ISOQUINOLINETRIONE DERIVATIVES AS HERBICIDES

The present invention relates to herbicidal compositions containing isoquinolinetrione derivatives, to novel herbicidal isoquinolinetrione derivatives, and to processes for their preparation.

According to the present invention there is provided a herbicidal composition comprising a compound of formula (I), or a salt thereof where

R is selected from hydrogen; optionally substituted alkyl; optionally

45 4 5 substituted alkoxy; acyloxy; hydroxy; NR R where R and R are

2 3 independently hydrogen or alkyl; or optionally substituted aryl; R and R together form a fused optionally substituted 5 or 6- membered aromatic carbocyclic or heterocyclic ring; and X, Y and Z are independently selected from 0, =C(CN) ₂ , NOH, NOR ⁶ , NNR ⁷ R ⁸ , NCN or NR ⁹ where R ⁶ , R ⁷ , and R ⁸ are independently selected from hydrogen, optionally substituted alkyl,

Q optionally substituted alkenyl and optionally substituted alkynyl; and R is optionally substituted phenyl; in combination with a carrier or diluent;

2 3 Suitable optional substituents for the ring formed by R and R include one or more groups selected from halogen; hydroxy; alkoxy; NR R where R and R are independently selected from hydrogen, alkyl or

11 12 12 sulphony1 and R may additionally be acyl; COR where R is hydrogen

1314 hydroxy, alkoxy, or optionally substituted alkyl or a group NR R where

13 14 R and R are independently hydrogen or alkyl, alkenyl or alkynyl any of which may be optionally substituted; optionally substituted phenyl; alkyl; cyano; nitro; haloalkyl; S(0) R where n is 0, 1 or 2 and R is optionally substituted alkyl or optionally substituted aryl; or any adjacent two of the said substituents together with the carbon atoms to which they are attached form a fused saturated or unsaturated carbocyclic or heterocyclic ring.

A particular class of compounds of formula (I) are those of formula

(II): where R ¹ , X, Y and Z are as defined above and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen or the groups listed above as t optional substituents for the fused aromatic carbocyclic or heterocyclic rings, including the case where any adjacent two of R , R , R and R together with the carbon atoms which they are attached form a fused saturated or unsaturated carbocyclic or heterocyclic ring.

In particular there is provided a herbicidal composition comprising a compound of formula (II), where X, Y and Z are all oxygen, R is selected from hydrogen; optionally substituted alkyl; optionally substituted alkoxy; acyloxy; hydroxy; NR R where R and R are independently hydrogen or alkyl; or optionally substituted aryl; and R ¹⁶ , R ¹⁷ , R ⁸ and R ⁹ are

2021 independently selected from hydrogen; halogen; hydroxy; alkoxy; NR R where R and R are independently selected from hydrogen, or alkyl and

71 22 22

R may additionally be acyl; COR where R is hydrogen or optionally

7". ? ^■ . 74 23 24 substituted alkyl or a group OR or NR ^J R where R" and R" are independently hydrogen or alkyl, alkenyl or alkynyl any of which may be

25 optionally substituted; alkyl; cyano; nitro; haloalkyl; S(0)_R where n is

25 0, 1 or 2 and R is optionally substituted alkyl or optionally substituted aryl; or any adjacent two of R , R , R and R together with the carbon atoms to which they are attached form a fused saturated or unsaturated carbocyclic or heterocyclic ring; in combination with a carrier or diluent.

2 3 Other compounds of formula (I) are those where R and R form a fused optionally substituted furan, thiophene, pyrrole, pyrazole, thiazole, isothiazole, oxazole, imidazole, isoxazole, pyridine, or pyrimidine ring.

In a further aspect, the invention provides novel compounds of formula

(III) wherein R , X, Y and Z are as defined above for formula (I), W and Q

27 27 are independently selected from =N-, =C-R , oxygen, sulphur, or =NR , and

7fi 77

R and R are independently hydrogen or are selected from the groups

7 3 7fi described above as substituents for the ring formed by R and R , or R

27 and R together form an optionally substituted fused saturated or

7fi unsaturated carbocylic or heterocyclic ring. R is preferably hydrogen or phenyl .

As used herein the term "alkyl" includes straight or branched alkyl chains, suitably containing up to 10 carbon atoms, preferably from 1 to 6 carbon atoms. The terms "alkenyl" and "alkynyl" includes unsaturated straight or branched chain containing up to 10 carbon atoms, preferably from 2 to 6 carbon atoms. The term "alkoxy" relates to such an alkyl group linked with an oxygen atom. The term "aryl" includes phenyl and naphthyl .

28 28 The term "acyl" includes groups of formula C(0)R where R is optionally substituted alkyl or alkoxy. Examples of acyl include acetyl and methoxy carbonyl. The term "carbocyclic" includes rings of up to 10, preferably up to 7 carbon atoms. The term "heterocyclic" includes rings containing up to

10, preferably up to 7 atoms, up to three of which are selected from oxygen, sulphur or nitrogen. The term "halo" or "halogen" includes chlorine, fluorine, bromine and iodine.

Suitable optional substituents for any alkyl, alkoxyalkyl, alkenyl or alkynyl groups mentioned above include one or more groups selected from halogen such as chloro; hydroxy; nitro; optionally substituted aryl; or

COR ²⁹ or S0 ₉ R ²⁹ where R ²⁹ is OR ³⁰ or NR ³¹ R ³² and R ³⁰ , R ³¹ , and R ³² are

33 34 independently selected from hydrogen or alkyl; or P(0)0R OR or

P(0)R ³³ R ³⁴ where R ³³ and R ³⁴ are alkyl.

Suitable optional substituents for any aryl groups mentioned above include halo, haloalkyl and nitro.

Suitably R is selected from hydrogen, C,_g alkyl or optionally substituted benzyl.

Particular examples of R are hydrogen, methyl or ethyl.

In compounds of formula (II), R , R , R and R suitably are selected from hydrogen, halogen, NR R , CONR or alkoxy or two of R ,

3 4 5 R , R and R together form a fused phenyl ring.

Examples of groups R , R , R and R are hydrogen, amino, hydroxy, acetamido.

In particular examples, R , R , R and R are all hydrogen.

When one or more of R , R , R or R is a salt or ester of carboxy, it is suitably an agriculturally acceptable salt or ester. Examples of agriculturally acceptable salts include sodium, potassium or calcium salts, sulphonium or sulphoxonium salts such as those of formula

^■ JC *JC *3 ^* T

S(0) R R R where q is 0 or 1, or ammonium or quaternary ammonium ions of formula N ⁺ R ³⁵ R ³⁶ R ³⁷ R ³⁸ where R ³⁵ , R ³⁶ , R ³⁷ and R ³⁸ are independently selected from optionally substituted alkyl, alkenyl, alkynyl, or aryl groups.

Examples of agriculturally acceptable esters include optionally substituted alkyl, alkenyl, alkynyl, or aryl esters.

The possibility of forming salts of compounds containing a carboxyl group has been referred to above. Where the compound of formula (I) contains a basic group (e.g. an NH ₉ group, or a tertiary amine group such

2 3 as that present when the groups R and R together form a thiazole, imidazole, or oxazole ring) there is also the possibility of forming acid addition salts. Such salts may be prepared from acids having

agriculturally acceptable anions, for examples sulphuric, hydrochloric, or phosphoric acid.

Examples of X, Y, and Z include oxygen, =N0H, or =N0Me. When any of X, Y and Z is a substituted imine group (e.g. =N0H, =N0R, =NCN, or the possibility of geometrical isomerism exists. The invention covers all individual isomers as well as mixtures thereof in all proportions. The invention also covers all tautomers.

Specific examples of compounds of formula (II) wherein X, Y and Z are all oxygen are listed in Table I.

TABLE I

Compound RI R16 R17 R18 R19

No

TABLE I (conti nued)

Compound RI R16 R17 R18 R19

No

TABLE I (continued)

Compound RI .16 J7 ,18 ,19 No

Specific examples of compounds of formula (I) are listed in Table II

2 3 below. In the column headed R + R , the left-hand end of the chain of atoms is connected to the R position in formula (I), and the right-hand

2 end is connected to the R position. Thus, for example, compound 100 has

•j ne the structure corresponding to formula (III) in which R is ethyl, R is hydrogen, Q is -CH=, and W, X, Y and Z are all oxygen.

TABLE I I

Compound R ¹ R ² + R ³

No

0 0 0

0 0 0

0 0 0

0 0 0

0 0 0

0 0 0

0 0 0

0 0 0

0 0 0

0 0 0

0 0 0

0 0 0

0 0 0 0 0 0

TABLE II c

TABLE II c t n

TABLE II

TABLE II c

In the above Tables, 'Me' represents methyl, 'Et' represents ethyl, and 'Ph' represents phenyl. Many of the compounds in the foregoing table are capable of existing as geometrical (E and Z) isomers. Where such isomers have been identified, they are designated in the rest of this specification by the letters A and B, where A stands for the E isomer and B for the Z isomer. Thus compound 200A is the E isomer of compound 200. (In the case of compounds 38 and 39, however, the A and B designation does not signify geometrical isomerism; here the compounds are positional isomers).

Compounds of formula (I) where X, Y and Z are oxygen may be prepared

1 2 for example by oxidation of a compound of formula (IV), where R , R , and

R , are as defined in relation to formula (I).

The oxidation may be carried out, for example, by condensing a compound (IV) with dimethyl p-nitrosoaniline followed by treatment with an acid such as dilute hydrochloric acid or sulphuric acid or other inorganic acids. The reaction may be effected in an organic solvent such as ethanol, methanol or isopropanol at moderate temperatures of from 10 to 50°C, conveniently at ambient temperature.

Alternatively the oxidation may be carried out using a strong oxidising agent such as sodium dichromate. The reaction may be effected in an acidic solvent such as aqueous sulphuric acid or glacial acetic acid, preferably a combination of both, at temperatures of from 0°C to 80°C, conveniently at ambient temperature.

Compounds of formula (I) where X, Y and Z are oxygen may also be obtained when compounds of formula (IV) are exposed to nitrating reagents which are also strong oxidising agents, for example mixtures of concentrated sulphuric acid and fuming nitric acid or solutions of potassium nitrate in sulphuric acid.

Compounds of formula (IV) can be prepared by cyclisation of a compound

1 2 3 of formula (V) where R , R , and R are as defined in relation to formula

(I). The reaction may be effected by heating the compound (V) to a temperature of from 100 to 250°C, either alone or in the presence of an inert solvent such as toluene, xylene or diphenyl ether.

Compounds of formula (V) can be prepared by reacting a compound of

2 3 formula (VI), where R , and R are as hereinbefore defined with a compound of formula (VII), where R is as defined in relation to formula (I).

The reaction may be effected in a protonic solvent such as water or an alkanol for example ethanol, at temperatures of from 10 to 110°C.

Compounds of formula (VI) can be prepared by reacting a compound of

2 3 formula (VIII), where R , and R are as defined in relation to formula (I) with acetic anhydride. The reaction may be effected by heating the compound (VIII) in an excess of acetic anhydride as solvent, to a temperature of from 80 to 120°C.

Alternatively compounds of formula (IV) can be prepared by reacting a compound of formula (VIII) as hereinbefore defined with a compound of

formula (VII) as hereinbefore defined. The reaction may be effected at elevated temperatures e.g. temperatures of from 80 to 100°C in the presence of a protonic solvent, such as water.

Compounds of formula (VII) are known compounds or can be prepared from known compounds by conventional methods.

Compounds of formula (VIII) are known compounds or can be prepared from known compounds by conventional methods.

Compounds of formula (VIII) may be prepared by reacting a compound of

2 3 formula (IX), where R and R are as defined in relation to formula (I), with a base such as potassium hydroxide or sodium hydroxide in water. The reaction can be carried out at temperatures of from 10°C to 100°C, conveniently at ambient temperature.

Compounds of formula (IX) can be prepared by reacting a compound of

2 3 formula (X), where R , and R are as defined in relation to formula (I), with an alkyl acetoacetate such as ethyl acetoacetate in the presence of a copper (I) species such as cuprous bromide and a strong base such as sodium hydride. The reaction is preferably carried out at temperatures from 70°C to 90°C, using an excess of ethyl acetoacetate as solvent.

