Technical Field

This invention concerns a novel process for the production of novel quinoline derivatives which possess pharmacologically useful properties in antagonising at least in part one or more of the actions of substances known as angiotensins, and in particular of that known as angiotensin II (hereinafter referred to as "All"). The invention also concerns various quinoline derivatives which are valuable chemical intermediates, for example for use in the abovementioned process.

Background tr nvention

The angiotensins are key mediators of the renin-angiotensin- aldosterone system, which is involved in the control of homeostasis and fluid/electrolyte balance in many warm-blooded animals, including an. The angiotensin known as All is produced by the action of giotensin c srting enzyme (ACE) from angiotensin I, itself produced by t. action of the enzyme renin from the blood plasma protein angiotensinogen. All is a potent spasmogen especially in the vasculature and is known to increase vascular resistance and blood pressure. In addition, the angiotensins are known to stimulate the release of aldosterone and hence result in vascular congestion and hypertension via sodium and flu- retention mechanisms. AH inhibitors are useful for the reduction or prevention of these effects produced by the action of AH. Although a number of AH inhibitors and processes for tneir preparation are known, for example certain substituted imidazoles described in European Patent Application, Publication No. (EPA) 253310 and EPA 324377, certain benzimidazoles described in U.S. Patent no. 4880804 and certain pyrroles, pyrazoles and tri es described in EPA 323841, there remains a continuing need for alternative inhibitors and for effective synthetic procedures for their production such as those provided by this invention.

Certain quinoline derivatives which are structurally related to the novel quinoline derivatives obtainable by the process of the present invention are described in EPA 348155 as having leukotriene D4 antagonist activity.

In our co-pending EPA 412848 there is described a series of quinoline derivatives of formula I (set out hereinafter) wherein R is hydrogen, (l-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted (l-4C)alkyl, the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, hydroxy, (l-4C)alkoxy or phenyl

2 substituent; R is hydrogen, (l-8C)alkyl, (3-8C)cycloalkyl,

(3-8C)cycloalkyl-(l-4C)alkyl, carboxy, (l-4C)alkoxycarbony1, cyano, nitro, phenyl or phenyl(l-4C)alkyl; R 3 and R4 are independently selected from hydrogen, (l-4C)alkyl, (l-4C)alkoxy, fluoro(l-4C)alkoxy, halogeno, hydroxy, trifluoromethyl, cyano, nitro, amino,

(l-4C)alkanoylamino, alkylamino and dialkylamino of up to 6 carbon atoms, dialkylamino-alkyl of 3 to 8 carbon atoms, (l-4C)alkanoyl, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, carboxy, (l-4C)alkoxycarbonyl, (l-βC)alkylthio,

(l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, and substituted

(l-4C)alkyl, the latter bearing an amino, hydroxy or (l-4C)alkoxy

3 4 substituent; or R and R together form (l-4C)alkylenedioxy attachteedd to adjacent carbon atoms of the benzene moiety of formula I; Ra and R are independently selected from hydrogen, (l-4C)alkyl, (l-4C)alkoxy, halogeno, trifluoromethyl, cyano or nitro; A is methylene; X is phenylene optionally bearing a substituent selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro, or X is a direct bond between the adjacent phenyl group and moiety A; Z is lH-tetrazol-5-yl, -C0.NH.(lH-tetrazol-5-yl) or a group of the formula -CO.OR or -C0.NH.S0 ₂ .R in which R is hydrogen or a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol, and R is (l-6C)alkyl, (3-8C)cycloalkyl or phenyl; and wherein any of said phenyl moieties may be unsubstituted or bear one or two substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a non-toxic salt thereof; but excluding methyl 2-[(3-methoxycarbonylquinolin-4-yloxy)-

methyl]benzoate.

It will be appreciated that the compounds of formula I, depending on the nature of the substituents, may possess one or more chiral centres and may be isolated in one or more racemic or optically active forms.

In addition, in the compounds of formula I generic terms such as "alkyl" include both straight and branched chain variants when the carbon numbers permit. However, when a particular radical such as "propyl" is given, it is specific to the straight chain variant, branched chain variants such as "isopropyl" being specifically named where intended. The same convention applies to other radicals.

A particular value for R 1 or R2 when it is alkyl is, for example, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or hexyl; and when it is cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl.

