mineral acid to form a hydroxy The hydroxy amide is then converted to the hydroxy acetic acid The acetic acid may then converted directly to the desired acetic By an alternative reaction the acetic converted into an acetic acid or the acetic acid is reduced to an acetic and if the alk group of the acetic is the methylene group it ma be further converted to a heterocyclic group whereby the acid a oarboxylic acid or a salt thereof latter compound can be converted a oarboxylic acid or a salt thereof process is used to prepare the compounds of structural formula II excepting the lower alkene and process is used for this process may be illustrated followsί Process A for Preparation of Formula II Equivalents and are as previously excepting auch groupe as later f 1 Reactions and Step Reaction with a cyano such as sodium potassium hydrogen lower ketone and the like hydrogen cyanide with an amine such as a or tertiary aliphatic amine 7 and trimethylamlnG in a solvent such as lower alkanols 9 and the liquid hydrogen cyanide 11 mixtures water and 12 the above organic lower acids 13 and the and mixtures of the acids and above using liquid hydrogen cyanide as reactant as well as the at any suitable 17 preferably but especially 18 until the reaction is substantially Step 2 Reaction with a mineral acid 20 hydrogen sulfuric phosphoric 2 and the preferably fortified hydrochloric 22 in an inert such as lower alkanols 23 2i tetrahydrofuran and the preferably employing the acid as the solvent between temperatures of and preferably at or 27 below temperature until the reaction is substantially 1 Step Reaction with aqueous alkali or alkali earth 2 such as and strontium or alkali and alkali earth hydroxides with lower alkanols and the 6 ethylene and the aqueous ammonium 7 hydroxide organic as lower aliphatic 8 and the preferably aqueous sodium 9 or potassium but especially concentrated 10 aqueous sodium hydroxide using 11 above aqueous hydroxides as the solvents or alkanols as the preferably using the aqueous hydroxide reactants as solvents a any desirable temperature to preferably at or near until the reaction is substantially Step Reaction with an acid such as lower 18 propionic acid and the 19 inorganic such as 20 phosphoric hydrochloric and the 21 and with phosphorus and iodine or hydrogen 22 preferably phosphorus and using the abov 23 acids as solvents also or 2 and the preferably the above acids as solvents at elevated temperature until reaction is substantially Reaction in an usi strong aclda auoh 2 as uene sulfonic 3 trichloroacetic a mixture of acetic acid and sulfuric and the like toluenesulfonic in an 6 solvent such as aromatic compounds 7 toluene xylene and the 8 lower alkanolc acids 9 propionic and the preferably acetic 10 acid or tetrahydrofuran at elevated temperatures 11 preferably at or near the reflux 12 temperature of the until the reaction 13 substantially Step a eatalyst such as or Raney preferably platinum oxide under moderate hydrogen pressure 17 preferably in an inert solvent as 18 lower alkanols and 19 aromatic compounds 20 and the 21 and the like at any suitable temperature 222 to the reflux temperature of the s 23 preferably at room in ethanol until 2k the reaction is substantially Step Reaction with diazomethane in an 26 such as aromatic hydrocarbons 27 and the or various at ambient 28 temperatures until the reaction eaction at elevated temperatures until reaction ia substantially on a steam 1 In Step 1 when it is desired to the cyanide 2 it is necessary to have the reaction mixture at a pH 3 below This is necessary in order to have the cyanide salt react as the When the preferred procedure is using hydrogen the use of an such 6 as piperidine or a tertiary is highly 7 although not absolutely 8 In Step an acid condition is necessary to 9 obtain this and those acids as previously indicated 10 may be The reaction may be run above a temperature of 11 when higher temperatures are a mixture 12 of the desired compound as well as the alkylenyl acid is 13 and it is possible that the reaction may be run at temperatures wherein only the alkylenyl acid compound is 16 In Step the reaction may be properly carried 17 out only under acid A dilute to concentrated acid 18 reaction mixture may be it la preferred carboxylic 19 to use a concentrated reaction preferably an aliphatic 20 acid such as acetic The nltro ketones may be converted 21 to the as previously described 22 prior to Step above or the nitro ketone may be first 23 converted to the nitro acid compound and the nitro group converted to the desircjd substituent at this It is to be noted that when a 26 or alkanoylarnino group 27 the acetic acid compound is prepared 28 after which the compound is nitrated to the desired nitro and the nitro compound tly converted to the other desired groups by the processes previously In Step generally an excess of diazomethane in an inert such as is added to the methylene compound at ambient After the excess diazomethane may be When the i methylene acid is the diazomethane also the free is obtained as the This ester may be converted to the acid by hydrolysis or converted to other compounds of this In Step o is formed as the ester when obtained directly from Step this step may be carried out on the free acid When the ester is the free acid may be obtained from the ester by 1 Process B Fo Preparation of 2 This process be used when Structural II 3 is desired wherein X is and a lower lower lower or halo lower this the acid 6 compound of Structural prepared as previously 7 is converted to an through a series 8 of reactions is alkylated to an compound 9 followed by conversion back to the desired 0 The process may be represented as follows 1 Equivalent a t 2 R la a lower lower lower or 3 halo lower Reactions and of Process Reaction a lower alkyl such as 6 diethyl dlbenzyl and the preferably dimethyl oxalate and with 8 a strong such as potassium 9 sodium sodium sodium hydride 0 methyl and the preferably an alkali 1 and especially potassium 2 in an inert such as aromatic solvents 3 and the like preferably aromatic solvents and especially at any suitable temperature preferably at elevated 6 but especially at or near the reflux 7 temperature of the system until the reaction substantially Step Reaction of the alkali enolato with a lower isopropyl ethyl 3 and the lower iodide and the lower alkene 6 halide and 7 the or a lower alkyne halide l 8 chloride and the 9 preferably a lower alkyl iodide and especially methyl iodide in an enolate 11 such as 12 and dimethylaulfoxide at any 13 suitable temperature to preferably elevated temperatures until the reaction is substantially Reaction an alkali such as sodium 1 methoxide an inert such as aromatic and the preferably 19 lower alcohols and especially methanol at any 20 suitable temperature to preferably 21 elevated and especially at or near 22 the reflux temperature of the system until the 23 reaction substantially followed by addition an aqueous dilute mineral auch as hydrohalic sulfuric and the 26 preferably hydrochloric Step Conversion to the corresponding acid by any 28 known auch as or hydrolysis preferably with an inorganic and neutralization of the acid with a dilute 1 In Reaction Step the type of ester used is 2 not since the ester is used primarily as a 3 tecting The amount of alkoxide oxalate used is only a factor in obtaining higher yields of less than equimolar ratios may be 6 it is preferred to use an excess of both the 7 xide and 8 In Reaction Steps and the molar ratios 9 of reactants are not critical as in Step are 0 only a factor in obtaining higher 1 Reaction Step is simply the conversion of 2 the ester back to its corresponding which can be 3 carried out by any known one such means being cated and If it is this step may be and the esters of Step will represent still 6 other compounds of Structural Formula The and substituents of the starting 8 in this process may be 9 lower trifluoromethyl lower 0 lower lower alkyl and 1 When the other and groups 2 are the 3 acid or ester compound may be converted to the desired group by proper reaction of the nitro stituent according to the description described The process for the preparation of the compounds of Group may be illastrated as Equivalents R is H or lower allcyl is lower Reactions and Conditions of Process A 2 Reaction with a thlonyl sulfuryl chloride 3 and a lower alkanol using the sulfuryl halide as solvent also or with an inert such as aromatic solvents and the 6 or alcohols and the like at any suitable 7 to preferably at elevated temperatures and especially or near 9 the reflux temperature of the until the 10 reaction is substantially complete to produce 11 the compound wherein R is lower alkylj or 12 the compound wherein R hydrogen ia 13 reaction with sulfuryl chloride without employing the thionyl halide and the Controlled 16 Step hydrolysis by any such as reaction in water with a dilute inorganic such as 18 dilute sodium potassium 19 and the or in water itself at any 20 suitable temperature to 21 preferably at ambient temperatures until the 22 reaction is substantially 23 Step Reaction with an alkali such as sodium fluoride and potassium in a high boiling such as diethylene at elevated temperatures preferably about 27 until the reaction is substantially Step Reaction with an alkali alkoxide and a lower alkanol in an inert such as solvents or using the alcohol itself as the solvent at any suitable temperature below room temperature until the reaction is substantially and when R is followed by addition of a mineral such as sulfuric and the preferably dilute hydrochloric to make the reaction mixture 1 In Reaction Step it is not required that the 2 be the eulfuryl chloride may be used 3 alone to chlorinate the It is preferred to use the sulfuryl compound both as the chlorinating agent and as solvent to produce the Although one may 6 use the acid instead of the ester to place the desired 7 upon the molecule use of the ester is 8 Reaction Step can be easily carried out by placing the preferably the in 10 water and an inert The sole purpose of the 11 solvent is to afford solubility of the reactant and it is 12 not required when the reactant is soluble in water 13 The use of base increases the ability to the compound and although is not needed In Reaction Step is preferred to use a 16 small amount of potassium iodide to act as a 17 The reaction ia generally carried out at temperatures of 18 and 19 In all of the above the and group 20 may be trihalomethyl or lower 2 the other and groups are the nitro aubstituent 23 is used and converted to the desired group as described after the final is In the process for preparing the compounds of 26 Group the acid is converted to the 27 as indicated The amide is reacted with 28 a dehydrating agent such as 0 S0C1 1 and the like in an inert solvent which 2 will dissolve both the dehydrating agent and the 3 preferably or pyridine as at any suitable temperature to preferably at elevated until the reaction is substantially The nitrile 6 thus produced is by reaction with an alkali 7 amide or hydride such as potassium hydride or sodium 8 amide preferably the and with a lower alkyl 9 halide such as methyl propyl and the 10 like preferably with methyl in an inert solvent 11 preferably at 12 temperatures above preferably at elevated temperatures 13 especially at until the reaction is substantially The alkyl nitrile compound is then hydrolyzed by any many such as 16 dilute aqueous mineral acid hydrolysis 17 sulfuric preferably hydrochloric in an inert 18 solvent in which both the water and nitrile are 19 such as acetic at any suitable