IL32505A - Preparation of quinazoline-2-one derivatives - Google Patents

Description

Preparation of q nazoline derivatives SANDOZ A.Gt C : 30740 la - This invention relates to the preparation of quinazoline derivatives of the formula in which R signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms, an alkoxy radical of 1 to 4 carbon atoms, an alkylthio radical of 1 to 4 carbon atoms, or a nitro, cyano or trifluoromethyl group, n is 1 or 2, provided that when n is 2, the radicals R which may be the same or different each signify a hydrogen, fluorine, chlorine cr bromine atom, an alkyl radical of 1 to 5 carbon atoms, or an alkoxy radical of 1 to 4 carbon atoms, signifies an alkyl radical of 1 to 5 carbon atoms or an allyl or propargyl radical, signifies a phenyl radical or a substituted phenyl radical of formula II, II in which Y signifies a fluorine, chlorine or bromine atom, an alkyl radical of 1 to 4 carbon atoms, an alkoxy radical of 1 to 4 carbon atoms or a tri-fluororaethyl group, and signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 4 carbon atoms or an alkoxy radical of 1 to 4 carbon atoms, characterised by a) producing a compound of formula la, in which R, and n have the significance stated above, and R'^ has the same significance as stated above except that it may not signify a tertiary alkyl group in which the tertiary carbon atom is directly attached to the nitrogen atom, by cyclising a compound of formula Ilia, - 3 - 600 -6220 In which R, R^, and n have the significance stated above, with a carbonic acid derivative selected from the group consisting of (i) a Cl 2 al^yl cnloroGarDonate (ii) a £. alkyl carbamate and (iii) 1,1 '-carbonyldiimidazole, provided that when a alkyl carbamate is employed the process is effected at a temperature above l40°C, or b) producing a compound of in which has the significance stated above, and either (i) R^ signifies an alkyl radical of 1 to 5 carbon atoms, an allyl radical, or a propargyl radical, m signifies 0 or 1, and R' signifies a fluorine, chlorine or bromine atom, or (ii) R^ signifies an isopropyl radical, R' signifies a fluorine, chlorine or bromine atom, an alkyl radical of 1 to 4 carbon atoms, an alkoxy radical of 1 to 4 carbon atoms, an alkylthio radical of 1 to 4 carbon atomSjOr a nitro or trifluoromethyl group, and m signifies 1 or 2j provided that when m is 1, R* is other than a halogen atom, and that when m is 2 the radicals R' which may be the same or different signify a fluorine, chlorine or bromine atom, an alkyl radical of 1 to 4 carbon atoms or an alkoxy radical of 1 to 4 carbon atoms, by cyclising a compound of formula Illb, NH Illb m C=NH in which R', R", R_ and m have the significance stated above, with phosgene, or c) producing a compound of formula Ic, in which has the significance stated above, R" signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms, an alkoxy radical of 1 to carbon atoms;or a nitro, cyano or trifluoromethyl group, and n has the significance stated above, provided that when n is 2, the radicals R" which may be the same or different each signify a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms, or an alkoxy radical of 1 to 4 carbon atoms, and R^' signifies an alkyl radical of 1 to 5 carbon atoms, by oxidising a compound of formula IV, - 5 - 60(_fP-6220 in which R", R"^, and n have the significance stated above, producing a compound of formula Id, in which ^, R^ and n have the significance stated above, and R"' has the same significance as R stated above. except that it may not signify a cyano group, by hydrolysing at a temperature of from 10° to 150°C a compound of formula V, in which R" 1 , R-, , R^ and n have the significance stated above, - 6 60^-6220 or e) producing a compound of formula Ie, in which R signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms or an alkoxy radical of 1 to k carbon atoms, n' signifies 1 or 2, provided that when n is 2,no more than one of the radicals R^ may signify a halogen atom or a branched chain substituent, and that the radical RIV is other than a branched chain substitu- ent when in the 5- or 8- position of the ring, R'^' has the significance stated above, and Y signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to .3 carbon atoms or an alkoxy radical of 1 to 2 carbon atoms, by oxidising a compound of formula VI .

(HIV)n - 7 - 6θθ'¾>220 in which R , n , R'^' and have the significance stated above.

Process a)(i) involving reaction of a compound of formula Ilia with methyl chlorocarbonate or ethyl chlorocarbonate, preferably ethyl chlorocarbonate, may suitably be carried out at a temperature of from 30°C to 150°C, preferably 60°C to 100°C. The reaction may be carried out in an organic solvent v/hich is inert under the reaction conditions, suitably an aromatic hydrocarbon, e.g. benzene, toluene, and xylene, preferably benzene. Other suitable solvents include dioxane. The mole ratio of the chlorocarbonate of the compound of formula Ilia is not critical but the reaction is preferably carried out with a substantial excess of the chlorocarbonate. The reaction time may, for example, range from Y2 to 10 hours, more usually 1 to hours. The cyclisation with the chlorocarbonate may be optionally carried out in the presence of an acid-binding agent such as an inorganic base, e.g. podium carbonate or potassium carbonate, or a tertiary amine, e.g. a trialkyl amine or pyridine, more preferably triethylamine.

Process a)(ii) is suitably carried out at a temperature of from 140°C to 200°C, preferably l60°C to l80°C. The mole ratio of the alkyl carbamate , preferably urethane, to the compound of formula Ilia is not critical. In the preferred forms of practice, there is employed a substantial excess of carbamate which also serves as the preferred solvent for the reaction. Other suitable high-boiling organic solvents which are inert under the reaction conditions may alternatively or additionally be employed, if desired. The reaction time may for example range from to 10 hours, more usually 1 to k hours. The cyclisatlon with the carbamate is optionally and preferably conducted in the presence of a Lewis acid as catalyst for the reaction. The amount of Lewis acid employed is preferably between about 5# to 20$ based on the weight of compound Ilia in the reaction mixture. The preferred catalyst is zinc chloride.

Process a)(iii) is suitably carried out at a temperature of from 20°C to 120°C, preferably 60°C to 90°C. The reaction is preferably carried out in an organic solvent which is inert under the reaction conditions, suitably an aromatic hydrocarbon, e.g. benzene, toluene or xylene, especially benzene. The mole ratio of 1 , 1 '-carbonyldiimidaz-ole to the compound of formula Ilia is not particularly critical but excess 1 , 1 '-carbonyldiimidazole is preferably employed.

Process b) is suitably carried out at a temperature of from 0°C to 50°C, preferably 10°C to 30°C. The reaction may be carried out in an organic solvent which is inert under the reaction conditions r suitably an aromatic hydrocarbon, e.g. benzene, toluene, and xylene, preferably benzene. The mole ratio of phosgene to the compound of formula Illb is not particularly critical but a substantial excess of phosgene is preferably employed. The process may optionally be carried out in the presence of an acid-binding agent such as an inorganic base, e.g. sodium or potassium carbonate, or a tertiary amine, e.g. a trialkylamine or pyridine, preferably triethylamine .

Process b), which is generally preferred, also has the - 9 - 600-6220 particular advantage of being applicable to the production of compounds I having a tertiary carbon atom attached directly to the ring nitrogen atom.

Process ,c). is suitably carried out in an organic solvent which is inert under the reaction conditions, at a temperature of from 0° to 120°C; typically from 15° to 100°C and preferably from 15° to 30°C. The oxidation may be carried out employing any oxidising agent suitable for converting an organic amino moiety to an imino moiety^ for example an alkali metal permanganate such as sodium or potassium permanganate, manganese dioxide and mercuric acetate, preferably manganese dioxide. Suitable solvents include aromatic solvents such as benzene, and acyclic or cyclic ethers such as dioxane, and lower ketones such as acetone.

Process d) is preferably effected by alkaline hydrolysis of the compound of formula V at a temperature of from 50° to 150°C, preferably 8o° to 120°C. The preferred reagents for effecting the alkaline hydrolysis are alkali metal hydroxides such as sodium and potassium hydroxide. The reaction is conveniently carried out in an aqueous solvent medium comprising water and a water-miscible organic solvent which is inert under the reaction conditions^ such as a lower alkanol, e.g. ethanol, or a cyclic ether, e.g. dioxane, and preferably dioxane.

Process d) may also be effected by oxidative hydrolysis of the compound of formula V, in an aqueous medium at a temperature of from 10° to 80°C, preferably 15° to 6o°C. The oxidative hydrolysis is - 10 - 600-6220 preferably effected In an alkaline medium employing a peroxide, preferably a hydroperoxide and more preferably hydrogen peroxide. The peroxide is preferably used in moderate excess, typically about a 1.5 to k molar equivalent excess. An alkali metal hydroxide; e.g. sodium or potassium hydroxide, is suitably employed to provide the alkaline medium and is preferably employed in large excess. The alkaline oxidative hydrolysis is conveniently carried out in an aqueous solvent medium comprising water and an organic solvent which is inert under the reaction conditions, such as a lower alkanol or cyclic ether. The oxidative hydrolysis may alternatively be effected in acidic medium employing an organic peracid such as peracetic acid. The acidic medium is preferably provided by aqueous acetic acid, preferably in substantial excess. A solvent medium similar to that described for the alkaline oxidative hydrolysis may also be employed for the acidic oxidative hydrolysis .