Compounds of formula (X) are known compounds or can be prepared from known compounds by conventional methods.

Alternatively compounds of formula (VIII) can be prepared by

2 3 hydrolysing a compound of formula (XI), where R and R are as defined in relation to formula (I), using a base such as potassium hydroxide or sodium hydroxide in water. The reaction can be carried out at temperatures of from 10 ^β C to 110°C, conveniently at reflux temperature.

Compounds of formula (XI) are known compounds or can be prepared from known compounds by conventional methods.

For example compounds of formula (XI) can be prepared by reacting a

2 3 compound of formula (XII), where R and R are as defined in relation to formula (I), with a source of cyanide ion, preferably potassium cyanide, in the absence of a solvent. The reaction can be conducted at temperatures of from 180°C to 250°C, preferably at 190°C to 210°C.

Compounds of formula (XII) are known compounds or can be prepared from known compounds by conventional methods.

Compounds of formula (I) where X, Y and Z are oxygen may also be

2 3 prepared by reacting a compound of formula (XIII), where R , and R are as

defined in relation to formula (I); with a compound of formula (XIV); where

1 2 X and X are leaving groups.

2 3 Preferably in this reaction, the ring formed by the groups R , and R include at least some electron-donating groups such as alkoxy in particular

2 3 methoxy, or alternatively the ring formed by the groups R and R is an electron rich heterocycle such as furan, pyrrole or thiophene.

1 2 The leaving groups X and X are preferably halogen, esylate or tosylate.

In particular they are halogen atoms such as chlorine.

The reaction may be effected at a temperature of from 60 to 180°C in a solvent selected from orthodichlorobenzene, toluene, or xylene, or by heating in the absence of a solvent.

Compounds of formula (XIII) may be prepared by reacting a compound of formula (XV), where R , and R are as defined above and R is a halide, with a compound of formula (VII) as hereinbefore defined.

The reaction may be effected at moderate temperatures of from 0 to 100°C, in a range of solvents such as water, or in the absence of a solvent.

40 Preferably R is chloride.

Compounds of formula (XV) can be prepared by halogenation of a

2 3 compound of formula (XVI), where R and R are as defined in relation to formula (I).

The reaction may be effected using a halogenating agent such as thionyl chloride, phosphoryl chloride or phosphorus pentachloride at temperatures of from 20 to 120 ^β C.

Compounds of formula (XIV) and (XVI) are known compounds or can be prepared from known compounds by conventional methods.

Another method of obtaining compounds of formula (I) where X, Y and Z

1 2 are oxygen is by oxidation of a compound of formula (XVII); where R , R ,

3 and R are as defined in relation to formula (I).

The oxidation is suitably effected using an oxidising agent such as chromium trioxide or sodium dichromate. The reaction can be effected at temperatures of from 0 to 50°C using an aqueous inorganic acid, preferably sulphuric acid and/or an organic acid, such as glacial acetic acid as solvent.

Compounds of formula (XVII) can be prepared by oxidation of compounds

1 2 3 of formula (XVIII) where R , R , and R are as defined in relation to formula (I) and ^" is an anion.

Suitable values for ^" include halides such as iodides or chlorides, or sulphonates such as para toluene sulphonate.

Again the oxidation can be effected using an oxidising agent such as potassium ferricyanide. Reaction conditions are suitably low temperatures of from -20 to +30°C in a solvent such as water, in the presence of a base, such as sodium or potassium hydroxide.

Compounds of formula (XVIII) can be prepared by reacting a compound of

2 3 formula (XIX); where R , and R are as hereinbefore defined with a compound of formula (XX); where R and are as hereinbefore defined, in the presence of a base.

Compounds of formula (I) where X, Y and Z are oxygen and R is an acyloxy group can be prepared by heating a compound of formula (XXI), where R and

R are as defined in relation to formula (I), with an acyl halide such as acetyl chloride. The reaction is suitably carried out at temperatures of from 20°C to 120°C, preferably at 60°C to 80°C.

Compounds of formula (XXI) are known compounds or can be prepared from known compounds by conventional methods.

Compounds of formula (II) wherein X, Y and Z are oxygen and the

18 substituent R is cyano may be prepared by nitrating a compound (V)

2 3 (wherein R and R and the carbon atoms to which they are joined form a benzene ring) to give the corresponding compound (V) with a nitro group in the para position relative to the -Q-LCONHR group.

The nitro group is then reduced to an amino group by conventional methods

(e.g. by reaction with hydrogen in presence of a palladium/charcoal catalyst) and the amino group then converted to a cyano group by diazotisation and treatment with cuprous cyanide and KCN (Sandmeyer reaction). The cyano compound so obtained is then cyclised by heating as described above to give a compound (IV). This is oxidised as described

18 above to give the required compound of formula (II) wherein R is cyano and X, Y and Z are oxygen.

Compounds of formula (III) wherein X, Y and Z are oxygen may be prepared by starting from the appropriate carboxy-substituted heterocyclic compound

(XXII) wherein R , W, and Q are as previously defined.

The acid (XXII) is converted to the corresponding acid chloride by treatment with a conventional chlorinating agent (e.q. SOC * POC ) and then into the corresponding amide (XXIII) by reaction with an amine R NH ₂ «

The amide (XXIII) is then heated with oxalyl chloride to a moderate temperature (e.g. 50-140°C) either with a solvent (e.g. CC1 _* or orthodichlorobenzene) or without, to give the required compound (III). Compounds of formula (III) may also be prepared by oxidising (e.g. with sodium dichromate in dilute sulphuric acid/acetic acid) a compound of

2 3 formula (IV) wherein R and R together comprise a heterocyclic ring. The compound (IV) required for this reaction may be prepared for example, by reacting the corresponding compound (VI) with an amine R NH ₂ as described above.

Compounds of formula (I) wherein X is an =N0H or =N0R group and Y and Z are oxygen may be prepared by several methods. In one method, the compound of formula (I) wherein X, Y and Z are oxygen is reacted with a hydroxylamine salt (e.g. the hydrochloride) in a solvent (e.g. ethanol) under the usual conditions for preparation of oximes to give the compound of formula (I) in which X is =N0H and Y and Z are oxygen. Compounds of formula (I) wherein X is =N0R and Y and Z are oxygen may be prepared by reacting a compound of formula (I) wherein X is =N0H and Y and Z are oxygen with a halide R Hal (e.g. R I) in the presence of a base (e.g. sodium hydride) in an aprotic solvent (e.g. dimethyl formamide), or with a dialkyl sulphate (e.g. dimethyl sulphate) in the presence of a base (e.g. potassium carbonate) in an aprotic solvent (e.g. dimethyl formamide).

In an alternative process for making compounds of formula (I) wherein X is

=N0R and Y and Z are oxygen, a compound of formula (I) in which X, Y and Z are all oxygen is reacted with an alkoxyamine R0NH ₂ in the form of a salt

(e.g. the hydrochloride) in a solvent (e.g. ethanol) under the usual conditions for preparation of oximes.

Compounds of formula (I) wherein X is =NCN and Y and Z are oxygen may be prepared by reacting a compound (I) wherein X, Y and Z are oxygen with the compound of formula Me,SiN=C=NSiMe ₃ in the presence of titanium trichloride and in a solvent (e.g. dichloromethane).

Compounds of formula (I) wherein X is a p_-Me ₂ N.CgH..N= group may be prepared by reaction of a compound of formula (IV) with p_--dimethylaminonitrosobenzene in a solvent (e.g. dichloromethane).

Compounds of formula (I) in which X is a =C(CN) ₂ group and Y and Z are oxygen may be prepared by reaction of a compound of formula (I) wherein X,

Y and Z are oxygen with a compound of formula CH ₂ (CN) ₂ in the presence of a base. Preferably the base is a secondary amine (e.g. piperidine). Compounds of formula (I) in which Y is an =N0H group and X and Z are oxygen may be prepared by reaction of a compound of formula (IV) with sodium nitrite in the presence of an acid (e.g. HC1) and in a solvent (e.g. a mixture of methanol and water).

Compounds containing a quaternary nitrogen atom (e.g. compounds 136-139 of Tabvle II) may be prepared for example by reaction of the corresponding heterocycle with an alkyl halide, preferably a bromide or iodide (e.g. methyl or ethyl bromide or iodide). Thus, compound 136 may be made by reaction of methyl iodide with compound 134. Compounds of formula (I) in which Y is an optionally substituted phenylimino group (e.g. a 2-methylphenylimino group) and X and Z are oxygen may be prepared by reaction of a compound of formula (XXIV) with a suitably substituted nitrosobenzene, preferably in a solvent (e.g. dimethylformamide.

2 3 Substituents on the ring formed by R and R can be introduced or modified at various stages during the preparation using techniques known to the chemist. Examples of such conversions are given hereinafter.

Compositions containing compounds of formula (I) include both dilute compositions, which are ready for immediate use, and concentrated compositions, which require to be diluted before use, usually with water. Preferably the compositions contain from 0.01% to 90% by weight of the active ingredient. Dilute compositions ready for use preferably contain from 0.01% to 2% of active ingredient, while concentrated compositions may contain from 20% to 90% of active ingredient, although from 20% to 70% is usually preferred.

The solid compositions may be in the form of granules, or dusting powders wherein the active ingredient is mixed with a finely divided solid diluent, e.g. kaolin, bentonite, kieselguhr, dolomite, calcium carbonate, talc, powdered magnesia, Fuller's earth and gypsum. They may also be in the form of dispersible powders or grains, comprising a wetting agent to facilitate the dispersion of the powder or grains in liquid. Solid compositions in the form of a powder may be applied as foliar dusts.

Liquid compositions may comprise a solution or dispersion of an active ingredient in water optionally containing a surface-active agent, or may

comprise a solution or dispersion of an active ingredient in a water-immiscible organic solvent which is dispersed as droplets in water.

Surface-active agents may be of the cationic, anionic, or non-ionic type or mixtures thereof. The cationic agents are, for example, quaternary ammonium compounds (e.g. cetyltrimethylammonium bromide). Suitable anionic agents are soaps; salts of aliphatic mono ester of sulphuric acid, for example sodium lauryl sulphate; and salts of sulphonated aromatic compounds, for example sodium dodecylbenzenesulphonate, sodium,calcium, and ammonium lignosulphonate, butylnaphthalene sulphonate, and a mixture of the sodium salts of diisopropyl and triisopropylnaphthalenesulphonic acid. Suitable non-ionic agents are the condensation products of ethylene oxide with fatty alcohols such as oleyl alcohol and cetyl alcohol, or with alkylphenols such as octyl- or nonyl- phenol (e.g. Agral 90) or octyl-cresol. Other non-ionic agents are the partial esters derived from long chain fatty acids and hexitol anhydrides, for example sorbitan monolaurate; the condensation products of the partial ester with ethylene oxide; the lecithins; and silicone surface active agents (water soluble surface active agents having a skeleton which comprises a siloxane chain e.g. Silwet L77). A suitable mixture in mineral oil is Atplus 411F.

The aqueous solutions or dispersions may be prepared by dissolving the active ingredient in water or an organic solvent optionally containing wetting or dispersing agent(s) and then, when organic solvents are used, adding the mixture so obtained to water optionally containing wetting or dispersing agent(s). Suitable organic solvents include, for example, ethylene di-chloride, isopropyl alcohol, propylene glycol, diacetone alcohol, toluene, kerosene, methylnaphthalene, the xylenes and trichloroethylene.

The compositions for use in the form of aqueous solutions or dispersions are generally supplied in the form of a concentrate containing a high proportion of the active ingredient, and the concentrate is then diluted with water before use. The concentrates are usually required to withstand storage for prolonged periods and after such storage, to be capable of dilution with water to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. Concentrates conveniently contain 20-90%, preferably 20-70%, by weight of the active ingredient(s) . Dilute

preparations ready for use may contain varying amounts of the active ingredient(s) depending upon the intended purpose; amounts of 0.01% to 10.0% and preferably 0.1% to 2%, by weight of active ingredient(s) are normally used.