temperature to 20 preferably at elevated until the 21 hydrolysis is substantially complete to a the 22 alkyl compounds of structural Pormula 23 In the reactions of group the substituents on the starting acid may not cyano or lower When these groups are 26 desired the group is first made from the 27 nitro followed by reaction of the nitro 28 group to the desired as described 1 Preparation of of Structural Formula IV 2 The preparation of compounds of Formula wherein 3 X is may be carried out b the following In this process the starting material is the yl known trifluoromethyl ketone or a substituted 6 trifluoromethyl which is prepared by 7 procedures similar to those previously 8 the reaction of an appropriately substituted 9 compound with trlfluoroacetic This 10 starting trifluoromethyl ketone is treated with a 11 carbalkoxymefchylene ohenylphospho ane to form the 12 which 13 is subsequently reduced to form an This ester is then reacted with a Grignard reagent to form a This 16 compound is then dehydrated to form a which is then oxidized to form the desired 18 acid The process be illustrated as 2 3 R3 and are as previously described with the exceptions hereinbelow Reactions and Conditions 2 Step Reaction with a lower carbalkoxymethylene phosphorane in an inert such as ethers and aromatic solvents and the preferably solvents and 6 especially at any suitable temperature 7 temperature to at elevated 8 temperatures and especially at or near until the reaction is substantially 10 Step Catalytic reduction in an inert such as and lower alkanolc preferably lower alkanols and especially 13 in the presence of a such as platinum palladium and the like preferably platinum under an atmosphere of 1 preferably greater pounds of hydrogen 17 but especiall pounds of hydrogen 18 at any suitable temperature to 19 preferably at ambient temperatures until 20 the reaction is substantially 21 Step Reaction with diphenylmagnesiuin bromide in an 2 such as ether or preferably at any suitable temperature to reflu j preferably at or near the reflux temperature of the until the reaction substantially followed by addition of an aqueous mineral hydrochloric and the or with an 1 aqueous halide preferably with 2 a dilute especially aqueous 3 sulfuric Dehydration by heating at any suitable temperature until all of the water is substantially split 6 out of the 7 Step such as by reaction with 8 trioxide in an inert solvent alkanoic 9 such as acetic propionic and 0 the preferably glacial acetic acid at an 1 suitable temperature temperature to 2 preferably at or near the reflux of 3 the until reaction is substantiall complete followed by addition of mineral acid hydrobromie 6 and the preferably aqueous sulfuric 7 1 In Reaction Step the mineral acid or 2 ammonium halide employed is used to hydrolyze the 3 nard addition Under these any of the many means to hydrolyze Grignard 5 i products may be 6 In Reaction Step it is preferred to first 7 remove the solvents of the product from Reaction Step 3 8 before dehydrating the the dehydration 9 step may be carried out directly on the reaction mixture 10 of Step In this the reaction mixture of Step 11 is continuously whereupon the solvent is 12 removed followed by the splitting of water from the 13 The temperature required in this dehydration step will vary depending upon the product as a practical the crude mixture is heated 16 to the minimum temperature required to split out the water 17 without substantially affecting the product thus 18 In Reaction Step any of the many 19 oxidation procedures for unsaturated compounds may be 20 In addition to the one procedure previously 21 oxidation may also be carried out with the use 22 of potassium permanganate under alkaline or acidic 23 Another appropriate method is the ozonation of the unsaturated In this procedure the unsaturated compound is placed in a such as methylene 26 at low temperatures an excess of 27 ozone the solvent removed and replaced by another 28 such as glacial acetic whereupon aqueous 1 hydrogen peroxide is added to complete the In 2 the procedure previously the mineral acid is 3 used to the chromate ester which is after the Under these any variety of procedures in the art may be used 6 to hydrolyze 7 In carrying out this Process the 8 group is restricted to 9 lower lower and 10 sulfamyle it desired to obtain the 11 acid compound containing other 12 the final acid cotapound is nitrated and 13 then treated according to the procedures previously described to obtain the desired The compounds of Formulas and IV of this wherein X is other than may be prepared from the corresponding acid 18 The process for the preparation of the esters 19 may be carried out by reaction of the corresponding 20 acid with a strong such as hydrochloric 21 sulfuric toluenesulfonic 22 benzenesulfonlc and the like 23 concentrated sulfuric and with the appropriate The alcohol may be as a solvent also or inert such as or 26 may be The reaction may be carried out 27 at any suitable it is preferably 28 carried out at or near the reflux temperature of the 1 Esterifications are reactions the and 2 although a particular esterirication reaction is indicated i 3 the acid may be estejfied by any known When the alcohol is not suitable for use as a inert solvents are used along h the When using 6 as the alcohol for the it is 7 highly preferred to azeotrope the formed 30 as 8 allow ester Another highly suitable procedure 9 for this esterification step is the reaction of the 10 acid with at least one of a as 11 and appropriate alcohol 12 in an inert such as 13 The process for the preparatio of the compounds of this may be carried out by reacting the corresponding acid with thionyl 16 thionyl phosphorus phosphorus 17 phosphorus or phosphorus 18 pentabromide in an inert solvent as ethe tetrahydrofuran and 20 the like followed by reaction with an excess of the 21 desired amine at any suitable temperature to 22 room temperature or reaction with hexylearbodlimide and an excess of amine at any temperature until the reactio is substantially primary amides are ammonia may be when secondary amides are primary aliphatic or aromatic amines are employed such 28 as and the To obtain cyclic cyclic amines such as and like It generally preferred to run this reaction with the amine acting as the solvent however when this cannot be conveniently an 6 solvent such as indicated above may be In it is preferred to remove the excess reagent 8 and acidic reaction prior 9 the addition of the the acid may be 10 neutralized b using an excess of the amine An 11 procedure is to react the acid compound with 12 dicyclohexylcarbodiimide and the desired 13 three components may be mixed at any suitable are preferably mixed at temperatures for several The 1 bodii ide procedure is exclusively used when the and groups are affected by the acid 18 Such groups are the monoalkyl and 1 and 20 The process fo the preparation of the aldehyde 21 compounds of invention may be carried out by reacting 22 the corresponding biphenyl acid compounds with a such as thionyl thionyl phosphorus phosphorus phosphorus phosphorus and but preferably thionyl chloride in a inert solvent to form acid and subsequent reduct on of acid chloride to 28 the The inert solvent sed may be 1 ethers or 2 the preferably benzene or Any suitable 3 te be employed to it is preferred to use temperatures at or near the reflux temperature of the system until the formation of the 6 acid halide is substantially The acid halide is 7 then reacted with a Rosenmund catalyst such as Pd on 8 or with a alkali 9 or alkali earth aluminum such as 0 or lithium aluminum hydride and the The 1 reduction is preferably carried out with a 2 or alkali earth aluminum hydridet particularly wi h tritertiarybutoxy lithium hydride In tetrahydrofuran or the solvent also be ethers 6 and the The reaction may be carried out 7 at any suitable temperature to room but preferably to until the reaction substantially It is preferred to remove the inorganic acid formed after the acid halide the 2 inorganic acid would preferentially consume the subsequent 3 addition of the if it is the inorganic may remain if an excess of the hydride is used to react with the inorganic acid as well as with the acid When the butoxlde reagent it preferred to use temperatures below If temperatures above are the reduction will lead to the 1 corresponding alcohol instead of the As 2 although higher may be it 3 is not economically for a reaction temperature will be reached wherein the corresponding alcohol will be almost exclusively if the this is still another way of going directly 7 from the acid to the 8 In the preparation of these 9 sold starting materials containing the primary 10 secondary amino group and group may not 11 be used unless these groups are protected some 12 may be accomplished by benz the amino grou prior to this During the the acid group will be reduced to the aldehyde and the protected amino group will be debenzylated to yield 16 desired amino 17 The process for the preparation of the acetal 18 compounds of this invention may be carried out by 19 reacting the previously prepared aldehyde compound with 20 a lower alkanol in the presence of a strong Examples 21 of strong acids contemplated for this reaction are 22 toluenesulfonic 23 mineral acids sulfuric and It is preferred to use a catalytic amount of toluenesulfonic acid or concentrated 26 chloric acid in a lower alkanol 27 and the at any suitable 28 the solvents used may be aromatic compounds or 1 combinations of the alcohol and ethers as well as the alcohol 2 The reaction temperature is not 3 temperatures from C to reflux may easily be although ambient temperatures are The quantity of acid is not all that 13 required is that the acid 6 be of sufficient strength to catalyze the 7 the reaction may be carried out by 8 employing the aldehyde and the appropriate lower alkyl When it is desired to isolate acetal 0 and water is to be used in the the reaction 1 mixture must be neutralized with base such as sodium 2 carbonate so as to prevent the hydrolysis of the acetal 3 back to the The alcohols of th s invention may be obtained by reaction of the corresponding acid compound with an alkali or alkali earth aluminum Almost any 7 solvent may be used as long as it is inert to the hydride and the reactants have 3ome degree of solubility in 9 Preferred inert solvents are tetrahydrof an diethyl 0 The temperature of this reaction is not criticalj 1 under these temperatures from 2 to reflux are well within the contemplation of 3 this The complex metal hydrides such as aluminum and the like used may be less than the theoretical it 6 to use of the preferred lithium 7 aluminum After the the excess hydride 8 is decomposed by addition of ethyl acetate or an active 1 hydrogen such as or dilute 2 aqueous mineral The alcohol compound obtained 3 reaction is in the form of its and therefore an aqueous acid is used to convert the alcohol salt to the free Such acids may be 6 and the 7 This portion of the reaction is preferably 8 carried out at to ambient temperatures by first adding 9 water followed by dilute sulfuric The ester may 10 also be reduced using such catalyst as 11 When the former procedure is the and subatituents 12 may only be lower trihal lower and dilower alkylamino0 When the later procedure is used the and may be any group other than nitro or 16 The ether compounds of this invention are 17 prepared from the corresponding The alcohol is reacted with a strongly basic condensing agent such as 19 sodium potassium potassium tertiary 20 or and a lower alkyl 21 alkyl bromide or ethyl 22 bromide