Process e) is suitably carried out' in an organic solvent which is inert under the reaction conditions at a temperature of from 0° to 60°C, preferably 15° to o°C. The process is preferably effected in aqueous medium employing as oxidising agent an aqueous solution of a alkali metal permanganate, such as sodium or potassium permanganate, more preferably the latter. The organic solvent may for example be an aromatic solvent such as benzene or an acyclic or cyclic ether such as dioxane, or a lower ketone such as acetone.

The resulting compound of formula I may be isolated and purified in manner known per se .

Certain of the compounds of formula Ilia) and b) employed as starting materials in process a) (i), (ii) and (iii) and b), i.e. those of formula IIIc, in which Rv signifies a fluorine or chlorine atom, an alkyl radical of 1 to 5 carbon atoms or an alkoxy radical of 1 to 4 -carbon atoms, m* signifies 0, 1 or 2, provided that when m* is 2, the radicals Rv may be the same ..or . different, Y' signifies a fluorine or chlorine atom, or an alkyl or alkoxy radical of 1 to 4 carbon atoms, and m" signifies 0, 1 or 2, provided that when mw is 2, the radicals Y* may be the same or different, can be prepared by reacting a compound of formula Vila, Vila - 12 - 6θθ"¾220 in which R , m1, Y1 and m" have the significance stated above, with ammonia.

The reaction is desirably carried out in a sealed reactor under anhydrous conditions and at an elevated temperature and pressure. The reaction temperature is suitably from 100°C to 200°C, preferably 110°C to 150°C. A catalyst such as a Lewis acid, e.g. zinc chloride, may be employed to advantage in the process. The reaction is preferably carried out using an excess of ammonia as solvent, although a suitable co-solvent, e.g. dioxane, may also be employed.

The compounds of formula IIIc may also be prepared by reacting a compound of formula Villa, Villa in which R and m' have the significance stated above, with a compound of formula IX, in which Q signifies a lithium atom, or an -MgX radical in which X signifies a chlorine, bromine or iodine atom, and Y' and m" have the significance stated abovet and hydrolysing the resulting product in manner known per se. 30740/2 - 15 .- 600-6220 The reaction of the compound of formula Villa with the compound IX is preferably effected at room temperature in an inert organic solvent, e.g. diethyl ether. The compound of formula IX is preferably a lithium compound. The resulting reaction mixture is suitably subjected directly to hydrolysis in manner known per se. The hydrolysis may suitably be effected for example by simply pouring the mixture over ice.

The resulting compounds of formula IIIc may be isolated and purified in manner known per se.

The compounds of formula Villa may be prepared in manner known per se by tosylation, isopropylation and detosylatlon of a compound of formula Xa, in which R and m' have the significance stated above.

Compounds of formula Villa are; however^ referably prepared by reaction of a compound of formula Xa stated above with a compound of formula XI, wherein X' signifies a bromine or iodine atom.

The reaction is desirably carried out in the presence of a base, preferably an inorganic base, such as an alkali metal carbonate, to take up the hydrogen halide liberated during the reaction. The reaction may be effected in an organic solvent which is inert under the reaction conditions, e.g. dioxane, benzene and toluene. However, the use of a solvent is not necessary and a substantial excess of the corn- used pound of formula XI may be/and is preferably employed to provide the solvent medium. The reaction is suitably carried out at an elevated temperature which is not especially critical but preferably lies in the range of from 70°C to 140°C, more preferably 80°C to 100°C.

The remaining compounds of formula Ilia and Illb may be prepared in analogous manner to the first process described above for the preparation of compounds of formula IIIc.

Further, those compounds of formula Illd, in which R signifies a hydrogen, fluorine, chlorine or bromine 600-6220 atom, an alkyl radical of 1 to 5 carbon atoms, an alkoxy or alk lthio radical of 1 to 4 carbon atoms, or the trifluoromethyl group, n has the significance stated above, provided that when is 2, the R7 radicals which may be the same or different each signify a hydrogen or halogen atom or an alkyl or alkoxy radical, and R and R2 have the significance stated above, which are outside the scope of formula IIIc, may be prepared in analogou manner to the second process described above for the preparation of compounds of formula IIIc, from those compounds of formula VIII, in which R and n have the significance stated above, which are outside the scope of formula Villa.

Those compounds of formula VIII which are outside the scope of formula Villa may be produced from those compounds of formula X, VI in wnich R and n have the significance stated above, which are outside the scope of formula Xa, in manner analogou to either of the processes described above for the production of the compounds of formula Villa.

The compounds of formula X are known or may be prepared in manner known per se. In accordance with the present invention, however, the compounds of formula X may be produced by reducing a compound of formula XII, in which R ,VI and n have the significance stated above.

The reduction of the compounds of formula XII may be effected according to any of several well-known procedures. Preferably, the reduction is carried out in an aqueous acidic medium employing a reducing metal of which illustrative examples include iron, zinc and tin, preferably iron. Suitable acids include hydrochloric acid and acetic acid, preferably hydrochloric acid. The reduction is preferably effected at a temperature of from 50°C to 100°C, and in a solvent which is inert under the reaction conditions. Suitable solvents include water and lower alkanols, especially ethanol, and combinations thereof. An alternate known method of reduction involves catalytic hydrogenation in a known manner, employing Raney nickel, palladium or platinum as catalyst, and a convenient organic solvent, for example methanol, ethanol or dioxane.

A process for producing the compounds of formula XII involves reacting a compound of formula XIII, - 17 - 60056220 in which R and n have the significance stated above, and X" signifies a fluorine, chlorine or bromine atom, with cuprous cyanide, and decomposing the resulting cuprous complex.

The reaction of a compound of formula XIII with cuprous cyanide is suitably carried out at elevated temperature and in the presence of an organic solvent, which is inert under the reaction conditions. The reaction temperature may, for example, range from about 100°C to 220°C, and preferably 130°C to l80°C. The preferred solvents are solvents boiling within the preferred range of reaction temperatures in order that reflux conditions may be employed, e.g. dimethylacetamide and dimethylformamide, more preferably dimethyl acetamide. The mole ratio of cuprous cyanide to compound of formula XIII in the reaction mixture is not particularly critical and typically ranges from approximately the stoichiometric amount required to form the desired product up to a moderate excess. The reaction time is typically about 1 to 10 hours. The substituent X" in the compound of formula XIII is preferably a chlorine atom. The decomposition of the resulting cuprous complex may, for example, be effected by addition of methylene chloride.

The compounds of formula XIII are either known or may be prepared in manner known per se.

The process described above for the preparation of the compounds involving production of the compounds of formula XII from the compounds of formula XIII and subsequent reduction thereof provides a highly efficient route thereto, especially when compared to the elaborate multi-reaction routes heretofore employed.

The resulting compounds of formula Ilia and Illb may be isolated and purified using conventional techniques.

The compounds of formula IV employed as starting materials in process c) may be prepared by (i) reacting a compound of formula XIV, in which Ru , H , and n have the significance stated above, with a compound of" formula XV, - 19 - 600-6220 R2' CHO XV in which R ' signifies a phenyl radical or a substituted phenyl radical of formula Ila, in which Y" signifies a fluorine or chlorine atom, or an alkyl radical of 1 to 3 carbon atoms, or an alkoxy radical of 1 to 2 carbon atoms, or a trifluoro- methyl group, and Y^ signifies a hydrogen, fluorine or chlorine atom, an alkyl radical of 1 to J carbon atoms, or an alkoxy radical of 1 to 2 carbon atoms, at elevated temperatures under substantially anhydrous conditions, to obtain a compound of formula IVa, JL V in which R , n, ^ and R^ have the significance stated above, or (ii) reacting a compound of formula XVI, in which R^V, R'"and n have the significance stated above, 600^220 with a compound of formula XVII, in which R^ has the significance stated above, and radical Q1 signifies a lithium atom, or an -MgX"'/in which Xftl signifies a chlorine or bromine atom, in the presence of an organic solvent which is inert under the reaction conditions and hydrolysing the resulting product to obtain a compound of formula IVb, in which ^R'^', and n have the significance stated above, or (iii) reacting a compound of formula XVIII, XVIII in which R , R2 and n have the significance stated above, with isocyanic acid of formula XIX, H = C = 0 XIX and cyclising the resulting compound of formula XX, 21 - 600 -6220 in which R , ^ , R2 and n have the significance stated above, to obtain a compound of formula IV stated above.