A preferred form of concentrated composition comprising the active ingredient which has been finely divided and which has been dispersed in water in the presence of a surface-active agent and a suspending agent. Suitable suspending agents are hydrophilic colloids and include, for example, polyvinylpyrrolidone and sodium carboxymethylcellulose, and the vegetable gums, for example gum acacia and gum tragacanth. Preferred suspending agents are those which impart thixotropic properties to, and increase the viscosity of the concentrate. Examples of preferred suspending agents include hydrated colloidal mineral silicates, such as montmorillonite, beidellite, nontronite, hectorite, saponite, and saucorite. Bentonite is especially preferred. Other suspending agents include cellulose derivatives and polyvinyl alcohol.

The compounds of formula (I) are active as herbicides and therefore, in a further aspect the invention provides a process for severely damaging or killing unwanted plants which process comprises applying to the plants, or to the growth medium of the plants, a herbicidally effective amount of a compound of formula (I) as hereinbefore defined.

The compounds of formula (I) are active against a broad range of weed species including monocotyledonous and dicotyledonous species.

The compounds of formula (I) may be applied directly to the plant (post-emergence application) or to the soil before the emergence of the plant (pre-emergence application). They are particularly useful when applied post-emergence.

The rate of application of the compounds of the invention will depend on a number of factors including, for example, the compound chosen for use, the identity of the plants whose growth is to be inhibited, the formulations selected for use and whether the compound is to be applied for foliage or root uptake. As a general guide, however, an application rate of from 0.001 to 20 kilograms per hectare is suitable while from 0.025 to 10 kilograms per hectare may be preferred.

The compositions of the invention may comprise, in addition to one or more compounds of the invention, one or more compounds not of the invention

but which possess biological activity for example herbicides, fungicides, insecticides (optionally with an insecticide synergist) and plant growth regulators. Accordingly in yet a still further embodiment the invention provides a herbicidal composition comprising a mixture of at least one herbicidal compound of formula (I) as hereinbefore defined with at least one other herbicide.

The other herbicide may be any herbicide not having the formula (I). It will generally be a herbicide having a complementary action in the particular application.

Examples of useful complementary herbicides include:

A. benzo-2,l,3-thiadiazin-4-one-2,2-dioxides such as bentazone;

B. hormone herbicides, particularly the phenoxy alkanoic acids such as MCPA, MCPA-thioethyl, dichlorprop, 2,4,5-T, MCPB, 2,4-D, 2,4-DB, ecoprop, trichlopyr, clopyralid, and their derivatives (eg. salts, esters and amides);

C. 1,3 dimethylpyrazole derivatives such as pyrazoxyfen, pyrazolate and benzofenap;

D. Dinitrophenols and their derivatives (eg. acetates) such as dinoterb, dinoseb and its ester, dinoseb acetate;

E. dinitroaniline herbicides such as dinitramine, trifluralin, ethalflurolin, pendimethalin, oryzalin;

F. arylurea herbicides such as diuron, flumeturon, metoxuron, neburon, isoproturon, chlorotoluron, chloroxuron, linuron, monolinuron, chlorobromuron, daimuron, methabenzthiazuron;

G. phenylcarbamoyloxyphenylcarbamates such as phenmedipham and desmedipham;

H. 2-phenylpyridazin-3-ones such as chloridazon and norflurazon; I. uracil herbicides such as lenacil, bromacil and terbacil; J. triazine herbicides such as atrazine, simazine, aziprotryne, cyanazine, prometryn, dimethametryn, simetryne, and terbutryn; K. phosphorothioate herbicides such as piperophos, bensulide, and butamifos; L. thiolcarbamate herbicides such as cycloate, vernolate, olinate, thiobencarb, butylate , EPTC , tri-allate, di-allate, esprocarb, tiocarbazil, pyridate, and dimepiperate; M. l,2,4-triazin-5-one herbicides such as metamitron and

metribuzin; N. benzoic acid herbicides such as 2,3,6-TBA, dicamba and chloramben; 0. anilide herbicides such as pretilachlor, butachlor, alachlor, propachlor, propanil, etazachlor, metolachlor, acetochlor, and dimethachlor; P. dihalobenzonitrile herbicides such as dichlobenil, bromoxynil and ioxynil; Q. haloalkanoic herbicides such as dalapon, TCA and salts thereof; R. diphenylether herbicides such as lactofen, fluroglycofen or salts or ester thereof, nitrofen, bifenox, aciflurofen and salts and esters thereof, oxyfluorfen, fo esafen, chlornitrofen and chlomethoxyfen; S. phenoxyphenoxypropionate herbicides such as diclofop and esters thereof such as the methyl ester, fluazifop and esters thereof, haloxyfop and esters thereof, quizalofop and esters thereof and fenoxaprop and esters thereof such as the ethyl ester; T. cyclohexanedione herbicides such as alloxydim and salts thereof, sethoxydim, cycloxyidim, tralkoxydim, and clethodim; U. sulfonyl urea herbicides such as chlorosulfuron, sulfometuron, metsulfuron and esters thereof; benzsulfuron and esters thereof such as DPX-M6313, chlorimuron and esters such as the ethyl ester thereof pirimisulfuron and esters such as the methyl ester thereof, 2-[3-(4-methoxy-6-methy1-1,3,5- triazin-zyl)-3-methylureidosulphonyl) benzoic acid esters such as the methyl ester thereof (DPX-LS300) and pyrazosulfuron; V. imidazolidinone herbicides such as imazaquin, imazamethabenz, imazapyr and isopropylammonium salts thereof, imazethapyr; W. arylanilide herbicides such as flamprop and esters thereof, benzoylprop-ethyl, diflufenican; X. amino acid herbicides such as glyphosate and glufosinate and their salts and esters, sulphosate and bialaphos; Y. organoarsenical herbicides such as monosodium methanearsonate

(MSMA); Z. herbicidal amide derivative such as napropamide, propyzamide, carbetamide, tebutam, bromobutide, isoxaben, naproanilide and

naptalam;

AA. miscellaneous herbicides including ethofumesate, cinmethylin, difenzoquat and salts thereof such as the methyl sulphate salt, clomazone, oxadiazon, bromofenoxim, barban, tridiphane, flurochloridone, quinclorac, dithiopyr and mefanacet;

BB. Examples of useful contact herbicides include: bipyridylium herbicides such as those in which the active entity is paraquat and those in which the active entity is diquat; * These compounds are preferably employed in combination with a safener such as dichlormid.

CC. triketone herbicides such as sulcotrione.

The following Examples illustrate the invention. The naming and numbering conventions used throughout the experimental section are set out on the attached sheet.

EXAMPLE 1: PREPARATION OF COMPOUND 1

A stirred solution of N-ethyl homophthalimide (prepared as described in

Preparative Example 1 below) (8.70g) in ethanol (65ml) was treated portionwise with solid N,N-dimethyl-p-nitrosoaniline (6.90g). The resulting dark solution was stirred at room temperature for a further 4 hours, before being poured onto cracked ice and acidified to pHl using 2M hydrochloric acid. The volume of the resultant mixture was reduced by evaporation under reduced pressure and the crystalline precipitate was filtered off, washed with hexane and dried, affording the title compound as a pale brown solid, yield 6.20g, p 95°C.

^X Hnmr data (CDC1 ₃ ): δl.28 (3H, t) , 4.13 (2H, q) , 7.79-7.94 (2H, m) , 8.21

(IH, dd), 8.36 (IH, d)

EXAMPLE 2: PREPARATION OF COMPOUND 2

By a method similar to that described in Example 1 but using homophthalimide instead of N-ethyl homophthalimide, the title compound was obtained.

EXAMPLE 3: PREPARATION OF COMPOUND 3

By a method similar to that described in Example 1 but using N-(l- methylpropyl) homophthalimide (prepared as described in Preparative Example

2 below) (0.220g), ethanol (8ml) and N,N-dimethyl-p-nitrosoaniline

(0.160g), the title compound was obtained as a pale yellow crystalline

solid, yield 0.152g, mp 83-84°C.

^! Hnmr data (CDCl _j ): δθ.89 (3H, t) , 1.51 (3H, d) , 1.89 (IH, m) , 2.09 (IH, ), 4.97 (IH, m) , 7.78-7.92 (2H, m) , 8.19 (IH, dd) , 8.35 (d)

EXAMPLE 4: PREPARATION OF COMPOUND 4

By a method similar to that described in Example 1 but using 8-hydroxy-N- ethyl homophthalimide (prepared as described in Preparative Example 3 below) (0.800g), ethanol and N,N-dimethyl-p-nitrosoaniline (0.585g), and recrystalusing the crude product from ethanol, the title compound was obtained as a green crystalline solid, yield 0.500g, mp 174-175°C. data (CDC1.-): δl.32 (3H, t) , 4.12 (2H, q) , 7.42 (IH, dd) , 7.69 (IH, dd), 7.79 (IH, dd) , 11.79 (IH, s)

EXAMPLE 5: PREPARATION OF COMPOUND 5

By a method similar to that described in Example 1 but using 6,7-benzo-N- ethyl homophthalimide (prepared as described in Preparative Example 4 below) (0.239g), ethanol (5ml) and N,N-dimethyl-p-nitrosoaniline (0.150g), and triturating the crude product with ethanol, the title compound was obtained a pale brown solid, yield 0.064g, mp 178-181°C.

^X Hnmr data (CDC1 ₃ ): δl.32 (3H, t), 4.19 (2H, q), 7.70-7.84 (2H, m) , 8.05-

8.15 (2H, m), 8.78 (IH, s), 8.88 (IH, s)

EXAMPLE 6: PREPARATION OF COMPOUND 6

By a method similar to that described in Example 1 but using N-methyl homophthalimide (prepared as described in Preparative Example 5 below)

(0.650g), ethanol (20ml) and N,N-dimethyl-p-nitrosoaniline (0.557g), and recrystalusing the crude product from ethanol, the title compound was obtained a pale red solid, yield 0.470g, mp 189°C.

^! Hnmr data (CDC1 ₃ ): δ3.50 (3H, s) , 7.81-7.96 (2H, ) , 8.23 (IH, dd) , 8.38

(IH, d)

EXAMPLE 7: PREPARATION OF COMPOUND 7

This compound was prepared by a method similar to that described in Example

1 but using N-ethyl-8-methoxy homophthalimide (prepared as described in

Preparative Example 6 below) (0.230g), ethanol (20ml) and N,N-dimethyl-p- nitrosoaniline (O.lβOg). The reaction mixture was evaporated to dryness in vacuo, then redissolved in a small amount of water and extracted with ethyl acetate. The ethyl acetate extract was dried over magnesium sulphate, and evaporated in vacuo to afford the title compound as a pale yellow solid, mp 143°C.

^X Hnmr data (CDC1 ₃ ): δl.29 (3H, t) , 4.06 (3H, s), 4.12 (2H, q) , 7.45 (IH, d), 7.76 (IH, dd), 7.88 (IH, d) EXAMPLE 8: PREPARATION OF COMPOUND 8

By a method similar to that described in Example 1 but using N-ethyl-7- ethoxy homophthalimide (prepared as described in Preparative Example 7 below) (0.300g), ethanol (7ml) containing dimethylformamide (1ml) and N,N- dimethyl-p-nitrosoaniline (0.225g), the title compound was obtained as a crystalline solid, yield 0.230g, mp 137°C.

^! Hnmr data (CDC1 ₃ ): δl.29 (3H, t), 4.00 (3H, s), 4.11 (2H, q) , 7.28 (IH, dd), 7.76 (IH, d) , 8.18 (IH, d) EXAMPLE 9: PREPARATION OF COMPOUND 9

By a method similar to that described in Example 1 but using 7-chloro-N- ethyl homophthalimide (prepared as described in Preparative Example 8 below) (0.250g), ethanol (7ml) containing dimethylformamide (0.5ml) and N,N-dimethyl-p-nitrosoaniline (O.lδOg), the title compound was obtained as a dark powder, yield 0.165g, mp 153°C.