A particular value for R when it is alkyl bearing one or more fluoro substitutents is, for example, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl; and when it is alkyl bearing a hydroxy, cycloalkyl, (l-4C)alkoxy or phenyl substituent is, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl or 2-phenylethyl.

2 A particular value for R when it is cycloalkyl-alkyl is, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or

2-cyclopentyl-ethyl; when it is phenylalkyl is, for example, benzyl,

1-phenylethyl or 2-phenylethyl; and when it is alkoxycarbonyl is, for example, me hoxycarbonyl, ethoxycarbony1 or propoxycarbonyl.

3 4 5 Appropriate values for R , R , R , or Ra, or for an optional substituent which may be present when X is phenylene, as defined

above, include by way of example:- for alkyl: methyl and ethyl; for alkoxy: methoxy and ethoxy; for fluoroalkoxy: trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy; for halogeno: fluoro, chloro, bromo and iodo; for alkanoylamino: formamido, acetamido and propanamido; for alkylamino: methylamino, ethylamino and butylamino; for dialkylamino: dimethylamino, diethylamino and dipropylamino; for dialkylamino-alkyl: dimethylaminomethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl and 3-(diethylamino)propyl; for alkanoyl: formyl, acetyl and butyryl; for -alkylcarbamoyl: N-methyl and N-ethylcarbamoyl; for di(N-alkyl)carbamoyl: N, -dimethylcarbamoyl and N, -diethylcarbamoyl; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; for alkylthio: methylthio, ethylthio and butylthio; for alkylsulphinyl: methylsulphinyl, ethylsulphinyl and butylsulphinyl; and for alkylsulphonyl: methylsulphonyl, ethylsulphonyl and butylsulphony1; for alkyl bearing an amino, hydroxy or alkoxy substituent: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 2-aminoethyl, 2-methoxyethyl and 2-ethoxyethyl; and alkylenedioxy: methylenedioxy and ethylenedioxy.

A particular value for R when it is a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol is, for example, a residue derived from a (l-6C)alkanol such as methanol or ethanol, or phenol, glycerol or the like.

A particular value for R when it is alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl or pentyl; and when it is cycloalkyl is, for example, cyclobutyl, cyclopentyl or cyclohexyl.

Particular values for optional substituents which may be present on one or more phenyl moieties include, by way of example, for halogeno: fluoro, chloro and bromo; for alkyl: methyl and ethyl; and for alkoxy: methoxy and ethoxy.

A specific value for X which is of particular interest is, for example, p-phenylene.

.

A preferred value for R or R is, for example, hydrogen and 1 for R is, for example, methyl, ethyl or propyl.

A preferred group of compounds described in our co-pending application comprises those compounds of the formula la (set out hereinafter) wherein R , R , R , R and R have any of their meanings as defined above and Z is carboxy, lH-tetrazol-5-yl or benzenesulphonamido, the latter optionally containing one or two substituents independently selected from halogeno (such as fluoro, chloro or bromo), (l-4C)alkyl (such as methyl or ethyl), (l-4C)alkoxy (such as methoxy or ethoxy), cyano, nitro and trifluoromethyl; together with the non-toxic salts thereof.

A preferred value for Z or Z is, for example, carboxy or lH-tetrazol-5-yl, which latter is especially preferred and, in particular, when it is attac' ''d ortho to the group X.

A particularly preferred combination of values in any of the above definitions is wherein the quinoline moiety together with the attached substituents R , R , R and R , and Ra when present, has any of the following values:- 2-methylquinoline, 2-ethylquinoline, 2-ethyl-6-methoxyquinoline, 6,7-dimethoxy-2-ethylquinoline, 2-ethyl- D , ⁽ .- ,7-trimethoxyquinoline, 2-ethyl-6-hydroxyquinoliπe, 2-ethyl-6- m. nylthioquinoline, 2-ethyl- ^" -hydroxymethylquinoline, 2-ethyl-6- ^■■ (2-fluoroethoxy)quinoline, 2-ethyl-6-(2,2,2-trifuoroethoxy)- quinoline, 2-ethyl-6-carboxamidoquinoline, 2-eth^l-6-fluoroquinoline, 2-ethyl-6-isopropoxyquinoline or 6-aminomethyl-2-ethylquinoline; and in which the substituent 0.A.X- is attached at the 4-position of the quinoline ring.