Process (i) is preferably carried out at a temperature of from 30° to 120°C, more preferably 50°-100°C. The reaction is suitably carried out in the presence of an acid as catalyst and dehydrating agent,which acid should otherwise be non-reactive with the compounds of formula XV and XVI. Suitable such acids include aryl-sulphonic acids or alkylsulphonic acids such as benzene-sulphonic or toluene-sulphonic acid and methane-sulphonic acids, preferably p-toluene-sulphonic acid or methane-sulphonic ■ acid3 or trifluor@aeeti-c acid err ■anhydrous hydrochloric aoid in a cuitablo inort organic oolvont ouotv ae ethane!. The amount of acid present desirably does not substantially exceed one molar equivalent based on the compound of formula XV and is most preferably from 0.005 "t° 0 * 5 molar equivalents. The process is most suitably effected under substantially anhydrous conditions and in an organic solvent which is inert under the reaction- conditionsypreferably an aromatic solvent such as benzene..The reaction time may^for example^ vary from 1 to 50 hours.

Process (i) is particularly applicable to the production of compounds of IVd - 22 - 600 -6220 IV in which the radicals which may be the same or different d each signif a hydrogen, fluorine or chlorine atom, an alkyl radical of 1 to 5 carbon atoms or an alkoxy radical of 1 to 4 carbon atoms, provided that no IV more than 1 of the radicalsR^ signifies a halogen or a branched chain substituent, and R" has the significance stated above.

Process (ii) is preferably carried out at a controlled temperature of from -4o° to 50°C, preferably 10° to 35°C and usually most conveniently at about room temperature (20°C) . The reaction is suitably carried out in an organic solvent which is inert under the reaction conditions, preferably an organic acyclic or cyclic ether such as tetrahydrofuran . The mole ratio of the compound of formula XVII to the quinazolinone of formula XVI is not particularly critical. In the more preferred forms of practice an excess of the compound of formula XVII is employed, typically to provide a ratio of from about 3 : 1 to 30 : 1, more preferably from 5 : 1 to 20 : 1. Lithium compounds of formula XVII are preferred. The reaction time may for exampl range from 15 minutes to 5 hours. The reaction is desirably conducted under .anhydrous conditions and followed 'by hydrolysis in known manner. The hydrolysis may; for example, be effected by addition of water to the resulting reaction mixture.

The reaction of the compound of formula XVIII with iso-cyanic acid in process (iii) is desirably carried out in an acid aqueous medium at a controlled temperature of from 0°C to about 80°C preferably from 15° to 35°C The isocyanic acid is preferably formed in situ by effecting the reaction in acidic medium and employing a salt of isocyanic acid of formula XXI, = = - 25 - 6θ δ220 which in an acidic medium yields isocyanic acid. The cation is suitably a cation of an alkali metal; e.g. sodium or potassium; an alkaline earth metal, e.g. calcium; or the cation of ammonia, and preferably the potassium cation. The acid employed to provide the acidic reaction medium and produce _in situ the desired isocyanic acid from the salt of formula XXI is preferably a strong inorganic acid, for example sulphuric acid or hydrochloric acid, or an organic acid such as acetic acid, more preferably the latter.

The cyclisation of the compound of formula XX essentially involves the removal of the elements of water, and is preferably carried out at elevated temperature and under acidic conditions. Suitable temperatures are; for example, from 8θ° to 150°C, preferably 95°C to 120°C. The acid employed in the dehydration is desirably a strong inorganic acid such as sulphuric acid or hydrochloric acid, or an organic acid such as acetic acid, more preferably the latter.Water may be employed as the sole reaction medium, although various co-solventSj e.g. ethanol, may also be used, if desired or required to ensure optimum solubility.

In the preferred method of effecting process (iii) the intermediary compound of formula XX is not isolated, the crude reaction product of the first stage being subjected directly to the cyclisation stage .

The compounds of formula XIV employed as starting materials in process (i) are either known or may be prepared in manner known per se . A preferred method involves subjecting a compound of formula in which R^, R'^' and n have the significance stated above, to reaction with isocyanic acid of formula XIX stated above. - 2 - 600-6220 The isocyanic acid may be formed in situ in similar manner to that described for process (iii), e.g. by effecting the reaction in an acidic medium, employing in place of isocyanic acid an alkali metal isocyanate. Suitable acids include lower aliphatic carboxylic acids, preferably acetic acid. The reaction is suitably carried out at temperatures of from 10° to 50°C and in an organic solvent which is inert under the reaction conditions, for example a lower aliphatic carboxylic acid such as acetic acid. The reaction may thus be effected employing an excess of acetic acid.

The compounds of formula XIV may also be produced by reacting a compound of formula XXII^ stated above, with nitrourea. The reaction is suitably effected at a temperature of from 8o°C to 120°C in an inert organic solvent, preferably a lower alkanol such as ethanol.

The compounds of formula XXII are either known or may be prepared in manner known per se . ..A preferred method involves subjecting a compound of formula XXIII, XXIII in which R and n have the significance stated above, to tosylation, alkylation and detosylation. It is also to be noted that compounds of formula XXII;in which R'^' is a branched alkyl radical with the branching occurring at the carbon atom attached to the amino nitrogen atom, e.g. compounds in which R'^' signifies. an isopropyl radical, may be also be prepared by reacting directly the compound of formula XIX with an appropriate alkyl halide. - 25 - 600-6220 The compounds of formula XVI employed as starting materials in process (ii) are either known or may be prepared in manner known per se . The compounds of formula XVI may also be prepared by reaction of a compound of formula XXIV, in which R ,R'^' and n have the significance stated above, with urea at an elevated temperature. The reaction is most suitably effected at a temperature of from 50° to 250°C; preferably 100° to 200°C. The reaction is conveniently carried out in the absence of a solvent in an inert atmosphere such as nitrogen gas. The reaction may also be effected in an organic solvent which is inert under the reaction conditions, for example an aromatic solvent such as benzene or toluene.

The compounds of formula XVIII employed as starting materials in process (iii) are either known or may be prepared in manner known per se . One preferred method involves reduction of an appropriate 2-amino-benzophenone with sodium borohydride in a suitable inert organic solvent as described in the literature by G. N. Walker, J. Org. Chem. 27 , 1929 (I962).

The resulting compounds of formula IV may be isolated and purified using conventional techniques.

The compounds of formula V employed as starting materials in process d) may be prepared by (iv) reacting a compound of formula V I, - 26 - 600-6^20 in which R , n, R^ and R^ have the significance stated above, with an acid chloride or bromide and an isothiocyanate of formula XXV, M' N = C = S XXV in which MT signifies an alkali or alkaline earth metal cation or the ammonium cation, or with the reaction product of such acid halide and isothiocyanate , or (v) reacting a compound of formula VII stated above with isothio-cyanic acid.

Process (iv) is conveniently effected in an organic solvent which is inert under the reaction conditions, at a temperature of from 10°C to 80°C, preferably 5 °C to 70°C. As indicated, the process may be effected by reacting a compound of formula VII with the reaction product of an acid chloride or bromide and an isothiocyanate of formula XVj and it is generally preferred to first react the acid halide and compound of formula XXV and then add the compound of formula VII to the resulting reaction mixture. The reaction of the acid halide and compound of formula XXV is exothermic and is preferably initiated at a temperature of from 10° to 30°C. It is to be understood that the acid halides employed should not carry substituents or functional groups which would interfere with the process. Suitable acid halides include acetyl chloride and benzoyl chloride, preferably benzoyl chloride. Naturally, the most suitable compounds of formula XXV are those most readily reacting with the acid halide to eliminate as a by-product a halide of the cation M1. Suitably, the compound of formula XXV is sodium or ammonium isothiocyanate, and preferably ammonium isothiocyanate . Suitable solvents include lower ketones and cyclic ethers, acetone being preferred. When the compound of formula VIII bears certain sub-stituents for example when R signifies an alkyl radical^ e.g. 4-methyl-2-isopropylamino-benzophenone, the reaction may lead to a mixture of products including the desired compound of formula V and a non-cyclized intermediate,and the latter may even represent the major product of the reaction. In such situations, the resulting mixture may be treated with a strong base at elevated temperatures to cyclize the previously non-cyclized intermediate to the desired compound of formula V in high yield. Such treatment is suitably effected at a temperature of from 60°C to 100°C in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, and in an aqueous solvent medium comprising water and an inert' organic solvent such as a cyclic ether, e.g. dioxane. Process (iv) is particularly suitable for the preparation of compounds of formula V in which Y and/or is other than an ortho-substituent.

Process (v) is suitably effected at a temperature of from 50°C to 150°C, preferably 100°C to l o°C. Isothiocyanic acid is well known to be unstable and is therefore desirably prepared iri situ.