^! Hnmr data (CDC1 ₃ ): δl.30 (3H, t) , 4.12 (2H, q) , 7.79 (IH, dd) , 8.17 (IH, d), 8.32 (IH, d)

EXAMPLE 10: PREPARATION OF COMPOUND 10

A solution of N-ethyl 3,4,5-trimethoxybenzamide (prepared as described in Preparative Example 9 below) (2.80g) in ortho-dichlorobenzene (12ml) was added to a stirred solution of oxalyl chloride (1.86g) in ortho- dichlorobenzene (15ml). The reaction mixture was heated to 140-150°C for 5 hours, and was then cooled (ice bath) and diluted with petroleum ether (60- 80). The precipitate which formed was filtered off, and recrystallised from ethyl acetate/petroleum ether(60-80) to give the title compound as a yellow crystalline solid, yield 1.30g, mp 147-150°C. ^nmr data (CDC1 ₃ ): δl.28 (3H, t) , 3.95 (3H, s) , 3.96 (3H, s), 4.06 (3H, s), 4.09 (2H, q), 7.70 (IH, s) EXAMPLE 11: PREPARATION OF COMPOUND 11

By a method similar to that described in Example 10 but using N-methyl 3,4,5-trimethoxybenzamide (prepared as described in Preparative Example 10 below) (2.00g), ortho-dichlorobenzene and oxalyl chloride (1.41g), and recrystalusing the product from chloroform/ethyl acetate/hexane, the title compound was obtained as a pale yellow crystalline solid, yield 1.20g, mp 210°C.

^nmr data (CDC1 ₃ ) : δ3.44 (3H, s) , 3.96 (3H, s) , 3.97 (3H, s) , 4.07 (3H, s) , 7.69 (IH, s)

EXAMPLE 12: PREPARATION OF COMPOUND 12

A stirred solution of 5-chloro-N-ethyl-l-isoquinolone (prepared as described in Preparative Example 11 below) (0.786g) in glacial acetic acid (15ml) was treated dropwise with a solution of sodium dichromate (1.845g) in 2M sulphuric acid (9.2ml) at such a rate that the reaction temperature did not exceed 30°C. The mixture was then stirred at room temperature for a further 3 hours, before being extracted with ethyl acetate (x3). The combined ethyl acetate extracts were washed with brine, dried (MgSO and evaporated in vacuo. This residue was then taken up in diethyl ether and washed with saturated sodium bicarbonate solution (to remove acetic acid). The ether solution was then dried (MgSO and evaporated in vacuo to leave a yellow solid. Recrystallisation from methanol afforded the title compound as a yellow crystalline solid, yield 0.190g, mp 186-187°C. ^X Hnmr data (CDC1 ₃ ): δl.28 (3H, t), 4.10 (2H, q), 7.71-7.83 (2H, m) , 8.36 (IH, dd)

EXAMPLE 13: PREPARATION OF COMPOUND 13

A stirred solution of N-ethyl-l-isoquinolone-5-N-ethylcarboxamide (prepared as described in Preparative Example 12 below) (0.235g) in glacial acetic acid (5ml) was treated dropwise with a solution of sodium dichromate (0.757g) in 2M sulphuric acid (4.6ml). The mixture was then stirred at room temperature for a further 3 hours, before being diluted with water and extracted with ethyl acetate (x3). The combined ethyl acetate extracts were washed with saturated sodium bicarbonate solution and brine, dried (MgSO and evaporated in vacuo to leave a green gum, which was triturated with hexane to afford the title compound as a pale green solid, yield 0.105g, mp 146-147°C.

^X Hnmr data (CDCI3): δl.21-1.38 (6H, m) , 3.55 (2H, m), 4.12 (2H, q), 5.69 (IH, broad s), 7.75 (IH, d) , 7.89 (IH, dd), 8.41 (IH, d) EXAMPLE 14: PREPARATION OF COMPOUND 14

By a method similar to that described in Example 13 but using ethyl N- ethyl-l-isoquinolone-5-carboxylate (prepared as described in Preparative Example 13 below) (0.160g), glacial acetic acid (3ml), sodium dichromate (0.513g) and 2M sulphuric acid (3.1ml), the title compound was obtained as a pale coloured solid, yield 0.090g, mp 100-101°C.

^X Hnmr data (CDC1 ₃ ): δl.30 (3H, t) , 1.39 (3H, t) , 4.11 (2H, q) , 4.46 (2H, q), 7.78 (IH, d) , 7.94 (IH, dd) , 8.45 (IH, d)

EXAMPLE 15: PREPARATION OF COMPOUND 15

By a method similar to that described in Example 13 but using 5-cyano-N- ethyl-1-isoquinolone (prepared as described in Preparative Example 14 below) (0.220g), glacial acetic acid (12ml), sodium dichromate (0.873g) and

2M sulphuric acid (4.3ml), the title compound was obtained as a pale coloured solid, yield 0.180g, mp 180°C (dec).

^! Hnmr data (CDC1 ₃ ): δl.28 (3H, t) , 4.08 (2H, q) , 8.02 (IH, dd), 8.19 (IH, d), 8.57 (IH, d)

EXAMPLE 16: PREPARATION OF COMPOUND 16

By a method similar to that described in Example 13 but using N-ethyl-1- isoquinolone-5-carboxamide (prepared as described in Preparative Example 15 below) (0.070g), glacial acetic acid (2ml), sodium dichromate (0.254g) and

2M sulphuric acid (1.3ml), the title compound was obtained as a pale coloured solid, yield 0.054g, mp 206-209°C.

^J Hnmr data (CDCl ₃ /dg_DMS0): δl.21 (3H, t), 4.00 (2H, q), 7.45 (IH, broad s), 7.53 (IH, broad s), 7.73 (IH, d), 7.88 (IH, dd), 8.29 (IH, d)

EXAMPLE 17: PREPARATION OF COMPOUND 17

By a method similar to that described in Example 13 but using N-ethyl-5- nitro-1-isoquinolone (prepared as described in Preparative Example 16 below) (0.400g), glacial acetic acid (10ml), sodium dichromate (1.442g) and

2M sulphuric acid (7.6ml), the title compound was obtained as a pale coloured solid, yield 0.265g, mp 198°C (dec).

^X Hnmr data (CDC dg MSO): δl.23 (3H, t) , 4.05 (2H, q), 7.98 (IH, d) , 8.05

(IH, dd), 8.49 (IH, d)

EXAMPLE 18: PREPARATION OF COMPOUND 18

By a method similar to that described in Example 13 but using N-ethyl-1- isoquinolone-5-carboxylic acid (prepared as described in Preparative

Example 17 below) (O.lOOg), glacial acetic acid (3ml), sodium dichromate

(0.362g) and 2M sulphuric acid (1.9ml), the title compound was obtained as a pale coloured solid, yield 0.062g, mp 243°C (dec).

^X Hnmr data (CDCl ₃ /dg_DMSO) : δl.14 (3H, t), 3.89 (2H, q), 7.79 (IH, d) , 7.92

(IH, dd), 8.22 (IH, d) , 13.42 (IH, broad s)

EXAMPLE 19: PREPARATION OF COMPOUND 19

By a method similar to that described in Example 13 but using N-ethyl-1-

isoquinolone-5-N,N-diethylcarboxamide (prepared as described in Preparative

Example 18 below) (0.188g), glacial acetic acid (8ml), sodium dichromate

(0.543g) and 2M sulphuric acid (3.6ml), the title compound was obtained as a pale coloured solid, mp 148-149°C.

^nmr data (CDC1 ₃ ): δl.01 (3H, t), 1.29 (lh, t) , 1.36 (3H, t) , 2.89-3.18

(2H, m), 3.35 (IH, m) , 3.87 (IH, m) , 4.12 (2H, q) , 7.63 (IH, d) , 7.91 (IH, dd), 8.39 (IH, d)

EXAMPLE 20: PREPARATION OF COMPOUND 20

By a method similar to that described in Example 13 but using 5-acetamido-

N-ethyl-1-isoquinolone (prepared as described in Preparative Example 19 below) (0.068g), glacial acetic acid (3ml), sodium dichromate (0.232g) and

2M sulphuric acid (1.3ml), the title compound was obtained as a pale yellow solid, yield 0.026g, mp 278-280°C.

^! Hnmr data (CDC1 ₃ ): δl.31 (3H, t) , 4.13 (2H, q) , 7.86 (IH, dd) , 8.09 (IH, d), 9.11 (IH, d), 11.55 (IH, broad s)

EXAMPLE 21: PREPARATION OF COMPOUND 21

This compound was prepared by a method similar to that described in Example

1 but using N-ethyl-7-hydroxy homophthalimide (prepared as described in

Preparative Example 20 below) (O.lOOg), ethanol (7ml) and N,N-dimethyl-p- nitrosoaniline (0.080g). After acidification of the reaction mixture, the resultant solution was evaporated to dryness in vacuo, and the residue was triturated with 2M hydrochloric acid (ca 5ml). The remaining crystalline solid was filtered off, washed with 2M hydrochloric acid, water and hexane, then dried to afford the title compound as a pale brown crystalline solid, yield 0.082g, mp 244-247°C.

^X Hnmr data (CDC1 ₃ ): δl.22 (3H, t) , 4.01 (2H, q) , 7.18 (IH, dd) , 7.59 (IH, d), 8.00 (IH, d), 11.13 (IH, broad s)

EXAMPLE 22: PREPARATION OF COMPOUND 22

By a method similar to that described in Example 10 but using N-ethyl 3,5- dimethoxybenza ide (prepared as described in Preparative Example 21 below)

(5.00g), ortho-dichlorobenzene (30ml) and oxalyl chloride (3.01g), the title compound was obtained as a crystalline solid, yield 5.27g, mp 171-

173°C.

^! Hnmr data (CDCI3): δl.27 (3H, t) , 3.99 (6H, s) , 4.08 (IH, q) , 6.73 (IH, d), 7.48 (IH, d)

EXAMPLE 23: PREPARATION OF COMPOUND 23

A stirred solution of N-ethyl-δ-nitroisoquinolin-l,3,4-trione (prepared as described in Example 17 above) (0.200g) in ethanol (10ml) was treated with iron powder (0.13δg) followed by concentrated hydrochloric acid (0.5ml).

The reaction mixture was heated under reflux for 3 hours, then cooled and filtered through a plug of hyflo to remove the iron residues (the hyflo plug was washed through with ethyl acetate). The combined filtrates were evaporated to dryness in vacuo, and the residue was purified by chromatography on silica gel, eluting with ethyl acetate/hexane mixtures

(1:4), to afford the title compound as a red solid, yield 0.053g, mp 200-

202°C.

^nmr data (CDC1 ₃ ): δl.27 (3H, t) , 4.10 (2H, q), 6.97 (IH, d) , 7.53 (IH, dd), 7.65 (IH, d) (NH signals broad - not observed)

EXAMPLE 24: PREPARATION OF COMPOUND 24

By a method similar to that described in Example 13 but using N-ethyl-6,7- dimethoxy-1-isoquinolone (prepared as described in Preparative Example 22 below) (0.200g), glacial acetic acid (5ml), sodium dichromate (0.675g) and

2M sulphuric acid (4.4ml), and purification of the crude product by chromatography on silica gel (eluting with ethyl acetate/hexane mixtures

(1:4)), the title compound was obtained as a pale yellow solid, yield

0.029g, mp 20δ-207°C.

^X Hnmr data (CDC1 ₃ ): δl.28 (3H, t) , 4.02 (3H, s), 4.08 (3H, s), 4.11 (2H, q), 7.57 (IH, s), 7.71 (IH, s)

EXAMPLE 25: PREPARATION OF COMPOUND 2δ

A solution of potassium nitrate (0.54g) in concentrated sulphuric acid

(δml) was added dropwise to a stirred solution N-ethyl homophthalimide

(prepared as described in Preparative Example 1 below) (l.Olδg) in concentrated sulphuric acid (5ml) at 0°C. The resultant mixture was stirred for a further 40 minutes, then diluted with water. The brown solid

(A) formed was filtered off, and the solution was extracted with ethyl acetate. The ethyl acetate extract was dried (MgSO.) and evaporated to dryness in vacuo. The residue was combined with the solid (A), and chromatographed on silica gel to afford the title compound as a buff solid, yield 0.235g. nmr data (CDC1 ₃ ) : δl .28 (3H , t) , 4.18 (2H , q) , 8.42 (IH , m) , 8.64 ( IH , m) , 9. 17 ( IH , d)

The remaining fractions consisted largely of N-ethyl isoquinolin-1,3,4-

trione (Compound 1).