Compounds disclosed in our co-pending application which are particularly preferred are 2-methyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl- 4-yl)methoxy]quinoline, 2-ethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl- 4-yl)methoxy]quinoline, 2-ethyl-7-hydroxymethyl-4-[(2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methoxy]quinoline, 2-ethyl-6-(2-fluoroethoxy)-4-

[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline, 2-ethyl-6- (2,2,2-trifluoroethoxy)-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4- yl)- methoxy]quinoline and 2-ethyl-6-isopropoxy-4-[(2'-(lH-tetrazol-5-yl)- biphenyl-4-yl)methoxy]quinoline together with their non-toxic salts.

Although all of the formula I compounds can form salts with suitable acids, it will be appreciated that those compounds of formula

3 4 . I wherein Z is other than an ester group or in which R or R is a carboxy group can form salts with acids as well as with bases.

Particularly suitable non-toxic salts for such compounds therefore also include, for example, salts with bases affording physiologically acceptable cations, for example, alkali metal (such as sodium and potassium), alkaline earth metal (such as magnesium and calcium), aluminium and ammonium salts, as well as salts with suitable organic bases, such as with ethanolamine, methylamine, diethylamine or triethyla ine, as well as salts with acids forming physiologically acceptable anions, such as salts with mineral acids, for example with hydrogen halides (such as hydrogen chloride and hydrogen bromide), sulphuric and phosphoric acid, and with strong organic acids, for example with p-toluenesulphonic and methanesulphonic acids.

The compounds of the formula I are described in our co-pending application as obtainable by a variety of standard procedures of organic chemistry well known in the art for the production of structurally analogous compounds. We have now discovered a simple alternative procedure for the production of quinoline derivatives of formula I wherein X is optionally substituted p_-phenylene and Z is tetrazolyl.

Disclosure of Invention

According to the invention there is provided a process for the manufacture of a compound of formula III, wherein R , R , R , R , R and Ra have any of the values defined hereinbefore and Rb is hydrogen or a substituent selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro, which comprises removal of

a trisubstituted tin moiety of the formula Sn(Q)-. from a compound of the formula IV wherein R , R , R , R , R , Ra and Rb have any of the meanings as defined hereinbefore and Q is a (l-6C)alkyl or phenyl group, the latter optionally substituted by an (l-4C)alkyl, (l-4C)alkoxy or halogeno group.

A particular value for Q is, for example, (l-4C)alkyl such as methyl, ethyl, propyl or butyl, of which butyl is preferred.

A particular value for Rb, or for an optional substituent on Q when it is phenyl, when it is alkyl is, for example, methyl or ethyl; when it is halogeno is, for example, fluoro, chloro or bromo; and when it is alkoxy is, for example, methoxy or ethoxy.

The process is particularly suitable for the manufacture of compounds of the formula III wherein the tetrazolyl group is in a position ortho to the adjacent phenyl group.

The trisubstituted tin moiety Sn(Q).. may be removed, for example, by acid or base hydrolysis. The reaction is conveniently carried out, for example, by treatment of the compound of formula IV with mineral acid, such as aqueous hydrochloric acid, in the presence of a suitable solvent or diluent. A suitable solvent or diluent is, for example, a hydrocarbon such as toluene or xylene, an ether such as dioxan or tetrahydrofuran, or water, or mixtures thereof. The reaction is generally carried out at a temperature in the range, for example, 0-50°C, and conveniently at or about ambient temperature.

Compounds of the formula IV as defined hereinbefore may be obtained, for example, by reaction of a nitrile of the formula V with an azide of the formula VI wherein R , R , R , R , R , Ra, Rb and Q have any of the meanings defined hereinbefore. The reaction is conveniently carried out in a suitable solvent or diluent, such as toluene or xylene, and at a temperature in the range, for example, 50-150°C, and preferably at 100-145°C. Preferably an excess of the azide is used, especially 1.5 to 5 equivalents excess. The procedure

is particularly suitable for obtaining compounds of the formula IV wherein the tetrazolyl group bearing the trisubstituted tin moiety of formula Sn(Q), is at a position ortho to the adjacent phenyl group.