and the preferably sodium hydride and 23 excess of methyl Although dimethylformamide is generally used as the any hydrogen 5 solvent may be such as aromatic solvents 26 ethers 2 nd the The reaction is generally carried out 28 at ambient temperatures from 1 may be conveniently used The quantity of 2 reagents used will affect the yield of the 3 it is generally preferred to use an excess of the hydride and the excess hydride is used to consume any active hydrogen which may be present in the starting alcohol 7 since this reaction employs a strongly 8 basic condensing as in the first alcohol 9 the same limitations as to apply to this 10 reaction as did with that alcohol 11 It is to be noted that whenever a nitro group 12 is desired on the biphenyl ring and the synthesis of the 13 side chain will affect the nitro the nitro group Is placed on the biphenyl ring by prope nitration the side chain has been 16 The salts of the acid compounds of 17 this invention may be conveniently prepared by procedures 18 well known in the For the acetic acid may be reacted with an inorganic base in an inert solvent and the solution evaporated to yield the deaired 21 22 following examples are given by way of 23 illustrations 1 EXAMPLE 1 2 tophenone a of grams of magnesium turnings in 8 of ether is added a solution consisting of 5 grams of and 5 grams of ethyl 6 bromide in 50 of The solution is brought to 7 reflux and the remainin solution is added over a period of 25 maintaining gentle The 9 solution is then cooled and grams of cadmium chloride 10 is added wise over approximately 7 The fi 11 solution is refluxed for 1 after which it is 12 to room A solution of 6 of chloride 13 in 20 of ether is added with stirring over a period of 5 The solution is then refluxed for 15 mately 2 recooled to room and poured 16 onto a mixture of 1 liter of ice in of 17 hydrochloric The ether layer is separated and washed h 25 of water and dried over magnesium 19 The ether solution is then ographed on a 20 silica gel The column is eluted 21 petroleum ether to yield 22 lace 23 v Ίl EXAMPLE pheny ace tophenone 2 To a mixture of mole of terphenyl and 26 mole of acetyl chloride in 80 of carbon disulfide 27 added mole of aluminum chloride in small portions 1 over 30 This reaction mixture is then placed reaction mixture is cool 2 in a water bath at and the allowed to 3 to room The reaction mixture is then stirred for The reaction mixture is then poured into mixture of 10 of concentrated hydrochloric acid and 6 200 grams of ice and water added to bring the volume to 7 500 The reaction mixture is then stirred over a 8 period of 1 The reaction mixture is then extracted 9 with x The combined chloroform 10 extract is then with an excess of water and dried 11 over sodium The chloroform extract is then 12 filtered and the filtrate concentrated in vacuo to yield n 13 I EXAMPLE 3 16 To a mixture of grams of turnings 17 in 8 of ether is added with stirring 3 of a solution 18 of of phenyl arid grams of 19 ethyl bromide and of dry The mixture 20 heated in a water bath and the remaining portion of the 21 bromobiphenyl solution is added dropwlse over a period 22 of After the 23 mixture is refluxed for approximately 2 At this the mixture is cooled and grams of cadmium chloride is added portionwise over a period of 3 26 The reaction mixture is refluxed for an additional 27 and a solution of 6 of acetyl chloride and 1 20 ml of ether is The mixture is refluxed again 2 for an additional hour and cooled to room temperature 3 The mixture is then poured a soluti on of 1 li ter of ice in of hydrochloric The ether 5 is then separated and over magnesium sulfate The 6 ether solution is then in vacuo to yield a 7 crude This residue is then dissolved in a 8 minimum amount of ether and chromatographed on a 9 silica gel column to yield henone 0 1 When i hylbiphenyl and 2 chlorobiphenyl are used in place of 3 in the above example there are obtained phenylacetophenone and 3 5 EXAMPLE 6 o th l ketone 7 To a cooled mixture of grams of aluminum 8 chloride in 100 of ethylene dichlori de ia added a 9 solution of 20 grams of and grams 0 of ace yl chloride in 50 of ethylene 1 After complete the mixture is allowed to slowly 2 come to room The reaction mixture is then 3 poured in to 300 of water and the resultant mixture is separated and the aqueous layer extracted with 150 5 of methylene chlori The combined organic layer is then 6 concentrated in The due thus obtained is 7 dissolved a minimum amount of benzene and chromatographed 1 a gel column using petroleum ether and 2 benzene as eluents to yield 3 EXAMPLE 5 zoic acid 6 Mole of 7 in 30 of dioxane is added to an aqueous solution of 8 mole of sodium hypobromite and the resulting mixture 9 stirred at room temperature for 1 The mixture 10 then warmed to and stirred for an additional 2 hours 11 at that temperature The reaction mixture is then 12 trated in vacuo The alkaline solution is treated with 13 sulfur dioxide and then acidified with dilute hydrochloric The mixture is then filtered and the cake washed with x 10 dilute hydrochloric The cake is 16 then dried vacuo to yield 18 When 19 hylsulf 20 acetophenone phenyl ophenone 22 rophenyl and trophenyl used in place of the th above there are obtained the corresponding 1 EXAMPLE 6 2 3 acid chloride Mole of phenyl acid and 02 of thionyl chloride are added to of After the initial the 7 is refluxed on a steam bath for 2 The reaction 8 mixture is then concentrated in 20 of benzene 9 and again concentrated in vacuo 0 azoace tophenone The residue obtained from Part A is added to 2 of cold ether and the solution added to 3 an excess of The reactio mixture to warm to room temperature and stirred for 6 The 5 solvent is removed in vacuo to yield crude 6 nitrophenyl 7 When the benzoic acid compounds obtained from 8 Example are used in place of tr ophenyl 9 acid in the above there are obtained the 0 ponding diazoace 1 when 2 hi 3 benzoic and benzoic acid are used in place of zoic acid in the above there are obtained the corresponding 6 1 EXAMPLE 7 2 Ethyl 3 To a solution of mole of diazoacetophenone in of ethanol at is added 5 portionwlse a slurry of 3 grams of freshly precipitated 6 silver oxide in 30 of ethanol and the reaction mixture 7 on of the rogen the Θ reaction mixture is re for approximately 1 subsequently treated with and the 10 filtrate concentrated in The crude ester residue 11 purified by chromatograph on an alumina 12 using acetate as the 13 When the henones from Example 6 are used in place of ace ophenone in the above there are obtained the 16 corresponding ethyl esters 19 A solution of grams of 20 diazoacetophenone in 100 of dioxane is added dropwise 21 with stirring to a mixture of 2 grams of silver 22 5 grams of anhydrous sodium carbonate and 3 grams of 23 sodium thiosulf in 200 of water at The reaction mixture is stirred for an hour at a temperature of The reaction mixture then 26 diluted with 200 of and aoidified with 27 dilute nitric The reaction mixture is then filtered 1 and the cake washed with x dilute nitric fi 2 The cake is then dried in to yield 3 acetic When the diazoacetophenones obtained from 5 Example 6 are used in place of 6 acetophenone in the example there are obtained the corresponding 8 EXAMPLE 9 acid 10 A solution of mole of potassium hydroxide 11 in 3 of mole 12 of ethyl of 13 Additional water or methanol is added until the faintest cloudiness and the mixture is stirred overnight room To this reaction mixture is added 16 an excess of water and the methanol is removed in 17 The aqueous mixture then washed well with made 18 acidic h hydrochloric and extracted with 19 x The combined ether extracts are dried 20 over anhydrous magnesium the mixture 21 and the ether removed in vacuo to yield 22 bipheny3acetic 23 When the e hyl esters obtained from Example 7 are used in place of ethyl in 25 the above there are obtained the corresponding 26 ace ic 6 at room temperature for 1 houre The product is then 7 dissolved as much as possible by heating on a steam bath 8 and The raoist cake is treated with 500 of 9 hot ethanol and the catalyst removed by After 10 removal of the combined solvents in vacuo the product 11 thus obtained is dissolved in extracted with 2N 12 hydrochloric and recovered by neutralization and 13 extraction of the aqueous layer with ether The ether extract then dried over sodium the solvent removed to yield 16 17 When the nitro acids obtained biphenylylacetic acid 18 from Example the ethyl esters obtained from 19 Example the nitro benzoic acid compounds obtained 20 from Example 5 are used in place of phenyl 21 acetic acid in the above there are obtained 22 the corresponding amino biphenyYacetie amino ethyl 23 and amino benzoic acid compounds when 26 phenylacetophe 27 phenyl 28 butyrophenone 3 1 2 3 phenyl phenyl 5 propiophenones 6 butyrophenones are obtained by carrying out the 7 Crafts reaction using the propionic or butanoic 8 chloride in place o acetyl and 9 phenyl are used in place of 0 bipheny acid in the above there are 1 obtained the corresponding amino ketone compounds A suspension of 9 grams of acetic acid and l8 of concentrated hydrochloric acid 6 in 16 of water is heated until the solid 7 e solution is then cooled to the 8 chloride and grams of sodium nitrite 9 and 6 of water are added to the stirred mixture 0 After the suspension has remained in the ice bath for 1 of cuprous chloride dissolved in 2 2 0 of concentrated hydrochloric acid added dropwise 3 with vigorous stirring to the chilled The mixture is then stirred overnight at room At this the reaction mixture is poured into grans of 6 the product extracted with 200 and 7 the combined ether extracts washed successively with 1 water until dried over magnesium 2 and concentrated in vacuo to yield a residue s 10 6 are used in place of the acid 7 in the above there are obtained the corresponding 8 and chlorobenzoic 9 acid 10 when the amino ketone compounds 11 from Example 10 are used in place of 12 acid in the above there are 13 obtained the corresponding chloro ketone When cuprous bromide in concentrated hydrobromic acid is used in place of cuprous chloride in concentrated 16 hydrochloric acid above there is obtained When an equivalent amount of fluoroboric 19 is used in place of the cuprous chloride in concentrated 20 hydrochloric acid in the above the reaction 21 mixture and the residue placed 22 heated poured into and the 23 organic layer washed with dried over sodium and concentrated in there is 25 obtained To 19 grama of acid 17 of concentrated hydrochloric acid 30 grams 5 of ice is added grams of sodium nitrite in a small 6 volume of The reaction mixture is then added 7 portionwise with stirring over a period to 8 grams of potassium ethyl in 21 of water heated 9 at After stirring an additional the 10 reaction mixture is cooled and extracted with 75 11 The combined ether extracts are then washed 12 successively dilute sodium and 13 water to neutrality The extract is then dried and evaporated in The residue then dissolved 15 of and while the reaction grams of potassium hydroxide pellets are 17 added After complete the reaction mixture is refluxed until a few drops of water give an 19 almost clear The reaction mixture is 20 concentrated to dryness in vacuo The residue is then 21 dissolved in water and extracted three times with ether 22 to remove the alkali insoluble The alkaline 23 layer is acidified with sulfuric and extracted with The ether solution is then dried 2 ove sodium sulfate and concentrated in vacuo to yield 26 27 When the 28 and amino benzoic acid compounds obtained from Example 10 1 are used in place of acetic