EXAMPLE 26: PREPARATION OF COMPOUND 26 δ% Palladium on Carbon (0.020g) was added to a stirred solution of N-ethyl-

7-nitro isoquinolin-l,3,4-trione (prepared as described in Example 2δ above) (O.lOOg) in methanol (4δml). This mixture was hydrogenated for l.δ hours. The mixture was then filtered through celite (washing through with methanol), and the filtrates were evaporated to dryness in vacuo. The residue was chromatographed on silica gel (eluting with ethyl acetate/hexane (1:1)) to afford the title compound, yield O.Olβg, mp 295-

297°C.

^n r data (CDC1 ₃ ): δl.24 (3H, t), 4.09 (2H, q) , 6.91 (IH, dd), 7.43 (IH, d), 8.04 (IH, d)

EXAMPLE 27: PREPARATION OF COMPOUND 27

By a method similar to that described in Example 1 but using N-(l-n-propyl) homophthalimide (prepared as described in Preparative Example 23 below)

(0.570g), ethanol (15ml) and N,N-dimethyl-p-nitrosoaniline (0.4δ0g), the title compound was obtained as a pale yellow crystalline solid, yield

0.230g, mp 60-62°C.

^X Hnmr data (CDC1 ₃ ): δθ.98 (3H, t) , 1.73 (2H, m), 4.04 (2H, t), 7.78-7.91

(2H, m), 8.21 (IH, dd) , 8.35 (IH, dd)

EXAMPLE 28: PREPARATION OF COMPOUND 28

By a method similar to that described in Example 1 but using N-(iso-propyl) homophthalimide (prepared as described in Preparative Example 24 below)

(O.lδOg), ethanol (δml) and N,N-dimethyl-p-nitrosoaniline (0.120g), the title compound was obtained as a reddish solid, yield 0.099g, mp 137-139 C.

^nmr data (CDC1 ₃ ): δl.63 (6H, d) , 5.21 (IH, m) , 7.78-7.93 (2H, m), 8.19

(IH, dd), 8.35 (IH, d)

EXAMPLE 29: PREPARATION OF COMPOUND 29

By a method similar to that described in Example 1 but using N-phenyl homophthalimide (prepared as described in Preparative Example 25 below)

(0.500g), ethanol (15ml) containing dimethylformamide (2ml) and N,N- dimethyl-p-nitrosoaniline (0.330g), the title compound was obtained as a pale coloured solid, yield 0.420g, mp 214-215 °C.

^nmr data (CDC1 ₃ ): δ7.20-7.28 (2H, m) , 7.41-7.58 (3H, m) , 7.82-7.98 (2H, m), 8.31 (IH, dd), 8.39 (IH. dd)

EXAMPLE 30: PREPARATION OF COMPOUND 30

By a method similar to that described in Example 1 but using N-n-butyl homophthalimide (prepared as described in Preparative Example 26 below)

(0.620g), ethanol (16ml) and N,N-dimethyl-p-nitrosoaniline (0.450g), the title compound was obtained as a pale yellow solid, yield 0.380g, mp 69-

60°C.

^X Hnmr data (CDC1 ₃ ): δ0.9δ (3H, t) , 1.38 (2H, m) , 1.66 (2H, m) , 4.04 (2H, t), 7.78-7.92 (2H, ) , 8.20 (IH, d) , 8.33 (IH, d)

EXAMPLE 31: PREPARATION OF COMPOUND 31

By a method similar to that described in Example 1 but using N-(2- methylpropyl) homophthalimide (prepared as described in Preparative Example

27 below) (0.370g), ethanol (12ml) and N,N-dimethyl-p-nitrosoaniline

(0.270g), the title compound was obtained as a buff crystalline solid, yield 0.260g, mp 113-114°C.

^nmr data (CDC1 ₃ ): δθ.94 (6H, d) , 2.17 (IH, m) , 3.91 (2H, d) , 7.78-7.92

(2H, m), 8.21 (IH, dd) , 8.36 (IH, d)

EXAMPLE 32: PREPARATION OF COMPOUND 32

By a method similar to that described in Example 1 but using N-(l,2- di ethylpropyl) homophthalimide (prepared as described in Preparative

Example 28 below) (0.260g), ethanol (8ml) and N,N-dimethyl-p-nitrosoaniline

(0.170g), the title compound was obtained as a red oil, yield 0.162g.

^! Hnmr data (CDC1 ₃ ): δθ.79 (3H, d) , 1.03 (3H, d), 1.51 (IH, d) , 2.57 (IH, m), 4.6δ (IH, m), 7.77-7.92 (2H, m) , 8.19 (IH, dd) , 8.34 (IH, d)

EXAMPLE 33: PREPARATION OF COMPOUND 33

By a method similar to that described in Example 13 but using δ-methoxy-N- methyl-1-isoquinolone (prepared as described in Preparative Example 29 below) (0.132g), glacial acetic acid (δml), sodium dichromate (0.δ49g) and

2M sulphuric acid (2.δml), and triturating with an ethyl acetate/hexane mixture, the title compound was obtained as a pale yellow solid, yield

0.04δg, mp 173-17δ°C.

^X Hnmr data (CDC1 ₃ ): δ3.42 (3H, s), 4.03 (3H, s), 7.33 (IH, d) , 7.81 (IH, dd), 7.98 (IH, d)

EXAMPLE 34: PREPARATION OF COMPOUND 34

By a method similar to that described in Example 13 but using N-ethyl-δ- methoxy-1-isoquinolone (prepared as described in Preparative Example 30 below) (0.163g), glacial acetic acid (6ml), sodium dichromate (0.631g) and

2M sulphuric acid (3ml), the title compound was obtained as a pale yellow

solid, yield 0.027g, mp 132-134°C.

^nmr data (CDC1 ₃ ): δl.26 (3H, t) , 4.02 (3H, s), 4.08 (2H, q) , 7.33 (IH, d), 7.91 (IH, dd), 7.98 (IH, d)

EXAMPLE 3δ: PREPARATION OF COMPOUND 35

A mixture of 5-methoxy-N-ethyl isoquinolin-l,3,4-trione (prepared as described in Example 34 above) (O.lOOg) and pyridine hydrochloride (l.OOg) were melted together at 170-180°C for 2 hours. The mixture was cooled, dissolved in 2M hydrochloric acid (a small amount of insoluble material was filtered off) and extracted with ethyl acetate (x3). The combined ethyl acetate extracts were washed with brine, dried (MgSO and evaporated to dryness in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate/hexane to afford the title compound as a pale yellow solid, yield O.Olδg, mp 144-14δ°C.

^X Hnmr data (CDCl ₃ /dg_DMS0) : δl.2δ (3H, t) , 4.04 (2H, q) , 7.34 (IH, dd) ,

7.74-7.88 (2H, m) , 11.30 (IH, broad s)

EXAMPLE 36: PREPARATION OF COMPOUND 36

A stirred solution of N-homophthalimido-acetic acid (O.lOOg) in glacial acetic acid (1ml) was treated dropwise with a solution of sodium dichromate

(0.447g) in 2M sulphuric acid (1ml). The mixture was then stirred at room temperature for a further 3 hours, before being diluted with water and extracted with ethyl acetate (x3) . The combined ethyl acetate extracts were washed with brine, dried (MgSO and evaporated in vacuo to afford the title compound as a pale yellow solid, yield 0.09δg.

^nmr data (dg_Me ₂ C0): δ4.89 (2H, s), 8.02-8.20 (2H, m) , 8.31 (lh, dd) ,

8.4δ (lh, dd)

EXAMPLE 37: PREPARATION OF COMPOUND 37

By a method similar to that described in Example 26 but hydrogenating a 1:1 mixture of δ- and 8-nitro-N-ethyl isoquinolin-l,3,4-triones (prepared as described in Preparative Example 31 below) (0.248g) and δ% palladium on carbon (0.02g) in methanol (lδml), followed by extensive chromatographic separation on silica gel (eluting with ethyl acetate/hexane mixtures), the pure title compound was obtained in low yield (O.Olδg).

^X Hnmr data (dg_Me ₂ C0) : 81.36 (3H, t) , 4.14 (2H, q) , 8.40-8.δδ (2H, m) , 8.67

(IH, m) (NH signals broad - not observed)

The remaining fractions contained mixtures of δ- and 8-amino-N-ethyl isoquinolin-l,3,4-triones in varying proportions.

EXAMPLE 38: PREPARATION OF COMPOUNDS 38A AND 38B

A solution of potassium nitrate (12mg) in concentrated sulphuric acid

(O.δml) was added dropwise to a stirred solution of δ-amino-N-ethyl isoquinolin-l,3,4-trione (prepared as described in Example 23 above) (24mg) in concentrated sulphuric acid (O.δml). Stirring was continued for 1 hour, and the mixture was quenched with ice. The red precipitate was filtered off, washed and dried to afford example compound 38A as a red solid, yield lO g.

^nmr data (CDCI3): δl.29 (3H, t) , 4.11 (2H, q), 7.69 (IH, d) , 8.δ2 (IH, broad s), 8.67 (IH, d) , 9.77 (IH, broad s)

The aqueous layer was extracted with ethyl acetate (x3), and the combined extracts were washed with water, dried (MgSO and evaporated in vacuo to afford a red solid, which was separated by chromatography on silica gel

(eluting with ethyl acetate/hexane mixtures) to afford firstly a further quantity of example compound 38A (δmg), followed by example compound 38B, which was obtained as a red solid, yield 2mg.

^X Hnmr data (CDCI3) : δl.27 (3H, t) , 4.06 (2H, q) , 7.02 (IH, d) , 7.61 (IH, d)

(NH signals broad - not observed)

EXAMPLE 39: PREPARATION OF COMPOUNDS 39A AND 39B

A solution of potassium nitrate (0.277g) in concentrated sulphuric acid

(δml) was added dropwise to a stirred solution N-ethyl-8-hydroxy isoquinolin-l,3,4-trione (prepared as described in Example 4 above)

(O.δOOg) in concentrated sulphuric acid (δml). Stirring was continued for

1 hour, and the mixture was quenched with ice. The precipitate (a mixture of N-ethyl-8-hydroxy-δ-nitro isoquinolin-l,3,4-trione and N-ethyl-8- hydroxy-7-nitro isoquinolin-l,3,4-trione) was filtered off and dried. This mixture was dissolved in methanol (lδml) and δ% palladium on carbon

(0.06δg) was added, and the mixture was hydrogenated under a hydrogen atmosphere, with stirring, for 2.δ hours. The reaction mixture was then filtered through celite, and the solvent was removed in vacuo to leave a dark residue, which was separated by chromatography on silica gel, eluting with ethyl acetate/hexane (1:2), to afford example compound 39A as a red solid, yield 0.031g.

^X Hnmr data (CDCI3) : δl.28 (3H, t) , 4.10 (3H, t), 6.98 (IH, d) , 7.24 (IH, d), 12.10 (IH broad s) (NH signals broad - not observed)

The remaining fractions contained mixtures of example compounds 39A and 39B

in varying proportions.

EXAMPLE 40: PREPARATION OF COMPOUND 40

By a method similar to that described in Example 3δ but using N-ethyl-δ,7- dimethoxy isoquinolin-l,3,4-trione (prepared as described in Example 22 above) (3.60g) and pyridine hydrochloride (lδ.30g), the title compound was obtained as a pale yellow solid, yield O.δOg, mp 261-264°C.

^! Hnmr data (CDCl ₃ /dg_DMS0) : δl.24 (3H, t) , 4.01 (2H, d), 6.61 (IH, d) , 7.28

(IH, d), 11.34 (IH broad s), 11.61 (IH, s)

EXAMPLE 41: PREPARATION OF COMPOUND 41 ^'

By a method similar to that described in Example 13 but using 5- ethoxycarbonylamino-N-ethyl-1-isoquinolone (prepared as described in

Preparative Example 32 below) (0.060g), glacial acetic acid (3ml), sodium dichromate (O.lβOg) and 2M sulphuric acid (2ml), the title compound was obtained as a pale yellow solid, yield 0.042g, mp 140-142°C.