Compounds of the formula V may be obtained, for example, by radical bromination of a nitrile of formula VII wherein R and Rb have any of the values defined hereinbefore to the corresponding bromomethyl derivative followed by alkylation of a quinolone of the

^* ϊ *ϊ / formula VIII wherein R , R , R , R and Ra have any of the meanings defined hereinbefore. The bromination is carried out using procedures and reagents well known in the art, such as by reaction with N-bromosuccinimide in the presence of benzoyl peroxide or azo(bisisobutyronitrile) in a solvent such as chlorobenzene or carbon tetrachloride, and the alkylation is generally carried out in the presence of a base, for example, an alkali metal alkoxide such as sodium methoxide or sodium ethoxide, an alkali metal carbonate such as sodium carbonate or potassium carbonate, or an alkali metal hydride such as sodium hydride and in a solvent or diluent, for example, a (l-4C)alkanol such as methanol or ethanol when an alkali metal alkoxide is used, or in a polar solvent such as N,N-dimethylformamide or N-methylpyrrolidone and at a temperature in the range, for example, 10-100°C. Alternatively, a quaternary ammonium hydroxide may be used in a mixture of an aqueous or non-aqueous solvent such as water and dichloromethane.

Compounds of the formula VII may be obtained, for example, . by the procedure described in European Patent Application, Publication no. 0253310 A2. Alternatively, they may be obtained, for example, by reaction of a Grignard reagent, formed from an unsubstituted or substituted 4-bromotoluene in a solvent such as tetrahydrofuran, with a trialkyltin halide, such as tributyltin chloride, at a temperature of 0-25°C, followed by reaction of the resulting (substituted)phenyltrialkyltin compound with a substituted or unsubstituted bromobenzonitrile in the presence of a palladium (0) catalyst, such as tetrakis(triphenylphosphine) palladium, and azo(bisisobutyronitrile). A further alternative to obtain compounds

of the formula VII is by reaction of 4-methylphenylboronic acid with a suitably substituted bromobenzonitrile in the presence of a palladium catalyst, such as palladium (II) chloride or tetrakis- (triphenylphosphine)palladium(O), and azo(bisisobutyronitrile). Yet another alternative to obtain formula VII compounds is by reaction of an unsubstituted or substituted 4-bromotoluene with an alkali metal alkane, such as butyllithium, and zinc chloride followed by reaction with a suitably substituted bromobenzonitrile in the presence of tetrakis(triphenylphosphine)palladium.

Compounds of the formula VIII are known, for example as described in EPA 412848, or may be obtained using standard procedures of organic chemistry, such as those described in Org. Syn. , Coll. Vol. Ill, p.374 and p.593.

In a modified procedure for carrying out the process of the invention, and which is provided as a further feature of the invention, a compound of the formula IV as defined above is generated in situ from a compound of the formula V as defined above by reaction with an az: e of the formula VI as defined above. The trisubstituted tin moiety Sn(Q) ₃ present may then be removed without isolation of the compound of the formula IV, for example, by addition of aqueous mineral acid to the reaction mixture. A mixture of sodium nitrite and hydrochloric acid may be used to acidify the reaction mixture, thereby conveniently destroying any excess azide present. The azides of formula VI are either commercially available or may be prepared oy standard procedures well known in the art, such as by reaction of a trialkyltin halide with an alkali metal azide.

Whereafter, when a non-toxic salt of a compound of formula II is required, it may be obtained, for example, by reaction with the appropriate base affording a physiologically acceptable cation, or with the appropriate acid affording a physiologically acceptable anion, or by any other conventional salt formation procedure.

Further, when an optically active form of a compound of

formula I is required, one of the aforesaid processes may be carried out using an optically active starting material. Alternatively, the racemic form of a compound of formula I may be resolved, for example by reaction with an optically active form of a suitable organic base, for example, ephedrine, N,N,N-trimethyl(l-phenylethyl)ammonium hydroxide or 1-phenylethylamine, followed by conventional separation of the diastereoisomeric mixture of salts thus obtained, for example by fractional crystallisation from a suitable solvent, for example a (l-4C)alkanol, whereafter the optically active form of said compound of formula I may be liberated by treatment with acid using a conventional procedure, for example using an aqueous mineral acid such as dilute hydrochloric acid.

Certain of the intermediates defined herein are novel, for example the compounds of the formula IV and V and in particular those compounds of formula IV and V wherein the substituted tetrazolyl group and the cyano group respectively are in a position ortho to the adjacent phenyl group, and are provided as a further feature of the invention.