Thus, the process may be effected in acidic medium employing a salt of isothiocyanic acid of formula XXV stated above. The compound of formula XXV is preferably an alkali metal, e.g. sodium or potassium salt, or most preferably the ammonium salt. The acid employed to produce in situ the- desired isothiocyanic acid from the compound of formula XXV is preferably a lower carboxylic acid, - 28 - 600-6¾) The compounds of formula VII are either known or maybe prepared in manner known per se. Where the benzene ring of compounds VII carries a 5-nit o or 5-trifluoromethyl substituent, the compounds are preferably prepared by reaction of a corresponding 5-nitro-(or tri-fluoromethyl)-2-chloro-benzophenone with an appropriate amine (R^NH^) i the presence of a suitable catalyst, e.g. a mixture of copper and cuprous chloride. Where the compound of formula VII is an o-alkylamino-benzo-phenone in which the alkyl moiety is a branched chain and the branching occurs on the carbon atom directly attached to the nitrogen atom, particularly when it is a compound of formula Vila stated above, it may desirably be produced by a method analogous to that described in Belgian Patent No. 723>0Hl, using an appropriate o-amino-benzophenone and alkyl bromide or iodide.

The resulting compounds of formula V may be isolated and purified using conventional techniques.

The compounds of formula VI employed as starting materials in process e) may be produced by vi) reacting a in which above, with isothiocyanic acid, or reacting a compound of formula XXVII, - 29- 6oo -6220' with a compound of formula XXVIII, XXVIII in which has the significance stated above, at elevated temperature.

Process vi) is preferably carried out in an acid aqueous medium at elevated temperature, for example at from 50°C to 150°C, preferably from 70°C to 110°C. In analogous manner to that described above in connection with process v), the process may be effected in an acidic medium employing a compound of formula XXV stated above. The cation M' is preferably a cation of an alkali metal, e.g. sodium, an alkaline earth metal, e.g. calcium^or most preferably the cation of ammonia, i.e. the ammonium salt. The acid employed to produce in situ the desired isothiocyanic acid from compound XXV is preferably a strong inorganic acid, for example sulphuric acid, nitric acid or hydrochloric acid, most preferably hydrochloric acid. If desired or required, an organic eo-solvent may be employed to ensure optimum solubility of compound XXVI in an aqueous reaction medium.

Suitable co-solvents for this purpose are well known and include methanol, ethanol and dioxane. The reaction time of process vi) is typically from 10 minutes to 5 hours, and more usually 15 to 60 minutes Process vii) is effected at elevated temperatures; suitably from 30°C to 120°C, preferably from 50°C to 100°C. The reaction is suitably carried out in the presence of an acid as catalyst and under - 30 - 6oo -6220 anhydrous conditions adapted to effect condensation of compounds XXVTI and XXVIII. The acid employed is desirably a strong acid which is also a dehydrating acid and which is also otherwise substantially non-reactive with compounds XXVII and XXVIII. An acid suitably employed is anhydrous hydrochloric acid (hydrogen chloride in e.g. an aromatic solvent), although one may employ other strong acids which are dehydrating agents including organic acids such as arylsulfonic acids, or alkylsulfonic acids, such as benzenesulfonic acid, p-toluenesulfonic acid and methanesulfonic acid, preferably p-toluenesulfonic acid. The amount of acid employed may vary depending upon the particular acid used and, in the case of hydrochloric acid, may be suitably a substantial excess. The reaction is conveniently carried out in an organic solvent which Is inert under the reaction conditions, preferably an aromatic solvent such as benzene. The reaction time may, for example, range from 1 to 50 hours.

The resulting compounds of formula VI may be isolated and purified using conventional techniques.

The compounds of,. formula XXVII used as- starting materials in process vii) may be suitably prepared by subjecting a compound of formula XXIX, in which R , n and R'!^' have the significance stated above, and A signifies the acid residue of an acid halide, to alkaline hydrolysis at elevated temperature.

The process may suitably be carried out at temperatures of from 50° to l 0°C, preferably 8o° to 120°C. The hydrolysis is solvent medium preferably comprising water and a water-miscible organic solvent which is inert under the reaction conditions^ such as an acyclic or cyclic ether, preferably dioxane.

The compound of formula XXIX may be prepared by reacting a compound of formula XXX, in which R v, n and R"^ have the significance stated above, with an isothiocyanate of formula XXV stated above, and an acid halide of formula XXXI» A Z XXXI in which A has the significance stated above^ and Z signi ies a chlorine or bromine atom, preferably a ' chlorine atom, or with the reaction product of said acid halide and iso¬ thiocyanate.

The process may be carried out in manner analogous to that described for process iv) above.

The compound of formula XXIX may be isolated from the resulting mixture and purified using conventional techniques,. However, complete isolation and/or purification of the compound of formula XXIX may not be necessary insofar as the resulting reaction mixture which may contain varying amounts of the compound of formula XXIX, may be employed directly for the production of compounds of formula XXVII.

The compounds of formula I have pharmacological activity.

In particular, they have anti-inflammatory activity as Indicated by the Carrageen-induced edema test on rats and are therefore Indicated for use as anti-inflammatory agents. Suitable indicated daily dosages range from about 10 milligrams to about 1000 milligrams, preferably administered in divided dosages of from about 3 to 500 rag, two to four times a day or in retard form.

The compounds of formula I, in which signifies an isopropyl radical, exhibit in general an exceptionally high anti-inflammatory activity.

The compounds may be used mixed with a pharmaceutically acceptable carrier and such other conventional adjuvants as may be desired, and administered orally in such form as tablets, capsules, elixirs, suspensions or solutions, or parenterally in such forms as injectable solutions and suspensions.

In the compounds of formula I, when R or signifies an alkyl or alkoxy radical, the alkyl or alkoxy radicals preferably contain respectively 1 to 3 and 1 to 2 carbon atoms.

Xt will be appreciated that in the formulae XIV, XXII, XXIII, XXVII, XXIX and. XXX stated above no subatituent may be present in the 2--oeition of the bensene ring.

The following ¾ample illustrate the invention* - 34- 600 -6220 EXAMPLE 1: 2-isopropylamino-tt-methylbenzophenonimine . a) -methyl-2-nitrobenzonitrile A mixture of 100 g of -chloro-3-nitrotoluene, 6θ g of cuprous cyanide and 150 ml of dimethylacetamide is refluxed for y2 hours. The resulting dark brown mixture is poured onto 1 liter of ice water and the resulting mixture filtered to separate the precipitated dark brown copper complex which is then decomposed by treating with 600 ml of methylene chloride with stirring at room temperature. The insoluble inorganic material is filtered off and the filtrate dried over anhydrous sodium sulfate, treated with 5 g of charcoal and 50 g of aluminium oxide and again filtered to remove insoluble material. The filtrate is evaporated to dryness _in vacuo to obtain a crude crystalline residue which is then crystallized from diethyl ether to obtain 4-methyl-2-nitrobenzonitrile, m.p. 96-97°C. b) 4-methylanthranilonitrile · To a solution of crude -methyl-2-nitrobenzonitrile, obtained from Example la), in 1.15 litres of hot ethanol is added 290 ml of concentrated hydrochloric acid. To the resulting mixture at boiling is added a total of 75 S of iron filings in 4 portions over a period of 1 hour. The resulting mixture is heated at reflux for an additional lV2 hours, cooled, filtered and the filtrate concentrated in vacuo to a volume of about 250 ml. The concentrated material is then diluted with about 1 liter of water to produce a crystalline solid which is recovered by filtration with suction and then washed on the filter with petroleum ether (b.p. 60-90°C) to obtain 4-methylanthranilonitrile, m.p. 88-90°C. -35 - 600 -6220 ^ c ) 2-isopropylamino-4-methylbenzonitrile A mixture of 36 g of 4-methylanthranilonitrile, 3 g of potassium carbonate, 0.5 g of copper powder and 120 ml of 2-iodo-propane is refluxed with stirring for 8 days. The excess 2-iodopropane is removed by evaporation in vacuo and the resulting solid residue is extracted three times each with 100 ml of methylene chloride. The extracts are combined, filtered through 250 g of alumina and evaporated in vacuo to obtain a low melting crystalline residue which is 2-isopropylamino-4-methylbenzonitrile . d) 2-isopropylamino-4-methylbenzophenonimine A solution of 5 -22 g of 2-isopropylamino-4-methylbenzo-nitrile in 40 ml of diethyl ether is added with stirring over a period of about 10 minutes at room temperature to a solution of 90 millimoles of phenyl-lithium dissolved in a 50-50 mixture of diethyl ether and benzene. Stirring is continued for an additional 15 minutes after such addition and then the resulting clear yellow solution is poured onto 200 ml of ice water. The organic phase is separated, dried over anhydrous sodium sulfate and evaporated _in vacuo to dryness to obtain a crude yellow oil of 2-isopropylamino-4-methylbenzophenonimine .