acid in the 2 above there are obtained the corresponding 3 and mercapto benzoic acid compounds when the amino ketone compounds 6 obtained from Example 10 are used in place of 7 acid in the above there are obtained the corresponding mercapto ketone 10 11 c acid 12 is mixed with 16 of water containing 1 gram of 13 To this reaction mixture is added dropwise of dimethylsulf ate while The reaction mixture is stirred for an additional 2 The reaction 16 mixture is then extracted with ether and the ether extract 17 washed with dried over sodium and 18 trated in vacuo The residue then dissolved in benzene 19 and chromatographed on 168 grams of silica The column 20 is benzene to yield hy liner cap 21 biphenyl acide 22 When dipropylsulf ate is used in place of 23 dime thylsulf ate in the above there is obtained 26 and mercapto benzoic acid compounds obtained 27 from Example 12 are used in place of 1 bipheny acid in the above there fj 2 obtained the corresponding henyjace tic 3 and methylmercapto benzoic acid compounds when the raercapto ketone compounds obtained from Example 12 are used in place of 6 acid in the above there 7 obtained the corresponding methylmercapto ketone 8 EXAMPLE 9 10 A mixture of mole of 11 excess potassium and 12 of 2N sodium hydroxide is stirred at room temperature 13 for 2 To the mixture is then added sufficient ethanol to consume the excess potassium permanganate The reaction mixture is then filtered and the filtrate treated 16 with an excess of dilute aqueous hydrochloric This 17 reaction mixture is then filtered and the cake washed with x 15 water to obtain 19 20 When pylmer c ap t ti c acid 21 and the me th 22 and methylmercapto benzoic acid compounds obtained from 23 Example 13 are used in place of 2if acid the above there are obtained the corresponding if 26 acetic methylsulf 27 and onyl benzoic acid compounds 1 the methylmercapto ketone 2 compounds obtained from Example 13 are used in place of acid in the above examples there are obtained the corresponding sulfonyl ketone 11 is treated with a slight excess of potassium 12 When the oxidation is the manganese dioxide is 13 removed by the filtrate concentrated to a small and the 15 acid is isolated by acidi ication with 16 chloric The sulfonic acid compound is then 17 ly dried and heated at reflux with an excess of thionyl 18 The excess thionyl chloride is then removed by 19 leaving a residue of 20 this residue is added a 21 solution of 100 of chloroform with an excess of 22 and the mixture stirred for an The 23 mixture is then washed with dried over sodium sulfate and concentrated in to yield ethyl 27 A solution of the ethyl ester thus obtained 28 in aqueous ethanol containing 2 equivalents of sodium 1 hydroxide is allowed to stand at room temperature for 18 2 The mixture is then concentrated in vacuo and 3 acidified with dilute hydrochloric acid to yield When the te a obtained 6 from Example 12 are used in place of ethyl pt 7 in the above example there are obtained the corresponding 9 acids 10 when the apt o ketone compounds 11 obtained from Example 12 are used in place of ethyl 12 in the above there 13 are obtained the corresponding ketone compounds EXAMPLE 16 16 acid 17 A solution of mole of 18 acetic acid in of hydrochloric acid is cooled 19 to and diazotlzed with mole of sodium nitrite 20 in of After the addition of 10 of 21 fluoboric the supernatant is decanted from the 22 remaining reaction This remaining portion of 23 the reaction mixture is warmed with 30 o toluene on a eam bath until evolution of nitrogen cooled mixture is extracted with dilute sodium 26 The alkaline solution is treated with 27 and extracted with x 2 The and concentrated c acids and esters ce of 5 blphenylacetic acid in the above there are obtained 6 the corresponding acids and 7 when the amino ketone compounds obtained 8 from Example 10 are used in place of 9 acetic acid in the above there are obtained the 10 corresponding fluoro ketone 11 EXAMPLE 17 acid 13 To a solution of mole of a hydrochloride yi of acetic acid in methanol is added gram of anhydrous sodium of 16 and grams of palladium on 17 The mixture is then hydrogenated at room 18 ture and The reaction mixture is filtered 19 and the solids washed with fresh The combined 20 methanol filtrate is then evaporated in vacuo and the 21 residue is extracted with boiling The benzene 22 extract is then evaporated in vacuo to yield amino When the acids obtained from Example 10 are used in place of the 26 acid in the above there are obtained 27 the corresponding 1 when the amino ketone compounds obtained 2 from Example 10 are used in place of 3 acetic acid in the above there are obtained the corresponding ketone compounds 5 6 7 A mixture of 10 mllllmoles of ethyl 8 3 of concentrated hydrochloric 9 and grama of ice is diazotlzed with by 10 adding a concentrated aqueous solution of sodium nitrite 11 until a slight excess of nitrous acid is presen The 12 solution la then carefully neutralized by adding solid 13 sodium This reaction mixture is then slowly added to a solution of 15 mllllmoles of cuprous cyanide 15 and 30 mllllmoles of potassium cyanide in 10 of water 16 maintained at The temperature of the solution is 17 slowly increased to until the salt 18 has The reaction mixture is then cooled and 19 rendered acidic and is extracted with x 20 The benzene solution is then dried and chromatbgraphed 21 on a silica gel column to yield ethyl 22 acetate 23 When the ethyl obtained 2 from Example 10 are in place of the ethyl 25 in the above there are obtained 26 the corresponding ethyl 27 when the amino ketone compounds obtained 1 from Example 10 are used place of ethyl 2 bipheny e the above there are obtained 3 the corresponding ketone When the amino tic acids obtained 5 from Example 10 are used in place of ethyl amino 6 bipheny in the above there are 7 corresponding 8 EXAMPLE 19 Ethyl 13 saturated with anhydrous hydrogen and the resulting mixture allowed to stand at room temperature for several The solvent is then removed 16 the residue triturated well with the ether 17 decanted from the 250 of water and 10 18 hydrochloric acid is then added to the residue 19 and the mixture refluxed or The cooled 20 reaction mixture is then extracted with x 50 21 the ether extract dried over anhydrous magnesium 22 and The ether filtrate 23 then concentrated in vacuo to yield ethyl yl 25 When the ethyl 26 obtained from Example 18 are used in place of ethyl yl in the above there 1 obtained the corresponding ethyl car bo phenyl 2 3 when the cyano ketone compounds obtained from Example 18 are used in place of ethyl Acetate in the above there are obtained the corresponding oarbobenzyloxy ketone 7 8 EXAMPLE 20 9 Ethyl 10 A solution of mole of ethyl in 200 of methanol 12 treated with hydrogen at room temperature and an initial 13 pressure of in the presence of grams palladium on When the theoretical yield hydrogen is the reaction mixture is 1 and the filtrate concentrated in This residue is 17 then partitioned between ether and dilute potassium hydrogen carbonate the layers the 19 ether extracted with fresh bicarbonate 20 and the bicarbonate layers The bicarbonate 21 reaction mixture is then washed with acidified 22 with hydrochloric acid with and extracted with 23 The ether extract is then dried over anhydrous magnesium and concentrated to yield ethyl When the ethyl 27 obtained from Example 19 are used in place of 1 the above 2 there are obtained the corresponding ethyl 3 bipheny when the carbobenzyloxy ketone compounds obtained from Example 19 are used in place of ethyl 6 in the above 7 there are obtained the corresponding carboxy ketone compounds 8 EXAMPLE 21 9 Ethyl 10 A mixture of mole of ethyl 11 blphenyiacetate and mole of sulfur tetraf luoride is heated at for 12 hours in a sealed stainless steel 13 After the bomb is vented to release all gaseous the residue taken up in washed 15 with dilute potassium bicarbonate and 16 dried over anhydrous magnesium sulfate The ether solution 17 is then and the filtrate concentrated 18 to The residue is then chrom tographed on a 19 silica gel column using an ether 20 system as to yield ethyl yi 21 t i 22 When the ethyl 23 obtained from Example 20 are used in place of ethyl carbox in the above there are obtained the corresponding ethyl 26 bipheny aceta chloride and the resulting mixture refluxed for 2 6 The excess thionyl chloride is then removed 7 residual acid halide is then taken up in of 8 dry ether and the resulting e solution slowly added 9 to a stirred solution of ammonium hydroxide over a 10 period of 30 minutese The reaction mixture is then 11 allowed to stir an additional hour at room 12 The reaction mixture then filtered and the cake 13 to yield ethyl 1 When the equivalent amount of di ropyl or in water is used in 16 place of the ammonium hydroxide in the above 17 there is obtained the 18 or th let esters 19 20 when the ethyl 21 obtained from Example 20 are used in place of ethyl 22 in the above there 23 obtained the corresponding ethyl biphenylacetateso when the carboxy ketone compounds 26 obtained from Example 20 are used in place of ethyl 27 carboxy in the above there are 28 obtained the corresponding carboxamido ketone 7 EXAMPLE 23 acid 9 A solution of of potassium hydroxide 10 in 3 of water is added to a cooled solution of 11 mole of ethyl acetate in 12 30 of additional water or added 13 until the faintest cloudiness and the resultin mixture stirred overnight at room Excess water is then added to the reaction the meth 16 removed in and the aqueous mixture washed 17 with The aqueous mixture is then made acidic with 18 hydrochloric extracted with 25 19 and the combined ether extracts dried over anhydrous 20 magnesium The ether extract is then filtered 21 and the filtrate concentrated in vacuo to yield 22 tri e tic 23 When the ethyl trif luoromet obtained from Example 21 are used in place of ethyl trif luorome in the above 26 there are obtained the corresponding 27 when the ethyl 2 acetates obtained from Example 22 are used in place 3 ethyl in the above l and dime thoxy ethane is used in place of methano 5 the above there are obtained the acids 7 EXAMPLE 2k β Me thyl tate 9 M thyl 10 The procedure of Example Part is 11 using methyl ate place 12 acid to obtain methyl 13 formyl yl Methyl 1 The residue obtained from A above is 16 with mole of lithium aluminum tertiary utoxy hydride in of a of 18 3 hours at The reaction mixture is then methyl 22 The residue obtained from B above la reacted 23 with mole of sodium borohydride in 2 of methanol at for 2 The reaction mixture is then 2 concentrated in vacuo to obtain methyl 26 pheny aoe t ate yl 1 Methyl ce ta te 2 The residue obtained from C above is treated 3 with of thionyl chloride at room temperature The reaction mixture then in vacuo to obtain a crude residue of methyl 6 yl Methyl 8 The residue obtained from D above is reacted 9 with loO gram of palladium on charcoal in 15 of 10 methyl acetate at over a period of 11 When the ethyl c lace ta tea 12 obtained from Example 20 are used in place of the methyl 13 in the above there are obtained the corresponding ethyl me phenyl 1 Me t hy 1 2 thy li dene bi lace tate formyl 19 To a solution of mole of methyl 20 ate in of benzene is added 21 mole of methylene triphenylphosphorane and the reaction 22 mixture stirred at room temperature for 2 hours followed 23 by the reaction at for an additional 6 hours The reaction mixture is then concentrated n vacuo to yield a crude residue of methyl 26 biphenyu 1 Methyl 2 The residue obtained from A above in 2 3 o methanol is reacted with of palladium on carbon of hydrogen pressure at room