^nmr data (CDC1 ₃ ): δl.28 (3H, t) , 1.35 (3H, t), 4.0δ (2H, q) , 4.28 (2H, t), 7.87 (IH, dd), 8.00 (IH, d), 8.82 (IH, d), 10.99 (IH, broad s)

EXAMPLE 42: PREPARATION OF COMPOUND 42

By a method similar to that described in Example 13 but using the N-ethyl-

1-isoquinolone prepared as described in Preparative Example 33 below

(0.062g), glacial acetic acid (4ml), sodium dichromate (0.142g) and 2M sulphuric acid (3ml), the title compound was obtained as a pale yellow solid, yield 0.047g, mp 225-227°C.

^J Hnmr data (CDC1 ₃ ): δl.30 (3H, t), 4.12 (2H, q) , 7.74 (IH, d) , 7.05 (IH, dd), 8.57 (IH, d)

EXAMPLE 43: PREPARATION OF COMPOUND 43

A suspension of 2-nitroindan-l,3-dione (l.OOg) in acetyl chloride (2.40g) was heated gently until a clear solution was obtained. The solution was evaporated to dryness in vacuo, and the residue was recrystallised from a large volume of acetic acid to afford the title compound as a crystalline solid, yield 0.095g, mp 184°C.

^nmr data (CDC1 ₃ ): δ2.43 (3H, s), 7.82-8.00 (2H, ) , 8.28 (IH, dd) , 8.38

(IH, dd)

EXAMPLE 44: PREPARATION OF COMPOUND 44

By a method similar to that described in Example 10 but using N-ethyl 2,δ- dimethoxybenzamide (prepared as described in Preparative Example 34 below)

(2.00g), ortho-dichlorobenzene and oxalyl chloride (1.08ml), the title

compound was obtained as a pale yellow crystalline solid, yield O.Oδg. ^l tinmr data (CDCI3): δl.27 (3H, t), 3.96 (3H, s), 4.01 (3H, s), 4.0δ (2H, q), 7.33 (IH, d) , 7.45 (IH, d)

EXAMPLE 45: PREPARATION OF COMPOUND 4δ

A solution of potassium nitrate (4δmg) in concentrated sulphuric acid (δml) was added dropwise to a stirred solution of 8-amino-N-ethyl isoquinolin-

1,3,4-trione (prepared as described in Example 37 above) (81mg) in concentrated sulphuric acid (O.δml). Stirring was continued for 1 hour, then the mixture was quenched with ice and extracted with ethyl acetate

(x3). The combined extracts were washed with water, dried (MgSO and evaporated in vacuo to afford a solid residue, which was separated by chromatography on silica gel (eluting with chloroform) to afford the title compound, yield lδmg, mp 224-227°C.

^! Hnmr data (CDC1 ₃ ): δl.31 (3H, t) , 4.12 (2H, q) , 7.49 (IH, d) , 8.4δ (IH, broad s), 8.66 (IH, d) , 9.68 (IH, broad s)

EXAMPLE 46: PREPARATION OF COMPOUND 46

By a method similar to that described in Example 13 but using 5- butanamido-N-ethyl-1-isoquinolone (prepared as described in Preparative

Example 3δ below) (0.16δg), glacial acetic acid (9ml), sodium dichromate

(0.503g) and 2M sulphuric acid (6ml), the title compound was obtained as a pale yellow solid, mp 14δ-147°C.

^! Hnmr data (CDC1 ₃ ): δl.04 (3H, t) , 1.29 (3H, t), 1.82 (2H, m), 2.δ0 (2H, t), 4.12 (2H, t), 7.87 (IH, dd) , 8.09 (IH, d) , 9.14 (IH, d) , 11.δδ (IH, broad s)

EXAMPLE 47: PREPARATION OF COMPOUND 47

By a method similar to that described in Example 3δ but using δ-methoxy-N- methyl isoquinolin-l,3,4-trione (prepared as described in Example 33 above)

(O.βOg) and pyridine hydrochloride (4.20g), the title compound was obtained as a pale yellow solid, yield O.δδg, mp lδ7-lδ9°C.

^nmr data (CDC1 ₃ ): δ3.47 (3H, s) , 7.34 (IH, d) , 7.79 (IH, dd), 7.89 (IH, d), 11.32 (IH, s)

EXAMPLE 48: PREPARATION OF COMPOUND 48

A stirred solution of N-ethyl-5,7-dihydroxy isoquinolin-l,3,4-trione

(prepared as described in Example 40 above) (0.300g) in dimethylformamide

(10ml) was treated with sodium hydride (0.031g). The mixture was stirred for 20 minutes, then methyl iodide (0.217g) was added. After stirring for

a further 2 hours the reaction was quenched wuth 2M hydrochloric acid, and the mixture was extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO and evaporated in vacuo to leave a residual gum, which, on trituration with a mixture of ethyl acetate and hexane, afforded the title compound as a pale yellow solid, yield 0.032g, mp 199-201°C.

^! Hnmr data (CDCI3): δl.28 (3H, t), 3.95(3H, s), 4.09 (2H, q), 6.69 (IH, d) ,

7.42 (IH, d), 11.68 (IH, s)

EXAMPLE 49: PREPARATION OF COMPOUND 49 ^'

A stirred solution of N-methyl-5-nitro isoquinolin-l,3,4-trione (prepared as described in Example 52 below) (0.555g) in acetone (10ml) was treated with titanium trichloride (12ml of a 10wt% solution in 20-30wt% HC1). When no starting material remained (as determined by tic), water was added, and the mixture was extracted with ethyl acetate (x3) . The combined extracts were washed with brine, dried (MgSO.) and evaporated in vacuo to leave a brown solid, which was purified by chromatography on silica gel (eluting with ethyl acetate/hexane mixtures) to afford the title compound, yield

0.093g, mp lδO°C (dec). nmr data (CDC1 ₃ ): δ3.44 (3H, s), 6.98 (IH, d), 7.53 (IH, dd), 7.65 (IH, d) (NH signals broad - not observed)

EXAMPLE 50: PREPARATION OF COMPOUND 50

A stirred solution of N-(2-acetamidoethyl)-homophthalimide (0.098g) in glacial acetic acid (δml) was treated dropwise with a solution of sodium dichromate (0.146g) in 2M sulphuric acid (δml). The mixture was then stirred at room temperature for a further 3δ minutes, before being quenched with ice and extracted with ethyl acetate (x3). The combined ethyl acetate extracts were dried (MgSO and evaporated in vacuo to leave a solid residue. This was purified by chromatography on silica gel (eluting with ethyl acetate), to afford the title compound, yield 0.062g, mp 181-183°C.

^X Hnmr data (CDCI3) : δl.8δ (3H, s) , 3.67 (2H, m) , 4.24 (2H, m) , 6.12 (IH, broad s), 7.78-7.93 (2H, m) , 8.19 (IH, dd) , 8.34 (IH, dd)

EXAMPLE 51: PREPARATION OF COMPOUND 51

A solution of δ-amino-N-ethyl isoquinolin-l,3,4-trione (prepared as described in Example 23 above) (0.324g) in tetrahydrofuran (10ml) was added dopwise to a stirred slurry of sodium hydride (0.072g of a δδ% dispersion in oil) in tetrahydrofuran (10ml) and the resulting mixture was heated

under reflux for 35 minutes. After cooling to ca 40 C, methyl iodide

(0.1ml) was added, and the mixture was stirred for 1 hour, then a further quantity of methyl iodide (0.1ml) was added, and the resulting mixture was stirred for a further 1 hour. Dilute hydrochloric acid (2M) was added, and the mixture was extracted with ethyl acetate (x3). The combined ethyl acetate extracts were dried (MgSO and evaporated in vacuo. The residue was separated by chromatography on silica gel (eluting with chloroform) to afford the title compound as a red solid, yield 0.045g.

^! Hnmr data (CDC1 ₃ ): δl.23 (3H, t) , 3.08 (3h, d) , 4.08 (2H, q) , 7.03 (IH, m), 7.55-7.65 (2H, m) , 9.35 (IH, broad s)

EXAMPLE 52: PREPARATION OF COMPOUND 52

By a method similar to that described in Example 13 but using N-methyl-5- nitro-1-isoquinolone (prepared as described in Preparative Example 36 below) (2.30g), glacial acetic acid (80ml), sodium dichromate (8.86g) and

2M sulphuric acid (70ml), the crude title compound was obtained as a pale coloured solid, yield 0.56g.

^X Hnmr data (CDCl ₃ /dg_DMS0): inter alia δ3.42 (3H, s), 7.98 (IH, d) , 8.08

(IH, d), 8.50 (IH, m)

EXAMPLE 53: PREPARATION OF COMPOUND 63

By a method similar to that described in Example 7, but using 7-cyano-N- ethyl homophthalimide (prepared as described in Preparative Example 37 below) (0.130g), N,N-dimethyl-p-nitrosoaniline (0.091g) and ethanol (10ml), the title compound was obtained as an orange solid, yield O.llOg. H nmr data (CDCl _j ): δl.31 (3H, t) , 4.1δ (2H, q), 8.08 (IH, d), 8.32 (IH, d), 8.66 (IH, s)

EXAMPLE 100: PREPARATION OF COMPOUND 100

A stirred solution of N-ethyl furan-3-carboxamide (prepared as described in

Preparative Example 38 below) (4.72g) in o-dichlorobenzene (40ml) was added to a solution of oxalyl chloride (δ.lβg) in o-dichlorobenzene (40ml), and the mixture was heated under reflux for 3 hours. The resultant solution was cooled, and hexane (ca. 60ml) was added. The crystalline precipitate was filtered off, washed with hexane and dried to afford the title compound, yield 3.80g. ^l H nmr data (CDC1 ₃ ): δl.26 (3H, t), 4.04 (2H, q) , 7.08 (IH, d) , 7.89 (IH, d)

EXAMPLE 101: PREPARATION OF COMPOUND 101

A solution of N-ethyl thiophene-3-carboxamide (prepared as described in Preparative Example 39 below) (7.7δg) in carbon tetrachloride (δOml) was added dropwise to a solution of oxalyl chloride (7.62g) in carbon tetrachloride (60ml), and the mixture was heated under reflux for 3 hours. The mixture was then evaporated in vacuo, and the residue was heated, under vacuum, at 160°C for 2.δ hours. The melt was cooled, and the resultant solid material was purified by silica-gel chromatography, eluting with ethyl acetate/hexane mixtures, to afford the title compound as an off- white, crystalline solid, yield δ.6δg, mp 138-140°C. ^l ti nmr data (CDC1 ₃ ): δl.26 (3H, t) , 4.0δ (2H, q) , 7.74 (IH, d), 7.98 (IH, d)

EXAMPLE 102: PREPARATION OF COMPOUND 102

By a method similar to that described in Example 101, but using S-chloro-N- methyl benzothiophene-3-carboxamide (l.OOg), oxalyl chloride (0.70g) and carbon tetrachloride (15ml), the title compound was obtained as a yellow solid, yield 0.065g. nmr data (CDCI3): δ3.47 (3H, s), 7.65 (IH, dd), 7.89 (IH, d), 8.90 (IH, d)

EXAMPLE 103: PREPARATION OF COMPOUND 103

A solution of N-methylpyrrole-2-(N-ethyl)carboxamide (prepared as described in Preparative Example 40 below) (0.800g) in o-dichlorobenzene (10ml) was treated dropwise with a solution of oxalyl chloride (0.801g) in 0- dichlorobenzene (2ml). The mixture was heated under reflux for 3 hours, and was then cooled and diluted with hexane (δml). The precipitate was filtered off, washed with hexane and dried to give the title compound, yield 0.86δg.