This compound is treated with maleic acid in a conventional manner to obtain 2-isopropylaniino- -methylbenzophenonimine maleate salt, m.p. 119°-122°C. - 36 - βοο-^20 EXAMPLE 2: 2-isopropylamlno-^-rnethylbenzophenonimine a) U-methyl-2-isopropylaminobenzophenone A mixture of 7 g of -methyl-2-aminobenzophenone, 6.35 6 of sodium carbonate and 18.8 ml of 2-iodopropane is stirred and refluxed for 3 days. The cooled reaction mixture is then diluted with 200 ml of benzene and washed twice with water and twice with brine.

The organic phase is separated, dried over anhydrous sodium sulphate and concentrated in vacuo to remove substantially all of the benzene. The resulting yellow oil is dissolved in about 10 ml of methylene chloride and subjected to column chromatography employing alumina (about 00 g) and methylene chloride as elu nt to give a first fraction which on concentration in vacuo to remove methylene chloride produced a yellow oil of 4-methyl-2-isopropylaminobenzophenone. b) 2-isopropylamino- -methylbenzophenonimine A mixture of 2.0 g of k.-methyl-2-isopropylaminobenzophenone, ml of anhydrous ammonia (low condensed air moisture content) and 20 mg of zinc chloride is heated in a sealed stainless steel cylinder at a o o temperature oi 110 to 120 C for 3 days. Excess ammonia is evaporated from the resulting mixture and the residue re rystallised from ethanol to obtain a crude yellow oil of 2-isopropylamino- -methyl- benzophenonimine .

EXAMPLE 3: l-isopropyl-7-methyl- -phenyl-2( 1H) -quinazolinone [process a) ( i) ] By reaction with ethyl chlorocarbonate A mixture of 5 g of 2-isopropylarnino- -methylbenzophenonimine obtained from Example Id) or 2b), 3 ml of ethyl chlorocarbonate and ml of benzene is refluxed for 2V hours. The resulting mixture is diluted with 70 ml benzene and then extracted twice with water. The organic phase is dried and evaporated _in vacuo to produce a crude product which is purified by column chromatography employing alumina and chloroform as eluant. The purified product is then crystallized from diethyl ether to obtain l-isopropyl-7-methyl-4~phenyl-2(lH)-quinazolinone, m.p. 135-137°C.

By reaction with ethyl chlorocarbonate in presence of an trialkylamine The run immediately above is repeated except that the reaction mixture also includes 6 ml of triethylamine. Crystallisation from diethyl ether yields l-isopropyl-7-methyl- -phenyl-2(lH)-quinazol-inone, m.p. 135-137°C.

EXAMPLE h ; l-isopropyl- -phenyl-7-methyl-2(lH)-quinazolinone (process a (ij.)) By reaction with urethane A mixture of 5 g of 2-isopropylamino- -methylbenzophenon-imine (prepared as in Example 1 or 2) and 10 g of urethane is heated at a temperature of l80-190°C for 2-g- hours. The cooled reaction mixture is taken up with 5 ml of methylene chloride, filtered to remove insoluble material, and the filtrate extracted with 50 ml of water. The organic phase is dried, evaporated in vacuo and the residue crystallised from ethylacetate/diethyl ether (1:2) to obtain l-lsopropyl-7-methyl-4-phenyl-2(lH)-quinazolinone, m.p. 135-137°C. - 38 - 600-6220 * By reaction with urethane in presence of Lewis acid The run immediately above is repeated except that the reaction mixture also includes 1 g of zinc chloride. Completing the procedure as in the preceding run there is obtained on crystallisation from ethylacetate/diethyl ether ( 1 : 2) crystals of l-isopropyl-7-methyl- 4-phenyl-2(lH)-quinazolinone, m.p. 135- 137°C.

EXAMPLE : l-isopropyl- -phenyl-7-methyl-2(lH)-quinazolinone (process b)) By reaction with phosgene To a solution of 5 g of 2-isopropylamino- -methylbenzophenon-imine (prepared as in Example 1 or 2) in O ml of benzene is added at . temperature of 10°C, 60 ml of a 12$ solution of phosgene in benzene. he resulting solution is allowed to stand for about 10 minutes at room temperature and is then extracted with 50 ml of 2N sodium hydroxide. The organic phase is separated, dried over anhydrous sodium sulfate, evaporated _in vacuo and the resulting residue crystallized from diethyl ether to obtain l-isopropyl-7-methyl-4-phenyl-2(lH)-quinazolin-one, m.p. 135-137°C.

EXAMPLE 6 : l-isopropyl- -phenyl-7-niethyl-2(lH)-quinazolinone (process a)(iii)) By reaction with Ι,ΐ'-carbonyldiimidazole When 2-isopropylamino-^ -methylbenzophenonimine (prepared as in Example lor 2) is reacted with 1, 11 -carbonyldilmidazole in re- fluxing benzene, there is also obtained a good yield of l-isopropyl-7-methyl- -phenyl-2(lH) -quinazolinone, m.p. 135-137°C. - 39 - 600-6222 'EXAMPLE 7 t (process a)(i)) Following the procedure of Example and employing appropriate starting materials in appropriate proportions,the following compounds may be obtained:- 6, 7-dimethyl-l-ethyl-4-phenyl-2(lH)-quinazolinone (m.p. 176-l80°C) l-ethyl-6-trifluoromethyl-4-phenyl-2(lH)-quinazolinone ( 180°C sublimation) l-ethyl-6-methylthio-4-phenyl-2(lH)-quinazolinone (m.p. 150-151°C) l-methyl-6,7-dimethoxy-4-phenyl-2(lH)-quinazolinone (m.p. 197-198°C) EXAMPLE 8 : (process a)(ii)) Following the procedure of Example ¾■ and employing appropriate starting materials in appropriate proportions, the following compounds may be obtained:- l-ethyl-6-methoxy-4-phenyl-2(lH)-quinazolinone (m.p. 158-l42°C) l-ethyl-6-nitro-4-phenyl-2(lH)-quinazolinone (m.p. 2l4-215°C) l-methyl-4-phenyl-2(lH)-quinazolinone (m.p. 141-143°C) 6-chloro-l-methyl-4-phenyl-2(lH)-quinazolinone (m.p. 223-224°C) - ko - 600-6220 EXAMPLE 9: (process b)) Following the procedure of Example 5 and employing appropriate starting materials in appropriate proportion, the following compounds may be obtained:- l-methyl-4-phenyl-2(lH)-quinazolinone (m.p. l l-l43°C) l-methyl-4-(p-chlorophenyl)-2(lH)-quinazolinone (m.p. 122-123°C) l-ethyl- -phenyl-2(lH)-quinazolinone (m.p. l83-l85°C) 6-chloro-l-methyl- -phenyl-2(lH)-quinazolinone (m.p. 223-224°C) l-methyl-4- (p-methoxyphenyl )-2(lH)-quinazolinone (m.p. l84°C) 6-chloro-'!l- (o-chlorophenyl)-l-isopropyl-2(lH)-quinazolinone (m.p, 1^7-1½9°C) l-isopropyl-4-phenyl-2(lH)-quinazolinone (m.p. l 0°C) 6-chloro-1-isopropyl-4-phenyl-2(1H)-quinazolinone (m.p. 150°C) 6-nitro-l-isopropyl- -phenyl-2(lH)-quinazolinone (m.p. 190-192°C) 6-methyl- -phenyl-l-isopropyl-2(lH)-quinazolinone (m.p. 170-171°C) 7-methoxy- h-phenyl-1-isopropyl-2(1H)-quinazolinone (m.p. 137-138°C) 7-chloro-l-ethyl- -phenyl-2(lH)-quinazolinone (m.p. l87-l88.°C) EXAMPLE 10 : (process a)(iii)) Following the procedure of Example 6 and employing appro-priate starting materials in appropriate proportion, the following compounds may be obtained;- 6-cyano-l-isopropyl-4-phenyl-2(lH)-quinazolinone (m.p. 125-128°C) 6,7-dimethyl-l-ethyl-4-phenyl-2(lH)-quinazolinone (m.p. 176-l80°C) EXAMPLE 11 : l-isopropyl-7-methyl -phenyl- (1H)-quinazolinone (process c)) N-isopropyl-3-methylaniline -hi - 600-6220 ^· To a solution of 3· ** g^s. of isopropyl iodide and 2 gas. of triet ylaxiine in 50 nils, n-propanol is added 1 gm. of -toluidine in one portion. The reaction mixture is then refluxed for l8 hours. mixture The reaction/is cooled and any precipitate which separates is re-moved "by filtration. The clear "brown filtrate is evaporated at reduced pressure and the resultant oil is triturated with 5 mis. of diethyl ether. Any solid which thus forms is removed by filtration and the filtrate is evaporated at reduced pressure. The treatment with diethyl ether is repeated as long as any solid separates. The oil obtained is subjected to column chromatography and the fraction el ted with 75 KLLS. of is collected and evaporated at reduced pressure. The resultant N-isopropyl-3-neth laniline has a b.p. of (ii) To a solution of 3. g of isopropyl iodide and 2 g of triethylamine in 50 ml n-propanol is added 1 g of m-toluidine in one portion. The reaction mixture is then refluxed for l8 hours. The reaction is cooled and any precipitate which separates is removed by filtration. The clear brown filtrate is evaporated at reduced pressure and the resultant oil is triturated with 0 ml of petroleum ether (b.p. 30-6o°C) . Any solid which thus forms is removed by filtration and the filtrate is evaporated at reduced pressure. The oil obtained is subjected to column chromatography and the fraction eluted with 75 ml of CH2C12 is collected and evaporated at reduced pressure. The resultant N-isopropyl-3-methylaniline has a b.p. of 109°C/51 mm Hg. b) N-isopropyl-N- (m-tolyl)urea (i) To a solution of h.5 gms. of N-isopropyl-3-methyl-aniline in 20 mis. of 95$ ethanol is added k.l gms. of nitrourea and the resulting mixture waded carefully on a steambath for 30 Eiinutes. The reaction mixture is then heated on a steambath for.2 concentrate hours, and concentrated at reduced pressure. The resultant/is treated with 200 mis. of boiling water, and the resulting aqueous phase concentrated at reduced pressure at about 60°C. The resulting residue is dissolved in 100 mis. of chloroform, washed twice with 15 nls. of a 10$ aqueous solution of sodium bicarbonate, once with 10 nls. of water, and the solutio dried and evaporated at reduced pressure. The residue is recrystal lized from petroleum ether to provide N-isopropyl-N-(m-tolyl)urea, n.p. 89-90°C. (ii) A solution of 3·5 £ s. of N-isopropyl-3-nethylaniline iso and 1.6 gms of powdered sodium cyanate in 25 mis. of glacial acetic acid is stirred at room temperature for 18 hours. The reaction mixture is then evaporated at reduced pressure with the addition of chloroform from time to time to facilitate the evaporation. The resultant semi-solid is triturated with 150 mis. of diethylether and the thus formed solid removed by filtration. The filtrate is evaporated" ' at reduced pressure and. the residue is taken up in sufficient petrol-leum ether to bring about dissolution at room temperature. The solution is decolorized with charcoal, washed twice with 15 mis. of a 10$ aqueous solution of sodium bicarbonate, once with 10 mis. of water, dried, and evaporated at reduced pressure. The resulting white solid is recrystallized from petroleum ether to provide N-isopropyl-N-( -tolyl) urea, n.p. 89-91°C. 600-6220 c) l-isopropyl- -ohenyl-7-methyl-5 , 4-dlhydro-2(lH)-quinazolinone A solution of 1 gni. of N-isopropyl-N-(n-tolyl)urea, O.h gm. of benzaldehyde and a catalytic amount (about 10 mg. ) of p-toluenesulphonic acid in 3° Eils. of benzene is refluxed for 22 hours. The cooled reaction mixture is crashed once with 10 nils, of 2H sodium hydroxide and 3 tidies v/ith 12 nls. of a 10$ aqueous solution of sodium bisulphite, dried and evaporated at reduced pressure. The residue is recrystallized fron petroleum ether or cyclohexane to provide 1-isopropyl U-pher¾^l-7-n-ethyl-3j^-Gihydro-2(lH)-quinazolinone, a.p. l50-lo0.1°C. d) l-isopropyl-7-methyl- -phenyl-2(lH)-quinazolinone A mixture of 0. g of l-isopropyl-4-phenyl-7-methyl-3, -dihydro 1 methyl- 'I-phenyl 2(lH)-quinazolinone, 0.5 g of manganese dioxide and 25 ml of benzene is refluxed for a period of 20 hours.