temperature until the theoretical amount of hydrogen is 6 taken The reaction mixture is then filtered and the 7 filtrate concentrated in vacuo to yield a crude residue 8 of methyl When ethylidene triphenylphos phorane is used 10 in place of methylene phorane in Part A of 11 the above example and the product thereof is reacted as in Part B there is obtained methyl 13 formyl when the ethyl 15 acetates obtained from Example Part are used in formyl place of the methyl in the 17 above there are obtained the corresponding ethyl yl 18 ethyl 19 EXAMPLE 26 20 When the lower alkyl obtained 21 in place of ethyl 22 trif in Example there 23 are obtained the corresponding lower alkyl 2 1 EXAMPLE 27 2 Ethyl phenyxacetate 3 To a solution of mole of ethyl 100 of benzene is added 5 mole of acetic anhydride and the reaction mixture is then 6 refluxed for 3 The reaction mixture is then cooled 7 to room washed with 8 benzene solution dried over sodium sulfate and concentrated yi 9 in vacuo to yield ethyl 10 When the amino ethyl esters obtained from 11 Example 10 are used in place of ethyl 12 acetate in the above there are obtained the 13 corresponding acetamido EXAMPLE 28 acid 16 A mixture of grams of 17 grams of and 8 of 18 morpholine is refluxed overnight under To the 19 solution is then added 105 of potassium hydroxide 20 and the reaction mixture refluxed for an additional 16 21 The reaction mixture is then filtered while hot 22 and the filtrate acidified with concentrated hydrochloric 23 The mixture is then filtered and the cake washed with x 10 The cake is then placed in 2 approximately 500 of the mixture boiled for 26 several and The filtrate taken 27 to a small volume in The solution is then heated 1 and added until it becomes The mixture is 2 then cooled and The cake thus obtained is 3 dissolved in chloroform and the solution evaporated to a small The solution is then diluted with an excess 5 petroleum cooled and the 6 solid washed with petroleum ether and to yield 7 l ce tic 8 When 9 and 10 are used in place of 11 the above there 12 are obtained l acid 13 cetic acid j acid 15 acid and 16 pheny acid 17 when the 18 19 20 21 and dime 22 phenones obtained from Examples 1 23 and 17 are used in place of in the above there are obtained the corresponding 1 EXAMPLE 29 acid 3 A mixture of 8 of phenyl methyl ketone grama of sulfur and 8 of 5 morpholine is refluxed under nitrogen for 16 hours 6 the reaction mixture added of potassium 7 hydroxide and the reaction mixture refluxed for an 8 additional 16 hours The reaction mixture is then 9 filtered while hot and the fi ltrate acidified with 0 concentrated hydrochloric acid and coole The reaction 1 mixture is then fi the cake washed with water 2 and dis solved in a minimum amount of chloroform The 3 chloroform solution is then taken to a small volume and an excess of petroleum e ther After begins the mixture is co oled in an ice subsequentl and the solid thus obtained washed with petroleum e ther and to yield yl 8 acid 9 EXAMPLE 30 0 ac id 1 2 To a solution of of hydrogen cyanide 3 containing of piperidine in an bath is added grams of 3 ophenone over a period of 8 minute s The solution is stirred in 6 the cold over a period of 80 minutes during which time 7 2 x ml portions of piperidine are 6 into the solution so as to saturate the The 7 solution is then allowed to warm to room temperature and 8 is stirred of water is then added and 9 the solution extracted with x 50 The 10 solution then washed with water and dried 11 over magnesium The ether solution is then 12 concentrated in vacuo to a 13 c d To 500 of the solid thus obtained in Part B 15 in 13 ral of methanol added a of of 16 potassium hydroxide in 3 of water and the mixture 17 refluxed gently under nitrogen for 15 To the solution is then added 25 of water and the solution extracted 19 with x The aqueous solution is then made 20 acid with dilute aqueous hydrochloric acid and 21 The cake is then washed with x 5 water and 25 methylmercapto 26 fluoro 27 dimethylamino and 26 obtained from Examples 1 and 2 respectively are used 2 of ophenone in the above 3 there are obtained the corresponding subs ti tut tic 5 and yl 8 EXAMPLE 31 yi 9 Ethyl oxala e 10 To a solution of 100 of carbon tetrachloride 11 and grams of ethyl oxalyl chloride at is added 12 with stirring 17 grams of aluminum chloride followed by 13 a solution of grams of in of After complete addition of the chloroform 15 solution 0 of ethylene 16 chloride is added and the reaction mixture allowed to rise 17 crone to room The reaction mixture is then 18 poured into 300 grams of ice and 10 hydrochloric 19 The organic layer is and concentrated 20 in vacuo The residue is then dissolved in a minimum 21 amount of ether and chromatographed 22 on grams of silica gel and Θ luted with benzene to 23 yield ethyl When henyl is used in place of and ethylene dichloride is used in place 26 of carbon tetrachloride in the above there is 27 obtained ethyl 28 1 EXAMPLE 32 yl 2 acid 3 To a mixture of grama of magnesium turnings in ml of ether is added with s tirring 3 grams of 5 methyl iodide After complete addition more methyl iodide 6 is added to consume any unreacted This Grignard 7 solut ion is then added dropwise to a cold stirred solution 8 of grams of ethyl in 9 of After complete additi the reacti on 10 mixture i s allowed to stir in the cold for an additional 11 The reaction mixture is then for 3 hours 12 and poured into 200 of sulfuric 13 acid soluti ons The ether layer is then washed with water and concentrated in to a crude syrupe The syrup is then placed in of potassium 16 hydroxide and refluxed for approximate ly 2 hours 17 The reaction is then poured into approximately 18 500 of acidified wi th hydrochloric 19 extracted with 2 x and the ether solution 20 dried and concentrated in vacuo to a The residue 21 then dis solved i n a minimum amount of methanol 22 and the filtrate concentrated in v The 23 residue is then di ssolved in a small volume of boiling benzene Sufficient petroleum ether is then added to 25 make the solution and after crystall on starts 26 a large excess of pe troleum ether is added and the mixture 27 allowed to remain at room temperature overnight The 28 mixture is then filtered and the cake washed with petroleum 1 and to yield 2 When ethyl is Used the above example in place of ethyl 5 bi phenyl there is obtained 6 7 EXAMPLE 33 8 t hyle o o e tic aci A of grams of 260 of sulfonic 11 acid and 30 of toluene is refluxed for hours and 21 acid and ce tic 22 acid are used in place of 23 ed 25 eny acid 26 27 1 2 and the 3 biphenylacetic acids obtained Example 30 and the and compounds obtained from Example 5 32 are used in place of 12 EXAMPLE yl 13 acid A mixture of gram of 15 acid and of platinum oxide 16 10 of ethanol is hydrogenated at room temperature 17 under The solution is then filtered and the filtrate concentrated in The crude material 19 then taken up in 25 of ether and the ether solution 20 washed with x 15 water and dried over magnesium 21 The ether solution is then extracted with 22 x aqueous sodium c The sodium carbonate 23 solution is then made acid by the addition of sufficient dilute hydrochloric and then extracted with ether and the ether extract dried over magnesium The ether solution is then 27 trated in vacuo to a crude solid of yl 28 biphenyVacetic When acid and acid are used in place of acid in the above there are obtained acetic a acid and when the biphenylylacetic acids obtained from Example 33 are used in of a cid in t he above there are obtained the corresponding l acetic EXAMPLE 35 acid To a solution of grams of acid in 40 glacial acetic acid is added gram of phosphorus and gram of The mixture is then refluxed for 16 filtered while and the filtrate poured into 150 of ice The mixture is then filtered and the cake thus obtained dissolved in washed dried over magnesium and the solvent removed vacuo to yield acetic When the acids obtained from Example 30 are used in place of acid in the above there are obtained the corresponding EXAMPLE 36 2 enyVace acid 3 acid acid A mixture of 100 of glacial acetic acid 6 and 150 of nitric acid is gradually added 7 to mole of ethyl in 100 of 8 glacial acetic The reaction mixture stirred 9 at room temperature for at which time the reaction 10 mixture is concentrated in vacuo to a The residue 11 is then on a silica gel column using 12 ether as the eluent to yield the 13 various fractions of ethyl ethyl and ethyl The ether fractions are 16 then concentrated in dryness and each residue is separately 17 saponified using the method described in Example 23 to 18 yield the corresponding nitro yl 19 When ethyl ethyl yl 20 cetate ethyl 21 acetate ethyl cetate ethyl 22 and ethyl l 23 acetate obtained from Example 7 are used in place of ethyl in the above there are 2 obtained the corresponding and 2 26 When the nitro compounds obtained from Example 36 are used in place of the acid in Example there are obtained the corresponding amino When these acetie acids are successively treated according Examples 11 14 and through the ponding appropriately substituted acids the mercapto compounds obtained from the above example are used in place of the acetic acid of Example 57 and the esters thus obtained treated in accordance with Example there are obtained the corresponding acetic EXAMPLE So a solution of mole of acid in 200 of acetate is added an excess of a solution of hane in The reaction mixture is stirred at room temperature for 16 At this the excess diazomethane is removed by the dropwise addition of acetic reaction mixture is concentrated in vacuo to a residue and the residue on 500 grams of silica gel using ether as eluent to yield 91 When the acetic acid obtained 33 are used in place of bip acid the above there are obtained the corresponding methyl 300 of is heated on a steam bath for the reaction mixture then added 20 of benzene and 300 of Osmium oxide and the reaction stirred for the reaction mixture is then poured into 25 of hydrochloric the organic layer is then washed with and on a silica gel using benzene as eluent to yield the methyl and obtained from Example are used and 92 When the lates from Example 38 and the obtained from Example 39 are used in place of ethyl acetate Example there are obtained the corresponding carboxylases and earbox 41 the from Example 40 are used in place of methyl in Example 39 and the compound heated above its melting there is obtained the corresponding 42 e mole of tic acid is added dropwise over a period of 5 minutes 100 grams of The reaction mixture is heated on a steam bath for reaction mixture is then in vacuo and to the residue is added of ether reaction mixture is then added dropwise to 500 of concentrated ammonium e reaction mixture is then stirred for an additional and cake washed with water until the washing is fhe cake is then dried in vacuo to yield 93 When and acids obtained 16 and 2 respectivel are used in place acid in the there are obtained the corresponding mole of 4 added phosphorus mixing for 30 of phosphorus added to reaction is then heated o a steam bath for 1 the phosphorus chloride is then removed in vacuo and the resulting reaction mixture poured into 200 of reactio mixture is stirred for 40 minutes and then extracted with x 50 combined ether extrac is then in vacuo to yield a crude of the 4 biphenylylacetamldes obtained Example 42 used in place of acetamide in the above there are obtained the ponding of pheny o 3 5 and 70 of anhydrous benzene is added mole of methyl iodide The reaction mixture is then allowed 7 warm to room temperature and then heated slowly to 8 for 1 The reaction mixture is