The antagonism of one or more of the physiological actions of All and, in particular, the antagonism of the interaction of AH with the receptors which mediate its effects on a target tissue, may be assessed using one or more of the following, routine laboratory procedures:

Test A: This jLn vitro procedure involves the incubation of the test compound initially at a concentration of 100 micromolar (or less) in a buffered mixture containing fixed concentrations of radiolabelled AH and a cell surface membrane fraction prepared from a suitable angiotensin target tissue. In this test, the source, of cell surface membranes is the guinea pig adrenal gland which is well known to respond to All. Interaction of the radiolabelled AH with its receptors (assessed as radiolabel bound to the particulate membrane fraction following removal of unbound radiolabel by a rapid filtration procedure such as is standard in such studies) is antagonized by compounds which also bind to the membrane receptor sites and the

degree of antagonism (observed in the test as displacement of membrane-bound radioactivity) is determined readily by comparing the receptor-bound radioactivity in the presence of the test compound at the specified test concentration with a control value determined in the absence of the test compound. Using this procedure compounds showing at least 50% displacement of radiolabelled AH binding at a concentration of 10 ^" M are retested at lower concentrations to determine their potency. For determination of the IC _C Q (concentration for 50% displacement of radiolabelled AH binding), concentrations of the test compound are ordinarily chosen to allow testing over at least four orders of magnitude centred about the predicted approximate ICC , which latter is subsequently determined from a plot of percentage displacement against concentration of the test compound.

In general, compounds of formula HI as defined above show significant inhibition in Test A at a concentration of 50 micromolar or much less.

Test B: This in vitro test involves the measurement of the antagonistic effects of the test compound against All-induced contractions of isolated rabbit aorta, maintained in a physiological salt solution at 37°C. In order to ensure that the effect of the compound is specific to antagonism of AH, the effect of the test compound on noradrenaline-induced contractions may also be determined in the same preparation.

In general, compounds of formula III as defined above show significant inhibition in Test B at a final concentration of 50 micromolar or much less.

Test C: This in vivo test involves using terminally-anaesthetised or conscious rats in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure. The AH antagonistic effects of the test compound following oral or parenteral administration, are assessed against angiotensin H-induced pressor responses. To ensure that the effect is specific, the effect of the test compound on vasopressin-induced pressor responses may also be determined in the same preparation.

The compounds of formula III generally show specific AH-antagonist properties in Test C at a dose of 50 mg/kg body weight

or much less, without any overt toxicological or other untoward pharmacological effect.

Test D: This in vivo test involves the stimulation of endogenous AH biosynthesis in a variety of species including rat, marmoset and dog by introducing a diet of low sodium content and giving appropriate daily doses of a saluretic known as frusemide. The test compound is then administered orally or parenterally to the animal in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure.

In general compounds of formula HI will show AH-antagonist properties in Test D as demonstrated by a significant reduction in blood pressure at a dose of 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.

By way of illustration of the angiotensin II inhibitory properties of compounds of formula HI,

2-methyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]q uinoline hydrochloride gave the following results in tests A, B and C described above:-

—8 In test A: an average ICC _Q of 1.7x10 M;

In test B an average pA„ of 8.95;

In test C: EDc _Q of 0.5 mg/kg (i.v. administration).

The invention will now be illustrated by the following non-limiting Examples in which, unless otherwise stated:- (i) concentrations and evaporations were carried out by rotary evaporation in vacuo;

(ii) operations were carried out at room temperature, that is in the range 18-26°C;

(iii) yields, where given, are intended for the assistance of the reader only and are not necessarily the maximum attainable by diligent process development;

(iv) H NMR spectra were normally determined at 270 MHz in CDC1-, using tetramethylsilane (TMS) as an internal standard, and are expressed as chemical shifts (delta values) in parts per million relative to TMS using conventional abbreviations for designation of major peaks: s, singlet; m, multplet; t, triplet; br, broad; d,

doublet; and

(v) the term "lH-tetrazol-5-yl" stands for

"1-H-l ,2,3, -tetrazol-5-yl" .