*H nmr data (CDC1 ₃ ): δl.23 (3H, t) , 4.01 (2H, q) , 4.09 (3H, s) , 6.73 (IH, d), 6.92 (IH, d)

EXAMPLE 104: PREPARATION OF COMPOUND 104

A solution of 2-(4-chlorophenyl)-6-ethyl-δ,7-dioxo-4,6,6,7- tetrahydrothiazolo[4,δ-c]pyridine (prepared as described in Preparative

Example 41 below) (O.OlOg) in acetic acid (1ml) was treated with a solution of sodium dichromate (O.OδOg) in 2M sulphuric acid (1ml). The mixture was stirred for 3 hours, then water was added and the mixture was extracted with ethyl acetate. The extract was dried (MgSO and evaporated in vacuo.

The residue was passed through a silica-gel plug, eluting with ethyl acetate/hexane (1:3), and the filtrate was evaporated in vacuo to leave the title compound, yield O.OOδg. ^l ti nmr data (CDC1 ₃ ): δl.30 (3H, t) , 4.09 (2H, q) , 7.62 (2H, m), 8.03 (2H, m)

EXAMPLE 106: PREPARATION OF COMPOUND 106

By a method similar to that described in Example 100, but using indole-2-

(N-ethyl)carboxamide (preparaed as described in Preparative Example 42)

(0.376g), oxalyl chloride (0.279g) and o-dichlorobenzene (60ml), the title compound was obtained as a yellow solid, yield 0.063g. H nmr data (dg_DMS0): δl.16 (3H, t) , 3.69 (2H, q) , 7.34-7.60 (2H, ) , 7.64

(IH, d), 6.05 (IH, d), 11.00 (broad s)

EXAMPLE 200: PREPARATION OF COMPOUND 200

A stirred solution of N-ethyl homophthalimide (prepared as described in

Preparative Example 1) (0.63δg) in methanol (10ml) containing concentrated hydrochloric acid (1ml) was treated with an aqueous solution of sodium nitrite (0.234g). Stirring was continued for a further 3 hours, when the precipitate which had formed was filtered off, washed with hexane and dried, to afford the title compound as a white solid, yield 0.169g, mp 189-

191°C. H nmr data (dg_DMS0): δl.24 (3H, t) , 4.07 (2H, q) , 7.66-7.76 (2H, m) , 6.31

(IH, dd), 9.00 (IH, d) [OH broad - not observed]

EXAMPLE 201: PREPARATION OF COMPOUND 201

By a method similar to that described in Example 200 but using N-ethyl-7- methoxy homophthalimide (prepared as described in Preparative Example 7)

(0.400g), methanol (δml), concentrated hydrochloric acid (1ml) and sodium nitrite (0.31δg), the title compound was obtained as a white solid, yield

0.32δg, mp lβ9-190°C.

*H nmr data (CDC1 ₃ ): δl.26 (3H, t) , 3.93 (3H, s) , (4.14 (2H, q), 7.26 (IH, dd), 7.64 (IH, d) , 9.09 (IH, d) , [OH broad - not observed]

EXAMPLE 202: PREPARATION OF COMPOUND 202

A stirred solution of Compound 100 (prepared as described in Example 100)

(2.91g) in ethanol (60ml) was treated with a solution of hydroxy1amine hydrochloride (2.0δδg) in ethanol (20ml). Stirring was continued for a further 6 hours, then the solution was left to stand for 16 hours. Water was added, and the precipitate was filtered off, washed with water and

dried, affording the title compound as an off-white solid, yield 2.87g, mp

211-213°C.

*H nmr data (CDC1 ₃ ): δl.24 (3H, t) , 4.03 (2H, q) , 6.94 (IH, d) , 7.69 (IH, m), 14.60 (IH, broad s)

EXAMPLE 203: PREPARATION OF COMPOUND 203

By a method similar to that described in Example 202 but using Compound 101

(prepared as described in Example 101) (0.209g), ethanol (10ml) and hydroxylamine hydrochloride (0.140g), the title compound was obtained as an off-white solid, yield 0.170g. nmr data (CDClj): δl.25 (3H, t) , 4.09 (2H, q) , 7.68 (IH, d) , 7.65 (IH, d) [OH broad - not observed]

EXAMPLE 204: PREPARATION OF COMPOUND 204

By a method similar to that described in Example 202 but using Compound 103

(prepared as described in Example 103) (0.53δg), ethanol (6δm1) and hydroxylamine hydrochloride (0.361g), the title compound was obtained as a pale yellow solid, yield 0.440g, mp 266°C. H nmr data (dg_DMS0): δl.04 (3H, t) , 3.79 (2H, q) , 3.90 (3H, s), 6.83 (IH, d), 7.26 (IH, d), 13.20 (IH, broad s)

EXAMPLE 206: PREPARATION OF COMPOUND 205

By a method similar to that described in Example 202 but using Compound 9

(prepared as described in Example 9), ethanol and hydroxylamine hydrochloride, the title compound was obtained.

EXAMPLE 206: PREPARATION OF COMPOUNDS 206A AND 206B

A stirred solution of Compound 200 (prepared as described in Example 200)

(0.300g) in dimethylformamide (10ml) was treated with sodium hydride

(0.037g). The mixture was stirred for 30 minutes, them ,ethyl iodide

(0.391g) was added dropwise. The solution was stirred for 4 hours, then the reaction was quenched with water and extracted with ethyl acetate (x3) .

The combined extracts were washed with brine, dried (MgSO and evaporated to dryness in vacuo. The residue was separated by chromatography on silica-gel, eluting with ethyl acetate/hexane (1:3), to give, firstly, compound 206A (E-isomer) as a pale yellow solid, yield O.Oδδg,

*H nmr data (CDCI3) : δl.30 (3H, t) , 4.16 (2H, q) , 4.62 (3H, s), 7.62 (IH, t), 7.74 (IH, t), 8.39 (IH, d) , 9.41 (IH, d) followed by compound 206B (Z-isomer) as an orange solid, yield 0.0δ7g. H nmr data (CDC1 ₃ ): δl.29 (3H, t) , 4.1δ (2H, q) , 4.39 (3H, s) , 7.60-7.76

(2H , m) , 8.37 (IH , d) , 8.72 ( IH , d)

EXAMPLE 207: PREPARATION OF COMPOUNDS 207A AND 207B

By a method similar to that described in Example 206 but using Compound 201

(Prepared as described in Example 201) (0.300), dimethylformamide (10ml), sodium hydride (0.032g) and methyl iodide (0.344g), and separation of the products by silica-gel chromatography (eluting with ethyl acetate/hexane

(l:5)mixtures) , compound 207A was obtained first, yield 0.045g, ^l ti nmr data (CDC1 ₃ ): δl.26 (3H, t) , 3.92 (3H, s), 4.13 (2H, q) , 4.47 (3H, s), 7.25 (IH, m), 7.83 (IH, m) , 9.41 (IH, d) followed by compound 207B, yield 0.065g. H nmr data (CDC1 ₃ ): δl.26 (3H, t), 3.91 (3H, s), 4.12 (2H, q), 4.32 (3H, s), 7.19 (IH, dd), 7.80 (IH, d) , 8.69 (IH, d)

EXAMPLE 20δ: PREPARATION OF COMPOUNDS 208A AND 208B

By a method similar to that described in Example 206 but using Compound 20S

(Prepared as described in Example 206) (0.176g), dimethylformamide (10ml), sodium hydride (0.02δg) and methyl iodide (0.210g), and separation of the products by silica-gel chromatography (eluting with ethyl acetate/hexane

(1:4)mixtures), compound 208B was obtained first, yield 0.006g,

*H nmr data (CDC1 ₃ ): δl.24 (3H, t), 4.08 (2H, q), 4.31 (3H, s), 7.59 (IH, dd), 8.02 (IH, d), 8.20 (IH, d) followed by and compound 208A, yield 0.013g. ^l nmr data (CDC1.-): δl.2δ (3H, t), 4.11 (2H, q) , 4.37 (3H, s), 7.65 (IH, dd), 8.32 (IH, d) , 8.67 (IH, d)

EXAMPLE 209: PREPARATION OF COMPOUNDS 209A AND 209B

By a method similar to that described in Example 202 but using Compound 15

(prepared as described in Example 15) (0.141g), ethanol (5ml) and 0- methylhydroxylamine hydrochloride (0.050g), and purification of the crude product by silica-gel chromatography (eluting with ethyl acetate/hexane mixtures), the title compounds were obtained as an inseparable 9:1 mixture of geometrical isomers, yield 0.026g.

¹ H nmr data (CDCI3) (major isomer only): δl.29 (3H, t) , 4.08 (2H, q) , 4.37

(3H, s), 7.74 (IH, t) , 7.98 (IH, dd), 8.53 (IH, d)

EXAMPLE 210: PREPARATION OF COMPOUNDS 210A AND 210B

A stirred solution of Compound 206B (prepared as described in Example 206)

(0.103g) in concentrated sulphuric acid (2.5ml) was treated with a solution of potassium nitrate (0.058g) in concentrated sulphuric acid (2.δml), and

the mixture was heated to 70°C for 3 hours. The mixture was then cooled, quenched with water and extracted with ethyl acetate. The extract was dried (MgSO and evaporated in vacuo to leave a mixture of the title compounds (0.094g).

EXAMPLE 211: PREPARATION OF COMPOUNDS 211A AND 211B

By a method similar to that described in Example 206 but using Compound 200

(Prepared as described in Example 200) (0.290g), dimethylformamide (δml), sodium hydride (0.038g) and ethyl iodide (0.41δg), and chromatography of the crude product on silica-gel (eluting with ethyl acetate/hexane mixtures), compounds 211B and 211A were obtained as an inseparable (97:3) mixture, yield 0.040g. H nmr data (CDC1 ₃ ) (major isomer only): δl.26 (3H, t) , 1.49 (3H, t), 4.12

(2H, q), 4.64 (2H, q)7.δ6-7.7δ (2H, m) , 8.34 (IH, dd) , 8.78 (IH, d)

EXAMPLE 212: PREPARATION OF COMPOUND 212B

By a method similar to that described in Example 202 but using Compound 100

(prepared as described in Example 100) (O.δOOg), ethanol (lδml) and 0- methylhydroxylamine hydrochloride (0.64δg), the title compound (Z-isomer) was obtained as a pale brown solid, yield 0.390g. H nmr data (CDCI3) : δl.22 (3H, t), 4.04 (2H, q), 4.38 (3H, s), 6.96 (IH, d), 7.68 (IH, d)

EXAMPLE 213: PREPARATION OF COMPOUNDS 213A AND 213B

A stirred solution of Compound 203 (prepared as described in Example 203)

(1.197g) in dimethylformamide (20ml) was treated with potassium carbonate

(O.βlg) and dimethyl sulphate (S.40g). The mixture was stirred for a further 4 hours, then left to stand for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water (x2) , dried (MgSO.) and evaporated in vacuo. The residue was separated by chromatography on silica-gel, eluting with wthyl acetate/hexane mixtures, to afford compound 213A (0.063g), ^l H nmr data (CDCI3) : 61.25 (3H, t) , 4.09 (2H, q) , 4.41 (3H, s), 7.63 (IH, d), 7.68 (IH, d) and compound 213B (0.625g). ^l nmr data (CDC1 ₃ ): δl.27 (3H, t) , 4.12 (2H, q) , 4.63 (3H, s), 7.47 (IH, d), 7.71 (IH, d)

EXAMPLE 214: PREPARATION OF COMPOUND 214B

By a method similar to that described in Example 202 but using Compound 103

(prepared as described in Example 103) (0.206g), ethanol (20ml) and 0- methylhydroxylamine hydrochloride (0.167g), and purification of the crude product by silica-gel chromatography (eluting with ethyl acetate/hexane mixtures), the title compound (Z-isomer) was obtained as a pale yellow solid, yield 0.144g, mp 170-171°C. nmr data (CDC1 ₃ ): δl.21 (3H, t) , 4.02 (2H, q) , 4.03 (3H, s) , 4.29 (3H, s), 6.87-6.91 (2H, m)