then refluxed 9 for an additional 8 hours To the cooled reaction mixture 1G ia then added drop ise of 50 of 11 hydrochloric each of benzene 12 and After stirring for several the layera 13 are allowed to The aqueous layer ia extracted with x 25 benzene and the combined benzene solution 1 ia dried over sodium The benzene solution is 16 then filtered and the filtrate concentrated to a residue 17 to yield When ethyl iodide or propyl iodide are used in here ia nit ri le 21 22 when the 23 obtained from Example are used in place of in the above there are 25 obtained the corresponding 26 1 yi 2 3 To a mixture of mole in 100 of acetic 5 acid is added 15 of hydrochloric acid and the 6 reaction mixture refluxed for 19 The cooled reaction 7 mixture is then poured into a mixture of 500 of ice 8 extracted with and the ether extract dried 9 and concentrated to yield 10 11 When the obtained from 12 Example are used in place of 13 biphenylacetonitrile in the above there are fJ obtained the corresponding acid 17 A mixture of mole of methyl 18 grams of and Q grams 19 of potassium terti in 500 of benzene is 20 refluxed under nitrogen for hours The 21 cooled reaction mixture is then filtered and the cake 22 washed with x 0 benzene followed by x 23 ether and the cake dried A mixture of mole of this cake and mole of methyl iodide in 300 25 is stirred at room temperature 26 for then heated on a steam bath until the reaction 2 mixture is To the cooled reaction mixture is 1 then added mole of sodium in 30 of 2 methanol and the reaction mixture heated for an additional 3 2 hours on a steam The Cooled reaction mixture is then added to 1 liter o containing mole 5 of hydrochloric The reaction mixture is then 6 extracted with x 200 ether and the combined ether 7 extract washed with sodium and 8 The ether solution is then dried over sodium sulfate and 9 concentrated in vacuo to yield methyl 10 11 When ethyl iodide or propyl la used in 12 place of methyl iodide in the above example there is 13 obtained methyl or I methyl ate when the ethyl 18 lower ethyl dilower 19 ethyl dilower 20 and ethyl dilower 21 are used in place of methyl j 22 in the above there are 23 obtained the corresponding ac ate when 26 and 2 c o o ropyl iodide are used in place of 27 methyl iodide in the above there are obtained the 28 corresponding and 29 propyl phenyl compounds EXAMPLE 2 Methyl 3 A mixture of mole of k acid and 300 of thionyl chloride Is refluxed for 2 hours sulfuryl chloride is then added over a 6 period of maintaining a gentle reflux during 7 the The mixture is then allowed to stand 8 night at room after which the excess thionyl 9 sulfuryl chlorides are removed in The residue 10 then carefully poured into 200 of cooled 11 methanol and allowed to stand at room temperature for 12 The excess methanol is then removed in vacuo to yield crude methyl Ik When the c acids obtained from Examples and 27 and 16 the obtained from Examples and are used in place of acid l8 in the above there are obtained the corresponding 19 20 EXAMPLE 21 etlc acid 22 A mixture of mole of 23 acetic acid in of sulfuryl chloride is refluxed over a period of The mixture Is then allowed to stand for 1 hour at room temperature and the excess 26 sulfuryl chloride removed in vacuo to yield crude 27 1 When the acids obtained 2 Examples and 27 are 3 used in place of acid in the above there are obtained the corresponding lace tic 6 EXAMPLE i Methyl 8 To a mixture of 20 of diethylene 9 Oo02 mole of fused potassium and gram of 10 potassium iodide maintained at is added mole 11 of methyl The reaction 12 mixture then at for 19 The 13 reaction mixture is then allowed to cool to room temperature I and poured into a stirred mixture of Ice and The mixture is then extracted with 60 of 16 form and the chloroform extract is washed with water and 17 dried over sodium The chloroform solution is 18 then concentrated in vacuo and the residue taken up in 19 The benzene reaction mixture is then concentrated vacuo to yield crude methyl 21 biphen 22 When the a obtained from 23 Example are used in place of the 1 EXAMPLE 50 2 When the compounds obtained from 3 Examples and are placed a mixture of and dilute sodium hydroxide and the reaction 5 mixture is stirred for approximately 1 there are 6 obtained the corresponding hydroxy 7 EXAMPLE 8 acid 9 A mixture of mole of 10 acid in of anhydrous methanol is 11 added to an solution of grams of sodium 12 in of anhydrous The reaction mixture 13 is stirred in the ice bath until the reaction mixture is at room The reaction mixture is then stirred at room temperature for an additional 16 16 whereupon the mixture is refluxed for 1 hour and allowed cool 17 to to room temperature Dilute hydrochloric 18 acid is then added to the reaction mixture the 19 reaction mixture becomes The reaction mixture 20 is then in vacuo and the residue partitioned 21 between ether and The ether layer is washed with and extracted with aqueous potassium 23 bicarbonate solution The bicarbonate solution is then made acid with dilute hydrochloric acid and the reaction 2 mixture extracted with The chloroform 26 is then dried over sodium sulfate and concentrated in 27 The residue is then re crystallized from benzene to yield the obtained from Example 47 and the acids obtained from Example are used in place of acid in the above there are obtained the corresponding and EXAMPLE To a mixture of mole of methyl lacetate in 20 of ethanol is added a mixture of mole of potassium hydroxide in 2 of The reaction is then allowed to stir for 2 hours at room At this an excess of chloric acid is added to the reaction mixture and it is thereafter concentrated vacuo to yield crude When mole of blphenylylacetate is used as starting material acid is When the obtained from Example 49 are used in place of methyl in the above there are obtained the corresponding when the obtained from Example are used in place of methyl in the above there are obtained the corresponding 3 Mole of ketone and mole of triphenylphosphorane 5 refluxed overnight in 75 of dry The 6 reaction mixture is then filtered and concentrated in vacuo 7 the residue is chromatographed on 300 grams of silica gel 8 and eluted with ether to give the 9 desired Ethyl 10 is from petroleum 13 trlfluoromethyl 15 16 carboxamidobi 17 ethylbi 18 19 20 phenyl ketone are used in place 21 of trl ketone in the above 22 there are obtained the corresponding ethyl 23 methyl EXAMPLE 25 Ethyl tr 1 t 26 Mole of ethyl in r 1 containing gram of is reduced with hydrogen at 2 pounds of pressure and at room temperature When an 3 equivalent amount of hydrogen is taken the reaction mixture is filtered and concentrated to yield crude e thyl 6 When the compounds obtained from 7 Example 53 are used in place of ethyl 8 in the above example there are 9 obtained the esponding 10 EXAMPLE 55 Bi p phenyl trif hyl 12 13 To gram of activated 15 with in of dry ether containing 1 drop of 16 methyl iodide is added dropwise mole of bromobenzene 17 in 15 of The mixture is heated at reflux 2 hours 18 after the addition is To the cooled mixture 19 is added mole of ethyl thyl 20 propanoate in 0 of dry and the reaction mixture 21 allowed to reflux for 3 then allowed to stir at 22 room temperature The mixture is then poured 23 onto a saturated ammonium chloride solution and extracted well with The ether is washed with 25 and the ether solution concentrated in The residue 27 ether in petroleum to yield 28 1 1 fluorome 3 The crude alcohol Part A is dehydrated by refluxing with sulfonic acid in 5 toluene for 3 The reaction mixture is then 6 washed wi h and The residue is 7 chroma to raphed on 200 grams silica gel and eluted with ether to give phenyl 9 ome t h 1 ene 10 When the luorome 11 compounds obtained from Example 12 excluding the compounds containing the 13 hylsulf and sulfamyl are used in place of 15 propanoate in Part A of the above example and 16 the product therefrom carried through Part B of the above 17 there are obtained the corresponding 18 19 EXAMPLE 20 acid 21 To a solution of mole of 22 23 in 10 of chloroform and of glacial is added mole of chromium oxide in of After 1 the acetic acid is removed in 100 26 of sulfuric acid is The mixture is then 27 extracted well the ether extracts washed with 28 bisulfite then dried and 1 The residue is crystallized from hexane to yield 2 3 When the compounds obtained from Example 55 are used in place of phenyl 5 in the above there 6 are obtained the corresponding 7 acid a 8 EXAMPLE 57 9 Ethyl uoro ta 10 A mixture of 0 mole of luoro phenyl 11 acetic 6 of concentrated sulfuric and 12 200 of anhydrous ethanol sulfuric 13 is stirred at room temperature The solution is then concentrated vacuo to approximately 15 the 200 of water are added and the mixture 16 extracted with x 75 The combined ether 17 extracts are then washed with saturated potassium 18 bonate solution and The ether solution then 19 dried over magnesium and concentrated 20 to a The residue is then tographed on a 21 silica gel column gram an 22 e he ether system as eluent to 23 yield ethyl luoro When a solution of gaseous hydrochloric acid 25 ethanol is used in place of the sulfuric 26 solution in the above there is obtained ethyl 27 1 When 2 3 phenol an inert solvent and azeotrope the me 5 dime 1 6 and amino eye opy chloride reacting 7 the chloride reflux the acid and chloride 8 compound in dry isopropanol for 12 are used in 9 place of ethanol in the above there are obtained 10 the corresponding methyl ce acid 11 esters jj 12 when the acids 13 obtained from Examples I 3 52 15 and are used in place of 16 acetlc acid in the above there 17 are obtained the l esters 18 EXAMPLE 56 19 20 Mole of phen acid 21 is treated with mole of thlonyl chloride and the 22 resultant mixture gently heated on a bath for 2 23 hours The excess chloride is then removed in vacuo of benzene is added and the solvent again 25 removed in of dry 26 ethane is then added and the resultant solution slowly 27 added to a mixture of mole of potassium 1 in 100 of dimethoxyethane with 2 The resultant mixture is then stirred at room temperature 3 hours and then concentrated to a residue in The residue is then dissolved in washed with sodium and ohromatographe on a 6 silica gel column gram using an 7 petroleum ether system as eluent to yield 8 9 When sodium sodium sodium 10 sodium sodium and sodium 11 phenylethoxide are used in place of potassium 12 in the above there are obtained the correspondin 13 and phenylethyl esters when the acids 16 obtained from Examples l 17 36 2 and those compounds containing an active 19 hydrogen are used in place of 20 acetic acid in the above there are obtained the 21 corresponding ethyl 22 EXAMPLE yl 2 To a solution of mole of acid in 30 of tetrahydrofuran 26 is added mole of methanol followed by mole of 27 has been dissolved in 1 a minimum amount of The mixture is then 2 shaken thoroughly for a minute and allowed to sit overnight 3 The mixture is then the precipitated obtained is washed with a small portion of fresh and the wash combined 6 with the The combined filtrate3 are 7 trated to dryness The residue is then taken up In 100 8 of washed with bicarbonate 9 dried over magnesium and concentrated 10 to a residue then on 11 a silica gel column 50sl gram using an 12 ether system as eluent to 13 yield methyl When benzyl 15 and 16 dlmethylethanolamlne are used in place of methanol in the 17 above there are obtained the 18 and 19 esters of 20 acid reepectivelyo The eaters from the 21 ethanolamines are extracted from the ether solution 22 indicated in the above example using dilute hydrochloric 23 the acid solution washed well with made