The resulting mixture is filtered through "Celite", evaporated to dryness, dissolved in methylene chloride, treated with charcoal, evaporated in vacuo and the residue crystallized; from diethyl ether on adding pentane (1 : 1 ) to obtain l-isopropyl-7-methyl-Jl-phen l-2(lH)-quinazolinone, m.p. 137-158°C. - 44 - 600 -6220 ~* EXAMPLE 12 ; 6-chloro-l-methyl-4-phenyl-2(lH)-quinazolinone (process c)) a) N-formyl-N-methyl-4-chloroaniline A mixture of 63 .8 g of p-chloroaniline and 28.9 g of trimethylorthoformate is prepared in a flask fitted with a 30" fractionation column. To the stirred mixture is added dropwise 2 g of concentrated sulphuric acid. The mixture is then heated and any methanol formed is permitted to distil from the reaction vessel. The y residue is distilled at a pressure of about 20 mm Hg and N-foriml-N-methyl-4-chloroaniline is collected at a temperature of about 13O-l40°C. b) N-methyl-4-chloroaniline A mixture of 80 g of N-formyl-N-methyl-4-chloroaniline and 200 ml of 10 hydrochloric acid is refluxed for l8 hours. The mixture is cooled and made basic with 50 aqueous sodium hydroxide. The resul-tant oil is separated from the aqueous phase, which later is saturated with solid sodium carbonate and extracted twice each with 250 ml of diethylether. The extracts are combined with the previously obtained oil and the whole dried and evaporated. Distillation of the residue at a pressure of 40 mm provides N-methyl-4-chloroaniline, b.p. 143-144°/ ^0 mm Hg. c) 6-chloro-l-methyl-4-phenyl- 3 ,4-dihydro- 2( 1H)-quinazolinone A solution of 0.5 S of N-methyl-N- (4-chlorophenyl)urea [prepared analogously to Step b) of Example n ],0.25 g of benzaldehyde and a catalytic amount of about 10 mg of p-toluenesulphonic acid in 25-30 ml of benzene is refluxed for 20 hours. The cooled reaction -^5 - 600-6220 mixture is washed twice with 25 ml of water, dried and evaporated at reduced pressure. The residue is triturated with about 400 ml of petroleum ether (b.p. 30-60°C) and about 10 ml of benzene is added to obtain on recrystallisation from the solvent system 6-chloro-l-methyl-4-phenyl-3, -dihydro-2(1H)-quinazolinone, m.p. 184-187°C . d) 6-chloro-l-methyl- -phenyl-2(lH)-quinazolinone Following the procedure of Step d) of Example 11 and employing approximately similar proportions there is obtained on crystallisation from ethyl acetate the compound 6-chloro-l-methyl- -phenyl-2(lH)-quinazolinone, m.p. 223-224°C.

EXAMPLE 13: (process c) ) Following the procedures of Examples. 11 and 12 and employing the appropriate corresponding starting materials in approximately similar proportions there is obtained the following: 6,7-dimethyl-l-isopropyl-4-phenyl-3,4-dihydro- 2(lH)-quinazolinone, m.p. 156-l60°C, which is oxidized to obtain 6,7-dimethyl-l-isopropyl- 4-phenyl-2(lH)-quinaz:olinone, m.p. 135-137°C.

EXAMPLE Ik': l-methyl-k-phenyl-2(lH)-quinazolinone (process c)) a) 1-methyl- (1H)-quinazolinone A mixture prepared by adding 15 g of 2-methylaminobenzalde-hyde to 15 g of urea is stirred and heated at 150°C for 15 hours - 1+6 - 000-6220 (nitrogen atmosphere). The reaction mixture is suspended in methylene chloride and extracted with water. The methylene chloride is evaporated in vacuo, the residue dissolved in aqueous hydrogen chloride, filtered and reprecipitated by slow addition of sodium hydroxide sol-ution. The resulting crystalline precipitate is filtered off and dried to obtain l-methyl-2(lH)-quinazolinone in a form for use in b) below. The product can also be dissolved in methanol containing 15$ chloroform and the solution saturated with hydrogen chloride to obtain after filtration l-methyl-2(lH)-quinazolinone hydrochloride, m.p. 233-235°C. b) l-methyl-4-phenyl-3, -dihydro-2(lH)-quinazolinone To a solution of 1 g of l-methyl-2(lH)-quinazolinone in 200 ml of anhydrous tetrahydrofuran is added 5·0 ml of phenyl-lithium in solution (2M) in benzene/diethyl ether (70/30). The temperature is kept at about 25-30°C. for one hour, after which water and methylene chloride are added, and the two resulting layers are separated. The aqueous layer is extracted with methylene chloride and the combined organic phases are repeatedly extracted with saturated sodium chloride solution. After drying the solvent is evaporated in vacuo and the residue crystallized from methanol to obtain l-methyl- -phenyl-5,4-dihydro-2(lH)-quinazolinone, m.p. l83-l84°C. c) l-methyl- -phenyl-2(lH)-quinazolinone To a solution of 4.7 g of l-methyl-4-phenyl-3, -dihydro-2(lH)-quinazolinone in 200 ml of purified dioxane is slowly added within 10 minutes at room temperature a solution of 2.35 g of potassium 600-6220 "Ί permanganate in 45 ml of water. The resulting mixture is stirred for 1 hour at room temperature and then formic acid is added dropwise to destroy excess permanganate. The resulting mixture is filtered, and the filtrate concentrated _in vacuo to about 30 ml. To this liquid residue is added slowly 50 ml of water to obtain a precipitate which is recrystallised from ethyl acetate to obtain l-methyl-4-phenyl-2(lH)-quinazolinone, m.p. 142-143°C.