Example 1

A solution of 2-ethyl-4-[(2'-(2-tributylstannyl-2H _z tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline in toluene (15 ml), prepared il situ by refluxing for 90 hours a mixture of 4'-[(2-ethylquinolin-4-yloxy)methyl]biphenyl-2-carbonitrile (0.9 g) and a solution of tributyltin azide in toluene (15 ml) [the latter prepared by reaction of tributyltin chloride (3.3 g) and sodium azide (1.13 g) in water (22.5 ml) at ambient temperature for 4 hours, followed by extraction with toluene and azeotropic removal of water from the extract to leave a volume of 15 ml], was added slowly over 1 hour to a solution of sodium nitrite (2.5 g) in water (10 ml) containing 12% w/v hydrochloric acid (10 ml), maintaining the temperature of the mixture below 5°C. A solution of sulphamic acid (1.43g) in water (10ml) was then added, maintaining the temperature below 5°C, and the mixture stirred for 1 hour. The resultant suspended semi-solid was collected by filtration and washed with water (3 x 10 ml), followed by toluene (10 ml). The semi-solid was then added to tetrahydrofuran (THF) (40 ml), which caused the product to dissolve and then crystallise as a white solid. After cooling for one hour the solid was collected by filtration, washed with THF (5 ml) and dried to give 2-ethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]- quinoline hydrochloride in 53% yield; m.p. 179-180°C (dec); NMR (d ₆ -DMS0): 1.46(t,3H), 3.18(q,2H), 5.68(s,2H), 7.22(d,2H), 7.5-7.8(m,7H), 7.83(t,lH), 8.08(t,lH), 8.18(d,lH), 8.32(d,lH).

Example 2

A mixture of 2-ethyl-4-quinolone (1.73 g), (prepared by a similar method to that described in Org. Syn. , Coll. Vol. HI, p.374 and p.593 from aniline and ethyl propionylacetate),

4'-bromomethylbiphenyl-2-carbonitrile (A) (3.1 g) and solid potassium carbonate (1.81 g) in N-methylpyrrolidone (40 ml) were stirred for 36 hours under nitrogen. The mixture was then added dropwise to water (100 ml) at 15-25°C and stirred for 30 minutes. The suspended solid was collected by filtration, washed with water, and dried at 60°C under vacuum. The solid was recrystallised from tert-butyl methyl ether to give 4'-[(2-ethylquinolin-4-yloxy)methyl]-biphenyl-2-

carbonitrile as a solid (1.9 g), m.p. 151-153°C; NMR(CDC1 ₃ ): 1.4(t, 3H), 2.97(q,2H), 5.35(s,2H), 6.76(s,lH), 7.4-7.6(m, 3H), 7.6-7.8(m, 6H), 8.0(d,lH), 8.25(d, 1H).

The starting material A was obtained as follows:-

(i) 2M Sodium carbonate solution (200 ml) was added to a stirred mixture of 4-methylphenylboronic acid (30 g), 2-bromobenzonitrile (36.4 g), palladium (II) chloride (0.4 g), methanol (200 ml) and toluene (200 ml) at 5°C. The temperature rose to approximately 20°C and a solid precipitated. The reaction mixture was then heated at reflux for 2 hours. The reaction mixture was allowed to cool and water (100 ml) was added, followed by diatomaceous earth (5 g). The mixture was stirred for 15 minutes, then filtered through diatomaceous earth. The organic phase of the filtrate was separated and washed with 2M sodium carbonate solution and then water. The organic phase was then filtered and the filtrate evaporated. The resultant solid was recrystallised from petroleum ether (b.p. 110-120°C) to give 4'-methylbiphenyl-2-carbonitrile in 80% yield, m.p. 44-46°C; NMR (d ₆ -DMS0): 2.40 (s,3H), 7.30(d,2H), 7.35-7.55(m,4H), 7.60-7.65(m,lH), 7.75(d,lH).

(ii) A mixture of 4'-methylbiphenyl-2-carbonitrile (3.86 g), N-bromosuccinimide (3.92 g) and azo(bisisobutyronitrile) (0.15 g) in chlorobenzene (75 ml) was heated at 70°C for 3 hours. Further N-bromosuccinimide (0.3 g) and azo(bisisobutyronitrile) (0.05 g) was added and the mixture was heated for another 15 minutes. Heating was stopped and the mixture stirred for 16 hours at ambient temperature. Water (50 ml) was added and the mixture stirred for 30 minutes and filtered. The organic phase was separated, washed with water (f r.l) and dried (MgSO,). The solvent was removed by evaporation and u.e resultant solid recrystallised from cyclohexane to give 4'-bromomethylbiphenyl-2-carbonitrile (3.9 g) (A) as a solid; NMR (CDC1 ₃ ): 4.55(s,2H), 7.4-7.85(m, 8H).

WO 92/02508

(<*),. S*. N VI