slightly alkaline with ammonium extracted with 25 the combined ether extracts washed with dried 26 over potassium carbonate and and the 2 resulting ether solution concentrated to a residue The volatile ethanolamines are then removed in 1 when the acids obtained 2 from Examples 3 52 and 56 are used in place of acid in 5 the above there are obtained the corresponding 6 ethyl 9 A solution of mole of sodium hydroxide 0 in l5 of water is added with stirring to a solution 1 of OoOl mole of luoro acid in 25 2 of At this additional methanol is added 3 as needed to obtain complete solution and the solution stirred for 1 The solution is then evaporated in 5 vacuo to obtain a residue of sodium luoro phenyl 6 acetate 7 When potassium hydroxide is used in place of 8 sodium hydroxide in the above there obtained the corresponding potassium 0 When 1 2 and choline are used in place of sodium 3 hydroxide in the above example and are dissolved in methanol in place of there are obtained the corresponding 5 6 and choline 7 acid salts 1 when the acids 2 obtained from Examples 3 3 52 4 and those compounds containing an active j are used in place of 6 acid in the above there are obtained the 7 ponding sodium 10 To a suspension of 0o005 mole of 11 lithium aluminum hydride in of anhydrous ether 12 is added dropwise a solution of mole of 13 acid with The reaction 14 mixture stirred at room temperature for 1 after 15 which time 10 of water is added dropwise with 16 coolinge The reaction mixture is then poured into dilute 17 sulfuric acid and the aqueous layer is extracted with 18 x 25 The combined ether extracts 19 washed with dilute and then 20 dried over sodium sulfate and concentrated in The 21 residue is then chroma to raphed on a silica gel column 22 and eluted with ether to yield 23 When the acids from 25 Examples 52 26 and 56 those containing an active 27 the acids of Example the lower and fluoro acids of Examples 33 land and the lower alkyl trifluorome thyl acetlc acids of Example 37 used in place of acid in the above there are obtained the corresponding alcoholSo The compounds of and are used in place of k c acid in the above after benzylating the active hydrogen grou to obtain the corresponding alcohols EXAMPLE 62 Methyl hyl ether To a suspension of mole of sodium hydride in of dry which has been cooled to is added dropwise a solution of mole of of The reaction mixture is stirred for 15 minutes and mole of methyl iodide is then added The mixture is allowed to stir overnight at room 200 of water Is added and the resultant mixture extracted well with The combined ether extracts are washed with dried over sodium and The residue is on 250 grams of silica gel and eluted with ether to yield methyl ethyl When ethyl benzyl 1 and ethoxyethyl chloride are vised place of methyl iodide 2 the above there are obtained the corresponding 3 and ethoxyethyl ethyl ethers respectivelyo 5 when the alcohols obtained from 6 Example 61 are used In place of 7 ethanol in the above there are obtained the 8 corresponding methyl 9 63 10 l ce taldehyde 11 chloride 12 To a solution of mole of J biphenylacetic acid in of benzene is added 1 mole of thionyl The solution is then heated on a steam bath for 1 subsequently concentrated in 16 vacuo to remove the solvent and any excess thionyl chloride 17 25 of benzene is then added and removed in vacuo to 18 yield a residue of 19 taldehyde 20 To a suspension of mole of 21 butoxy lithium aluminum hydride in of dry 22 hydrofuran is added dropwise with stirring a solution of yl 23 mole of henylacetyl chloride in 2 of dry tetrahydrof The reaction mixture is stirred 2 at for 3 hours followed by the addition of 200 26 of sulfuric added cautiously and the resultant 27 mixture extracted with x 75 The combined 1 ether extracts are washed with dried over 2 and The residue is chroma tographed 3 on grams of silica gel and with k petroleum ether to yield cetaldehyde When the acids obtained from 6 Examples 7 and those 8 containing an active and the 9 acids of Examples 33 and those with an active 10 and the lower trifluorome 11 and lower alkanoylamino obtained 12 from Example 37 are used in place of 13 acetic acid in the above there are obtained the l corresponding When the compounds of Examples 10 20 22 27 and containing active hydrogens 16 are benzylated and subsequently treated according to the 17 above there are obtained the corresponding 19 EXAMPLE 20 dimethyl ace al 21 To a solution of mole of k 22 in 100 of anhydrous methanol 23 is added mole of toluene sul onic The reaction mixture is stirred a room temperature for 5 5 A solution of sodium methoxide in methanol is 26 then added until the solution is just alkaline to moistened 27 The methanol is removed in vacuo and the 1 residue taken up in ether and washed well with 2 The ether solution is over sodium sulfate and 3 The residue is then chroma ographed neutral Elution with ether gives the dimethyl acetal of phenyl 6 7 When and are Θ used in place of methanol in the above example there 9 are obtained the corresponding die and 10 dibutyl acetals 11 when the aldehydes obtained from 12 Example 63 those containing an active 13 are used in place of in the above there are obtained the corresponding 15 dimethyl 16 when the aldehydes of Example 17 containing an active hydrogen are then treated 18 according to the above and then reduced 19 according to Example there are obtained the co 20 ponding 21 EXAMPLE 22 ce t amide 23 Mole of acid is slowly treated with mole of thionyl The resultant mixture is heated gently on a steam bath for 26 2 hours and the excess thionyl chloride remo ed in vacuo 27 To this concentrated material is added of 1 hane and the solution then added dropwiae to 2 100 of stirred ammonium hydroxide with The acetamide washed with and dried in vacuo When methyl ami e 6 3 hydroxy 7 methyl eye lohexyl 9 carboxyme thylaraine aminorae 10 2 11 l pyrrolidine 12 13 eth l and pyrrolidine are in the above example in place of ammonium there are obtained the corresponding subs 17 18 when the acids obtained from Examples 20 luoro and 56 21 those compounds containing an active 22 the Lace acids of Examples 33 and 23 those with an active and the lower trlfluorome lower alkanoylamino and acids obtained from Example 37 yl 26 are used in place of acid in 27 the above there are obtained the corresponding 28 amides 1 obtained from 2 Examples 33 3 56 containing an 3 active hydrogen are benzyl subsequently treated in accordance with the above and then reacted 5 according to Example there are obtained the 6 ponding 7 EXAMPLE 66 o 9 To a solution of mole of 10 acid in of thane is 11 added mole of trieth The resulting mixture 12 is and mole of 13 formate is addede Stirring is then continued in the cold for an additional 30 The triethylamine hydrochloride 15 is then removed by filtration and the cooled 16 Dry thoxye thane saturated with dry ammonia 17 gas then added and the ammonia gas bubbled through 18 the resultant mixture for approximately 1 The 19 mixture is then stirred at for 16 The solvent 20 is removed vacuo to yield 21 When 22 23 carbobenzyloxy 25 aminoraethyl 26 and 27 pyrrolidine are used in the above example in place of ii5 1 there are obtained the corresponding 2 3 when the c acids from Examples 5 52 and 6 those oompounds containing an active yl 7 the acids of Examples 33 and 8 those with an active and the alky 9 lower and carboxamido yl 10 ample 37 are used 11 in place of acid in the above 12 there are obtained the corresponding 13 when the compounds obtained from 2 The recrystallizatian is until the acid 27 obtained from the hydrolysis of a small aliquot of the 28 salt has a constant optical insufficientOCRQuality

Claims

1. X7 Substituted biphenylylacetic acids and eaters and amides thereof and the corresponding and salts of the formula wherein and both hydrogen or lower or one of them is hydrogen and the other is lower alkox as and the lower alkyl as and the lower lower halo lower alkyl as or and form together a methylene or ethylidene or togethe with the a cyclopropyl and of and one may be hydrogen and other one or both of them lower lower lower lower alky tri or with the that whereof and one is hydrogen ant other one is halo lower both and may independently be hydrogen or have any of the other connotations stated and provided further that where a or is the other must be 0 or X is wherein R is lower lower lower alk o lower lower a lower lower poly lower alkoxy lower poly h drossy lower or di lower wherein Y is lower hydroxy lower poly hydroxy lower phenyl lower lower al alkyl ilwer lower alkyl alkyl pyrrolidyl lower or both Y atom to which they are heterocyclic ring whose Y Y chain apart said nitrogen is one of the wherein is lower and wherein is is and the pharmaceutically salts 119 Compounds according to Claim 1 of the formula wherein a and have the same meaning as in Claim A compound according to Claim wherein is is n is 1 and is Compounds according to Claim 1 of the formula wherein is is lower halo lower lower lower or and form together a or ethylidene group or together with the a cyclopropyl group and and and X have the same meaning as in Claim A compound according to Claim wherein is lower is is is 1 and X is A compound according to Claim wherein lower la E is n is 1 and X is 4 3 A compound according to Claim wherein is is n is 1 and X is 120 Compounds according to Claim 1 of the formula wherein is lower or lower la hydrogen or lower being hydrogen when is other lower and have the same meaning as in Claim A compound according to Claim wherein is is is is 1 and X is A compound according to Claim wherein and are each lower is n is 1 and is ylylacetic Compounds according to Claim 1 of the formula wherein and X have the same meaning as in Claim 121 Compounds of formula A Claim substantially as described herein with reference to the A process preparing compounds of the formula I in Claim which comprises the following reacting a biphenylyl ketone of the formula 1 except that they are not amino or cyano with ammonium polysulfide in an inert solvent at elevated or with sulfur in an organic amine at elevated the compound obtained with an alkali metal or alkalisearth metal and acidifying to form a ylyl compound wherein and are other than or cyano and X is a carboxyl and if nitrating the compound obtained from step reducing the nitro compound obtained from step to the corresponding amino diazotizing the amino compound of step and reacting the compound thus with cuprous cyanide to the corresponding cyano reacting any of the compounds obtained from steps or with an alcohol in the presence of at least a catalytic amount of a strong acid to form the corresponding reacting any of the compounds obtained from 122 steps or active hydrogen with a thionyl halide or phosphorus halide in an inert solvent followed by reaction with ammonia or an organic primary or secondary or with dicyclohexylcarbodiimide and or with an organic primary or secondary compound wherein X of formula I is or reacting any of the compounds obtained from steps or groups containing active with a thionyl halide or phosphorus halide in an inert solvent followed by catalytic reduction with and quinoline under an atmosphere of hydrogen or reduction an alkali metal or alkaline earth metal butoxy aluminium hydride below to form a compound wherein X is reacting the compound obtained from with a lower alkanol in the presence of at least a catalytic ount of a strong acid to form a compound wherein X is when is or reducing the compound obtained from step is lower or with an alkali metal or alkaline earth metal or aluminium hydride in an inert solvent