EXAMPLE 15: l-isopropyl-7-methyl-4-phenyl-2(lH)-quinazolinone (.process c)) a) 1-isopropyl-7-methyl-3,4-dihydro-2(lH)-quinazolinone Following the procedure of Example 14 b) and employing approximately equivalent amounts, l-isopropyl-7-methyl-2(lH)-quinazol-inone is reacted with phenyl lithium to obtain l-isopropyl-7-methyl-4-phenyl-3,4-dihydro-2(lH)-quinazolinone, m.p. 159-l62°C. b) 1-isopropyl-7-methyl-4- henyl-2(1H)-quinazolinone Following the procedure of Example l^c) and employing approximately equivalent amounts, l-isopropyl-7-methyl-4-phenyl-3>4-dihydro-2(lH)-quinazolinone is reacted with potassium permanganate to obtain on crystallisation from ethyl acetate the compound which is l-iso-propyl-7-methyl-4-phenyl-2(lH)-quinazolinone, m.p. 137-138°C.

EXAMPLE -^: l-isopropyl-4-phenyl-2(lH)-quinazollnone (process d)) ) o-isopropylaminobenzophenone A mixture of 20 g of o-aminobenzophenone, 10 g of sodium arbonate and 50 ml of isopropyl iodide is refluxed with stirring for -¾8 - 6θΟ -6220 * ' days. The excess isopropyl iodide is then evaporated off jLn vacuo, and the resulting residue extracted with 200 ml of benzene. The benzene extract is then filtered, washed twice with 100 ml (each) of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness _in vacuo to obtain o-isopropylaminobenzophenone as an oil. e b) Preparation of l-isopropyl-4-phenyl-quinazolir 2(lH)-thione To a solution of 11.3 g of ammonium isothiocyanate in 100 ml of acetone at room temperature is added dropwise I8.8 g of benzoyl chloride. The resulting suspension is refluxed for 5 minutes, cooled and there is then added 30 g of o-isopropylaminobenzophenone. The resulting mixture is refluxed for 3 hours, cooled, evaporated _in vacuo suspended in methylene chloride, insoluble material filtered off, and the filtrate evaporated followed by crystallisation from ethyl e acetate/diethyl ether to obtain l-isopropyl-4-phenyl-quinazolin^2(lH)-thione, m.p. 212-214°C. c) l-isopropyl-4-phenyl-2(lH)-quinazolinone To a solution of 5 S of l-isopropyl- -phenyl-quinazoline-2(lH)-thione in 100 ml dioxane is added 50 ml of 25$ sodium hydroxide solution and the resulting mixture is refluxed for l6 hours, poured onto ice- ater, extracted twice with ethyl acetate, washed with saturated sodium chloride solution, then with water and dried. The resulting solution is evaporated in vacuo to crystallize l-iscpropyl-4-phenyl 2(lH)-quinazolinone, m.p. 131-135°C - 1+9 - 600-6220 EXAMPLE 17 : l-isopropyl-7-methyl-4-phenyl-2(lH)-quinazolinone (process d)) a) 4-methyl-2-isopropylaminobenzophenone A mixture of 7 g of 4-methyl-2-aminobenzophenone, 6.35 g of sodium carbonate and 18.8 ml of 2-iodopropane is stirred and refluxed for 3 days. The cooled reaction mixture is then diluted with 200 ml of benzene and washed twice with water and twice with brine.

The organic phase is separated, dried over anl/drous sodium sulfate and concentrated _in vacuo to remove substantially all of the benzene.

The resulting yellow oil is dissolved in about 10 ml of methylene chloride and subjected to column chromatography employing alumina (about 400 g) and methylene chloride as eluant to give a first fraction which on concentration in vacuo to remove methylene chloride produced a yellow oil of 4-methyl-2-isopropylaminobenzophenone . e b) l-isopropyl-7-methyl-4-phenyl-quinazolin^2- (lH)-thione * To a solution of 3 ·5 g of ammonium isothiocyanate in 100 ml of acetone at room temperature is added dropwise 6.2 g of benzoyl chloride. The resulting suspension is refluxed for 5 minutes, cooled and there is then added 10 g of 4-methyl-2-isopropylaminobenzophenone. The resulting mixture is refluxed for 3 hours, cooled, evaporated _in vacuo, and the residue dissolved in 500 ml of tetrahydrofuran . To the resulting solution is added 50 ml of 2N NaOH followed by refluxing on a steam bath for 1 hour. The resulting mixture is evaporated to. remove solvent and the mixture extracted with methylene chloride, the oiganic phase dried and evaporated _in vacuo to obtain an oil which is recyrstallised from ethanol/diethyl ether to obtain l-isopropyl-7- e methyl-4-phenyl-quinazolin 2(lH)-thione, m.p.185 -1 0°C 600-6220* c) l-isopropyl-7-methyl- -phenyl-2(lH)-quinazolinone Following the procedure of Example l6c) and employing approximately similar proportions, l-isopropyl-7-methyl- -phenyl-quinazolin 2(lH)-thione is hydrolysed with sodium hydroxide followed by crystallisation from ethyl acetate to obtain l-isopropyl-7-meth l-4-phenyl-2(lH)-quinazolinone, m.p. 137-138°C.

EXAMPLE 18; (process d)) Following the procedure of Examples 16 and 17 and employing appropriate starting materials in appropriate proportions, the following compounds may be obtained: l-ethyl- -phenyl-quinazolin¾2(lH)-thione, m.p. 232-235°C, and hydrolysis thereof to l-ethyl- -phenyl-2(lH)-quinazol- inone, m.p. l83-l85°C. e 6-chloro-l-methyl-4-phenyl-quinazolir 2(lH)-thione, m.p. 228-230°C, and hydrolysis thereof to 6-chloro-l-methyl-4- phenyl-2(lH)-quinazolinone, m.p. 223-224°C. e. l-isopropyl-6-methoxy-4-phenyl-quinazolii -2(lH)-thione m.p. l44-l45°C, and hydrolysis thereof to l-isopropyl-6- methoxy-4-phenyl-2(lH)-quinazolinone, m.p. l40-143°C. and l-allyl-4-phenyl-quinazoli¾2(lH)-thione, m.p. l80°C, and hydrolysis thereof to l-allyl-4-phenyl-2(lH)-quin- . azolinone, m.p. 159-l60°C.