followed by reaction with an active hydrogen compound and a dilute mineral acid or with a dilute mineral acid alone or catalytically reducing the compound obtained from step wherein and are other than or to form a compound wherein is and 123 reacting the compound obtained from step with a strongly basic condensing agent in a lower alkyl halide in ah inert solvent to form a compound wherein is when is alk provided that when it is desired to carry out steps the halide method is or wherein the and groups contain an active these groups are benzylated prior to such and in the ease of step the benzyl group is reduced after carrying out this and when it is desired to obtain a nitro step is first carried out and subsequently the product obtained from this step is process according to Claim 19 for preparing a biphenylyl compound of the formula wherein and are both halogen or one of them is 4 which comprises reacting a biphenylyl ketone of the formula with sulfur in an organic amine at elevated metal hydrol the compound obtained with an and acidifying the reaction A process for preparing aeetic which comprises reacting acetophenone with sulfur in an organic amine at elevated and hydrolyzing the compound obtained with a alkali metal A process for preparing compounds of the formula I in Claim which comprises the steps reacting a compound of the wherein is a k carboxamido or with an alkali metal hypohalite in an inert consuming the excess hypohalite with a reducing agent and acidifying the reaction mixture with a mineral acid to form a acid reacting the benzoic acid compound in an inert solvent with an acid halide of an inorganic acid to a benzoyl halide reacting the benzoyl halide compound with diazomethane in an inert solvent at room temperature or below to form a diazoketone reacting the diazoketone compound with a lower and a silver copper or platinum catalyst in the lower alkanol as solvent or in an inert to form an acetate saponifying the acetate compound and the mixture with a mineral acid to form a acetic acid compound wherein X is and are 124 as defined or reacting the diazoketone of with water and a silver copper or platinum catalyst in water as the solvent or in an inert solvent to form the acetic acid compound of step if reducing any of the acid or ester compounds obtained from steps or wherein is to the corresponding amino acid or acetate alkylating the amino compound obtained from step with a lower alkyl halide to the mono or or acylating the amino compound obtained from with a lower alkanoic acid halide or lower alkanoic acid anhydride to the lower alkanoylamino or the amino compound obtained from step and treating the salt thus formed with a lower alkyl xanthate under alkaline conditions to alkylating the mercapto compound of step with a lower alkyl halide to form a lower alkylthio oxidizing the lower alkylthio compound obtained from step and reacting the product obtained with an amine to form a dilower admixing the diazonium salt of step with cuprous cyanide to form a cyano 125 subjecting the compound obtained from step to alkaline saponification to form a carboxamido and converting any of the compounds obtained in steps to A process according to Olaim 22 for preparing a compound of the formula given in Olaim 20 which prises the steps o reacting a compound of the formula wherein and are both halogen or one of them is hydrogen with an alkali metal hypobromite in consuming the excess hypobromite with sulfur dioxide and acidifying the reaction mixture with dilute hydrochloric acid to form a biphenylylbenzoic reacting the benzoic acid compound in ether with a thionyl halide to form a benzoyl halide reacting the benzoyl halide compound wit diazomethane in ether below room temperature to form a ketone reacting the compound in a lower alkanol with silver oxide at elevated temperatures to form an acetate acetate reacting with alkali metal base at elevated temperatures and neutralizing the mixture with 126 X dilute hydrochloric acid to form a acid or if reacting the compound of step in water with silver at elevated tures to form a acid process for preparing a compound of the formula II in Claim which comprises the steps reacting a compound of the formula CO excluding those compounds in which and represent the carboxamido and lower alkanoylamino with an alkali metal or alkaline earth metal cyanide and a mineral liquid hydrogen or a lower aliphatic ketone to form a biphenylyl cyanohydrin compound reacting the cyanohydrin compound with a mineral acid to produce a hydroxy amide reacting the hydroxy amide compound with a base to produce a hydroxy acid reacting the hydroxy acid compound with an and phosphorus and or hydrogen iodide in an inert solvent to form a biphenylyl earboxylie acid compound wherein X is is and is lower or if reacting the biphenylyl hydroxy acid compound of step with a strong acid in an inert solvent at elevated temperatures to form a biphenylyl compound 127 wherein X is CCOH and and form together a idenyl and reacting the compound obtained from step with diazomethane in an inert solvent to pound wherein X and and form together with the a pyrazolino or the compound thus formed to the corresponding and heating the carboxylic acid compound obtained from step to form a compound wherein X is or and and together with the atom form a cyclopropyl or catalytieally reducing the compound of step in an atmosphere of hydrogen to form a compound wherein X is is and is lower nitrating any of the carboxylic acid compounds obtained from step or to form a nitro reducing the compound of step to the amino compound and subsequently acylating the compound with a lower alkanoic acid halide or a lower alkanoic acid anhydride to form a lower alkaloylamino or the amino compound of step to fork a treating the diazonium salt with cuprous cyanide to form a cyano compound and subjecting this latter compound to an alkaline saponification to form a carboxamido and converting any of the compounds obtained in step or into the ponding compounds in which X is 128 or by the methods of steps to in Claim A process according to Claim for preparing a compound of the formula wherein and and are both halogen or one of them is which comprises steps reacting a ketone compound of the formula with liquid hydrogen cyanide under pressure at elevated tures to form a biphenylyl cyanohydrin compound reacting the cyanohydrin compound with trated hydrochloric acid below ambient temperatures to form a biphenylylhydroxy amide reacting biphenylylhydroxyamide compound with a concentrated aqueous alkali metal hydroxide to form a biphenylyl hydroxy acid and reacting the biphenylylhydroxy acid compound with an acid and phosphorus and iodine in an inert solvent at elevated or if the biphenylylhydroxy acid compound obtained step with toluenesulfonic acid in at elevated temperatures to form as 129 idenyl biphenylyl and reacting t e compound obtained from step with platinum oxide under moderate hydrogen pressure in a lover at ambient A process according to Claim wherein is used as starting material and compound obtained is acetic A process according to Claim wherein phenylacetophenone is used as starting material and the pound obtained is A process for preparing a compound of the formula II in Claim 5 which comprises the steps reacting a compound of the formula is alkyl lower lower phenyl lower trifluoromethylthio and is an alkyl with a lower alkyl oxalate and with an alkali tertiary alkoxide in an inert solvent to form a enolate ester reacting the enolate ester compound with a lower alkyl a lower alkyl a lower alkenyl or a lower halide an enolate solvent to form an enolate acetate reacting the enolate acetate compound with an alkali metal in an inert solvent followed by the addition of an aqueous mineral acid to form an acetate compoundj hydrolysing or saponifying the acetate compound and neutralizing with a dilute mineral acid to form a compound wherein X is if reducing the compound of step wherein is in the presence of a catalyst to the ponding amino compound if converting this latter by any of the steps or in Claim 22 into the corresponding lower cyano or boxaaiido compound if converting any of the in which is or A process for preparing a compound of the formula III in Claim 11 wherein is fluoro or lower alkoxy and is which comprises the steps reacting a acid compound of the formula X in Claim 2 with a thionyl halide or sulfuryl reacting the halide in a lower acetate compound obtained from step with an alkali metal fluoride in a alcohol to form an acid or acetate or reacting the acid 131 or aoetate compound of step with an alkali metal alkoxide and a lower and when the acid compound is used adding mineral acid to orm an lower if verting any of the compounds obtained in step or into the corresponding compounds in which X is by the of A process for preparing a biphenylyl compound formula III Claim having the formula wherein and are both halogen or one of them is hydrogen which comprises the steps acid compound according to Claim having the formula in which and are vith chloride at an elevated temperature to an acetic acid and reacting the acid compound with an alkali meta fluoride in diethylene glycol at an elevated process according to Claim wherein acid is used as starting 132 A process for preparing a compound of the formula III Claim 11 wherein and are each lower which comprises the steps reacting a ie acid compound of the wherein and be lower lower alk trifluorometh lthio or at least one of and being other than hydrogen and n and have the same meaning as in Claim a dehydrating agent in an inert solvent to form a acetonitrile reacting the acetonitrile compound obtained from step with an alkali metal amide or hydride and with a lower alkyl halide in an inert solvent to form an alk of step the acetonitrile compound form the corresponding compound wherein X is if reducing the compound of wherein is to the corresponding amino verting the amino compound into a mono o compound or into an the amino compound and converting the diazonium salt into a mercapto or cyano alkylating or oxidizing the mercapto 133 compound to form an alkylmercapto or alkylsulfonyl compound reacting a compound of the formula wherein and are each lower at least one said being other than H at any one time lower or with phenylmagneslum bromide in an inert followed by addition of a mineral acid or of an ammonium halide solution to form a dehydrating the compound by heating to form a oxidizing the compound to form a blphenylyl compound wherein X is if nitrating the compound of step to the corresponding reducing the compound to the amino and converting the amino compound into a 134 or d lower alk or alkano lamino wherein and are both halogen or or one o them is hydrogen and the other is which comprises the steps reacting a compound of the formula wit bromide in e ther at elevated tures by addition of aqueous sulfuric acid to form 135 a dehydrating the compound by heating to form a and oxidizing the compound with chromium trioxide a alkanolc acid at an elevated temperature followed by the of a mineral process according to 54 for preparing prises the o reacting a lower of acid with diphenylylmagnesium bromide in ether at an elevated temperature by addition of aqueous sulfuric acid to a the compound by heatin to form a oxidising the compound with chromium trioxide in a lower acid at an elevated temperature followed by the addition of aqueous sulfuric Processes fo the preparation of acetic acids and salts and derivatives according to Claim described reference to the Examples For the Applicants insufficientOCRQuality