EXAMPLE 19: l-isopropyl-7-methyl-4-phenyl-2(lH)-quinazolinone (process e)) a) N-isopropyl-3-methylaniline - 51- 600 -¾220 To a solution of 3·*+ g^s. of isopropyl iodide and 2 gms. of triethylamine in 50 mis. n-propanol is added 1 gm. of m-toluidine in one portion. The reaction mixture is then refluxed for l8 hours. The reaction is cooled and any precipitate which separates is re- moved by filtration. The clear brown filtrate is evaporated at reduced pressure and the resultant oil is triturated with 5° mis. of diethyl ether. Any solid which thus forms is removed by filtration and the filtrate is evaporated at reduced pressure. The treatment with diethyl ether is repeated as long as any solid separates. The oil obtained is subjected to column chromatograph and the fraction eluted with 75 mis. of CHgClg is collected and evaporated at reduced pressure. The resultant N-isopropyl-3-methylaniline has a b.p. of b) N-isopropyl-N- (m-tolyl)-N'-benzoylthiourea - _... · ' . _ iso To a solution of 10 gms. of ammonium^thiocyanate in 100 mis. of acetone is added a solution of 9· gms. of benzoyl chloride in 75 nils, of acetone. The mixture is stirred during this addition and for 3° minutes subsequently. Then a solution of 10 gms. of N-isopropyl- 3-nethylaniline in 75 mis. of acetone is added dropwise, also with stirring. At the end of this addition the reaction mixture is refluxed for 3 hours, cooled, 200 mis. of methylene chloride are added, and the mixture filtered. The filter cake is washed with a further 100 mis. of methylene chloride and the filtrates combined, evaporated under reduced pressure. The residue is recrystallized from isopropanol to obtain N-isopropyl-N- (m-tolyl)-N' -benzoylthiourea, m.p..112-113°C. - 52 - 600- 622*5 c) N-isopropyl-N-(m-tolyl) thiourea To a solution of h$ inls. of dioxane in 200 mis. of water is added 27 g s. of sodium hydroxide and the mixture stirred until dissolution is complete. Then 15 gms. of N-isopropyl-N-Cm-tolylJ-N1-benzoylthiourea is added and the resulting reaction mixture refluxed for h hours. The resulting mixture is cooled, acidified with concentrated hydrochloric acid, and made slightly basic with concentrated ammonium hydroxide. The resulting basic aqueous solution is filtered free of any solids and the solids are washed with 100 mis. of chloroform. The clear filtrate is extracted three times each with 200 mis. of chloroform and to these filtrates is added the chloroform used to wash the solids. The combined solution is dried, evaporated at reduced pressure, and the residue recrystallized from cyclohexane to obtain N-isopropyl-K-(m-tolyl) hiourea, m.p. 126-127°C Q d) l-isopropyl-7-methyl-^(-phen l-3,^-dihydro-quinazolir^2(lH)- thione To 2 nils, of a saturated solution of anhydrous hydrogen chloride gas in anhydrous benzene is added 1 gm. of N-isopropyl-N-(m-tolyl)thiourea. The resulting mixture is stirred and a solution of 2 gms. of benzaldehyde in 10 mis. of anhydrous benzene is added dropwise. The reaction mixture is then refluxed for 15 hours, cooled,, and evaporated at reduced pressure to obtain a semi-solid which is triturated with 0 mis. of diethyl ether. The thus-formed solid is removed by filtration and the filtrate washed several times with 10$ aqueous solution of sodium bisulphite. The ethereal solution is then evaporated at reduced pressure to obtain l-isopropyl-7-raethyl-¾-phenyl-3,^-dihydro-quinazolin^2(lH)-thione as an amorphous powder which can be crystallized from diethyl ether/petroleum ether to - 53 - 6οο - .0 e) l-isopropyl-7-methyl-4-phenyl-2(lH)-quinazolinone To a solution of 500 mg. of l-isopropyl-7-nethyl-4-phenyi- e 3,^-dihydro-quinazolir>^2(lH)-thione in 20 nl. of dioxane is added about 25Ο mg. of potassium permanganate as an aqueous solution in divided portions with stirring. The resulting mixture is stirred at roon temperature (20°C. ) for 5 hours, then treated by addition of water and extracted with methylene chloride. The resultin methylene chloride solution is treated with charcoal, filtered through "Celite", concentrated and the resulting residue crystallized from ethyl acetate' to obtain l-isopropyl-7-methyl- -phenyl-2(]Ji)-quinazolinone, m.p. 137-138°C

Claims (1)

1. - 51» - we claim is:- 1. A process for the preparation of a compound of formula I, in which R signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms, an alkoxy radical of 1 to 4 carbon atoms, an alkylthio radical of 1 to carbon atoms, or a nitro, cyano or trifluoromethyl group, n is 1 or 2, provided that when n is 2, the radicals R which may be the same or different each signify a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of "1 to 5 carbon atoms, or an alkoxy radical of 1 to h carbon atoms, signifies an alkyl radical of 1 to 5 carbon atoms or an allyl or propargyl radical, R signifies a phenyl radical or a substituted phenyl 2 radical of formula II, II - 55 - 6oo-6?20 In which Y signifies a fluorine, chlorine or bromine atom, an alkyl radical of 1 to 4 carbon atoms, an alkoxy radical of 1 to 4 carbon atoms or a trifluoromethyl group, and signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to carbon atoms or an alkoxy radical of 1 to 4 carbon atoms; characterised by a) producing a compound of formula la, in which R, R^ and n have the significance stated above, and R^ has the same significance as R^ stated above except that it may not signify a tertiary alkyl group In which the tertiary carbon atom is directly attached to the nitrogen atom, by cyclisinga compound of formula Ilia, 56 - 600-6220 in which R, R^, and n have the significance stated above, with a carbonic acid derivative selected from the group consisting of (i) a J alkyl chlorocarbonate (ii) a ^ alkyl carbamate and (iii) l,l'-carbonyldiimidazole. provided that when a alkyl carbamate is employed the process is effected at a temperature above l 0°C, or b) producing a in which Rg has the significance stated above, and either (i) R^ signifies an alkyl radical of 1 to 5 carbon atoms, an allyl radical, or a propargyl radical, m signifies 0 or 1, and R' signifies a fluorine, chlorine or bromine atom, or (ii) R^ signifies an isopropyl radical, 1 signifies a fluorine, chlorine or bromine · atom, an alkyl radical of 1 to carbon atoms, an alkoxy radical of 1 to carbon atoms, an alkylthio radical of 1 to carbon atomSjOr a nitro or trifluoromethyl group, and ra signifies 1 or 2? provided that when m is 1, R' is other than a halogen atom, and that when ra is 2^ the radicals R' which may be the same or different signify a fluorine, chlorine or bromine atom, an alkyl radical of 1 to 4 carbon atoms or an alkoxy radical of 1 to 4 carbon atoms. - 57 - 600-6220 by cyclising a compound of formula Illb, In which R' , R^, R≥ and m have the significance stated above, with phosgene, * ■ ■ " or c) producing a compound of formula Ic, in which R„ has the significance stated above, R" signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms, an alkoxy radical of 1 to 4 carbon atoms^or a nitro, cyano or trifluoromethyl group, and n has the significance stated above, provided that when n is 2, the radicals Rn which may be the same or different each signify a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms, or an alkoxy radical of 1 to 4 carbon atoms, an R"' signifies an alkyl radical of 1 to 5 carbon atoms, by oxidising a compound of formula IV, - 58 - 600-6220 in which R", R"', R and n have the significance stated above. producing a compound of formula Id, in which R^, R^ and n have the significance stated above, and R*1' has the same significance as R stated above^ except that it may not signify a cyano group . by hydrolysing at a temperature of from 10° to 150°C a compound of formula V, in which R" ' , R-,,R &nd n have the significance stated above,. - 59 - 600-6220 producing in which R signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms or an alkoxy radical of 1 to h carbon atoms, n" signifies 1 or 2, provided that when n is 2, no more than one of the radicals may signify a halogen atom or a branched chain substituent, and that the radical RIV is other than a branched chain substituent when in the 5- or 8- position of the ring, R'^' has the significance stated above, and signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 3 carbon atoms or an alkoxy radical of 1 to 2 carbon atoms, by oxidising a compound of formula VI, 32505/2 - 60 - ** 2. A process according to Claim 1, in which the cyclisation with an alkyl chlorocarbonate is effected in the presence of an acid-binding agent. 3· A process according to Claim 1 or 2, in which the alkyl chlorocarbonate is ethyl chlorocarbonate and the cyclisation theretvith is effected in an organic solvent which is inert under the reaction conditions and at a temperature of from 60° to 100°C. 4. A process according to Claim 1, in which the cyclisation with an alkyl carbamate is effected in the presence of a Lewis acid. 5. A process according to Claim 1 or 4t in which the alkyl carbamate is urethane and the cyclisation therewith is effected at a temperature of from 140° to 200°C employing an excess of the urethane to provide a solvent. 6. A process according to Claim 1, in which the cyclisation with lsl*-carbonyldiimldazole is effected in an organic solvent which is inert under the reaction conditions at a temperature of from 60° to 90°C. 7. A process according to Claim 1, in which the cyclisation with phosgene is effected in the presence of an organic solvent inert under the reaction conditions 8. A process according to Claim 1 or 7, in which the cyclisation with phosgene is effected in an organic solvent which is inert under the reaction conditions at a temperature of from 10° to 30°C. 9. A process according to Claim 1, in which the oxidation of a compound of formula IV is effected in an organic solvent which is inert under the reaction conditions 32505/2 - 61 - which the oxidation of a compound of formula IV is effected with manganese dioxide or potassium permanganate . lie A process according to Claim 1» in which the hydrolysis of a compound of formula V is effected with an alkali metal hydroxide at a temperature of from 80° to 120°C in a solvent medium comprising water and a water-miscible organic solvent which is inert under the reaction conditions. 12. A process according to Claim 1, in which the oxidation of a compound of formula VI is effected in an organic solvent which is inert under the reaction conditions at a temperature of from 0° to 60°C and employing an alkali metal permanganate aB oxidising agent . 13. A process for the production of a compound of formula I, stated in Claim 1, substantially as herein described with reference to any one of Examples 3 to 19· For the Applicants RC/ru