EXAMPLE 216: PREPARATION OF COMPOUND 215B

By a method similar to that described in Example 202 but using Compound 63

(prepared as described in Example 63) (O.lOOg), ethanol (20ml) and 0- methylhydroxylamine hydrochloride (0.183g), the title compound was obtained as a pale yellow solid, yield O.Oβδg. ^l ti nmr data (CDCI3): δl.27 (3H, t) , 4.13 (2H, q) , 4.41 (3H, s), 7.91 (IH, d), 8.65 (IH, s), 8.84 (IH, d)

EXAMPLE 300: PREPARATION OF COMPOUND 300

A solution of Compound 1 (prepared as described in Example 1) (O.lOδg) in ethanol (δml) was treated with N,N-dimethyl hydrazine (0.038ml) and concentrated hydrochloric acid (ca. 0.2ml), and the mixture was left to stand for 70 hours. The solution was then evaporated in vacuo, and the residue was chromatographed on silica-gel to afford the title compound,

0.060g. nmr data (CDCI3) : δl.23 (3H, t), 3.48 (6H, s), 4.11 (2H, q), 7.31 (IH, t), 7.52 (IH, dt), 8.00 (IH, d) , 8.19 (IH, dd)

EXAMPLE 400: PREPARATION OF COMPOUND 400

A stirred solution of Compound 1 (prepared as described in Example 1)

(O.lδOg) in methylene chloride (10ml) was treated with bis(trimethylsilyl)carbodiimide (0.17ml) and titanium tetrachloride

(0.72ml). The mixture was stirred for 3 hours, and was then diluted with ethyl acetate, washed with water and dried (MgSO . The solvent was evaporated in vacuo to leave a brown solid residu, which was recrystallised from methylene chloride/diethyl ether to afford the title compound, yield

0.146g. ^l W nmr data (CDC1 ₃ ): δl.30 (3H, t) , 4.15 (2H, q) , 7.80-8.00 (2H, ) , 8.28-

8.42 (2H, )

EXAMPLE 401: PREPARATION OF COMPOUND 401

By a method similar to that described in Example 400 but using Compound 102

(prepared as described in Example 102) (0.418g), methylene chloride (δOml), bis(trimethylsilyl)carbodiimide (0.4δml) and titanium tetrachloride

(2.00ml), the title compound was obtained as a yellow solid, yield 0.198g. ^l nmr data (CDC1 ₃ ): δl.29 (3H, t) , 4.09 (2H, q) , 7.78 (IH, d) , 7.92 (IH, d)

EXAMPLE 600: PREPARATION OF COMPOUND 600

A stirred solution of N-ethyl homophthalimide (prepared as described in

Preparative Example 1 below) (O.lδOg) in methylene chloride (δml) was treated with N,N-dimethyl-p-nitrosoaniline (0.119g). The mixture was stirred under a nitrogen atmosphere for 16 hours, then evaporated in vacuo.

The residue was triturated with diethyl ether/hexane to afford the title compound as a 2:1 mixture of E- and Z-isomers. H nmr data (CDC1 ₃ ) (major isomer only): δl.23 (3H, t) , 3.05 (6H, s), 4.05

(2H, q), 6.65 (2H, d) , 7.31 (2H, d) , 7.59 (IH, t) , 7.70 (IH, dt) , 8.39 (IH, dd), 9.45 (IH, d)

EXAMPLE 600: PREPARATION OF COMPOUND 600

A stirred solution of Compound 1 (prepared as described in Example 1)

(O.lOOg) in a mixture of toluene (1ml), ethanol (1ml) and hexane (1ml) was treated with malononitrile (0.046ml) and piperidine (ca 0.01ml). The mixture was stirred for 16 hours, then evaporated in vacuo. The residue was separated by chromatography on silica-gel, eluting with diethyl ether/hexane, to give the crude product, which was recrystallised from methylene chloride/diethyl ether to afford the title compound, yield

0.059g.

^! H nmr data (CDC1 ₃ ): δl.27 (3H, t), 4.13 (2H, q), 7,79-7.91 (2H, m), 8.41

(IH, m), 8.60 (IH, m)

EXAMPLE 700: PREPARATION OF COMPOUND 700

By a procedure method to that described in Example 200 but using 1,2,3,4- tetrahydroisoquinoline-l-4-dione (0.500g), sodium nitrite (0.257g), concentrated hydrochloric acid (1ml) and a 2:1 mixture of methanol and water (15ml) as solvent, the title compound was obtained as a solid, yield

0.278g.

^! H nmr data (CDCI3) : δ2.15 (3H, s), 6.78 (IH, d) , 7.12 (IH, t) , 7.25 (IH, m), 7.79-7.93 (2H, m) , 8.09 (IH, broad s) , 8.24-8.41 (2H, m)

EXAMPLE 701: PREPARATION OF COMPOUND 701

A stirred solution of l,2,3,4-tetrahydroisoquinoline-l-4-dione (O.lOOg) in

dimethylformamide (25ml) was treated with o-nitrosotoluene (0.075g). The mixture was stirred for 16h hours, then water was added, and the resultant mixture was extracted with diethyl ether. The extract was washed with water (x3), dried (MgSO and evaporated in vacuo to leave a gum. This was chromatographed on silica-gel, eluting with ethyl acetate/hexane mixtures, to afford the solid title compound, yield O.OlOg.

*H nmr data (CDC1 ₃ ): 57.78-7.91 (2H, m) , 8.21 (IH, dd) , 8.28 (IH, d) , 9.72

(IH, broad s), 12.48 (IH, s)

PREPARATIVE EXAMPLES

Preparative Example 1 - Preparation of N-Ethyl Homophthalimide

An aqueous solution of homophthalic acid (lO.OOg) was treated dropwise with a 70%w/v solution of ethylamine in water (lO.OOg), and the mixture was heated iunder reflux for 4 hours. The solvent was then removed in vacuo, and the residual oil was heated to 170-180°C, under reduced pressure, for 2 hours, on cooling, the resultant oil solidified, this was found to consist largely of N-ethyl homophthalimide (ca 90%), yield 8.70g.

^X Hnmr data (CDC1 ₃ ): inter alia δl.24 (3H, t), 4.00-4.20 (5H, m), 7.27(1H, d), 7.44 (IH, dd), 7.69 (IH, dd), 8.22 (IH, d)

Preparative Example 2 - Preparation of N-(l-methylpropyl) Homophthalimide

A solution of homophthalic anhydride (2.00g) and sec-butylamine (15ml) in water (10ml) was heated under reflux for 46 minutes, then cooled and acidified to pHl using 6M hydrochloric acid. A small amount of solid crystallised out, which was filtered off and discarded. The filtrate was evaporated to dryness in vacuo, and the residue was extracted with hot ethyl acetate (2xδ0ml). These extracts were evaporated to dryness in vacuo, and the residue was heated to 190-200°C for 30 minutes, then allowed to cool. This was then dissolved in ethyl acetate (70ml) which was extracted with 2M hydrochloric acid (2xδ0ml), water (60ml), saturated sodium bicarbonate solution (3x50ml) and then dried (MgSO . The sooution was evaporated in vacuo, and the residue was purified by chromatography on silica gel (eluting with ethyl acetate/hexane mixtures) to afford the title compound as a pale yellow oil, yield 0.22g.

^! Hnmr data (CDC1 ₃ ): δθ.79 (3H, t) , 1.39 (3H, d) , 2.78 (IH, ) , 1.98 (IH, m), 3.95 (2H, s), 4.89 (IH, m) , 7.16 (IH, d) , 7.3δ(lH, dd) , 7.48 (IH, dd) ,

8.10 (IH, d)

Preparative Example 3 - Preparation of N-Ethyl-8-Hydroxy Homophthalimide

A stirred solution of 2-carboxy-3-hydroxyphenylacetic acid (2.00g) in water (10ml) was treated with a 70%w/v solution of ethylamine in water (0.66g), and the mixture was heated under reflux for 7 days. The solution was evaporated to dryness in vacuo, and the residual gum was distilled in a Kugelrohr apparatus under high vacuum to give the title compound as a white solid, yield 0.91g.

^nmr data (CDCI3) : δl.23 (3H, t), 4.00 (2H, s), 4.21 (2H, q) , 6.70 (IH, d), 6.90 (IH, d), 7.46 (IH, dd) , 11.80 (IH, broad s) Preparative Example 4 - Preparation of B,7-Benzo-N-Ethyl Homophthalimide Step 1 Preparation of 2,3-Naphthalide

A stirred slurry of sodium borohydride (3.84g) in tetrahydrofuran (60ml) was cooled in an ice bath and a solution of naphthalene-2,3-dicarboxylic anhydride (20.00g) in tetrahydrofuran (100ml) and dimethylformamide (100ml) was added dropwise over 16 minutes. The pale yellow solution was then allowed to warm to room temperature and was stirred for a further 35 minutes. The reaction was carefully acidified to pHl using 6M hydrochloric acid and the mixture was left to stand for 10 minutes, before being concentrated in vacuo to a volume of ca 80ml. The thick crystalline precipitate was filtered off, washed with water and diethyl ether, then dried to leave the product as a white crystaline solid, yield 19.20g. Step 2 Preparation of 3-Carboxynaphthalene-2-acetonitrile A stirred mixture of 2,3-naphthalide (prepared as described in step 1 above) (lO.OOg) and finely ground potassium cyanide (12.00g) was heated to 210-215°C for 6 hours, then cooled and left to stand for 42 hours. The brown mixture was digested with water (100ml) and insoluble material was filterd off and discarded. The filtrate was acidified to pHl using 6M hydrochloric acid, and the brown precipitate was extracted into ethyl acetate (300ml+100ml) . The combined extracts were washed with brine (100ml), dried (MgSO.) , and evaporated in vacuo to leave the product as a pale brown solid.

Step 3 Preparation of 3-Carboxynaphthalene-2-acetic Acid 3-Carboxynaphthalene-2-acetonitrile (prepared as described in step 2 above) (3.50g) was added to a solution of potassium hydroxide (7.00g) in water (30ml). The dark solution was heated under reflux for 136 minutes, when no more ammonia was evolved. The brown solution was cooled and filtered to remove a trace of insoluble material, then acidified to pHl using 6M

hydrochloric acid. The crystalline precipitate was filtered off, washed and dried to afford the product, yield 3.24g.

Step 4 Preparation of 3-Carboxynaphthalene-2-N-ethylacetamide

A stirred slurry of 3-carboxynaphthalene-2-acetic acid (prepared as described in step 3 above) (3.00g) in acetic anhydride (20ml) was heated under reflux for 30 minutes, then cooled, evaporated to dryness in vacuo, and triturated with ether/hexane (1:1) to give the anhydride as a crystalline solid, which was filtered off and dried. This was then added to a 70%w/v solution of ethylamine in water (20ml), and the mixture was heated under reflux for 40 minutes. The mixture was cooled and left to stand for 72 hours before being acidified to pHl using 6M hydrochloric acid. The crystalline precipitate whci slowly formed was filtered off, washed and dried to afford the product as a pale brown crystalline solid.

Step 5 Preparation of 6,7-Benzo-N-Ethyl Homophthalimide

3-Carboxynaphthalene-2-N-ethylacetamide (prepared as described in step 4 above) (0.70g) was melted and heated to 200°C, with stirring, for 15 minutes. The mixture was then cooled, and separated by chromatography on silica gel (eluting with ethyl acetate/hexane mixtures) to give the title compound as a pale yellow solid, yield 0.29g.

^! Hnmr data (CDCI3): δl.27 (3H, t), 4.10 (2H, q), 4.20 (2H, s), 7.50-7.65

(2H, m), 7.70 (IH, broad s), 7.83 (IH, d) , 8.00 (IH, d), 8.79 (IH s)

Preparative Example 5 - Preparation of N-Methyl Homophthalimide

By a method similar to that described in Preparative Example 3 above but using homophthalic acid (3.00g) and a 40%w/v solution of methylamine in water (5.16g), the title compound was obtained as a white crystalline solid, yield 0.79g.

^X Hnmr data (CDC1 ₃ ): δ3.40 (3H, _. s), 4.04 (2H, s), 7.30 (IH, d) , 7.45 (IH, dd), 7.60 (IH, m), 8.20 (IH, dd)

Preparative Example 6 - Preparation of N-Ethyl-8-methoxy Homophthalimide

Step 1 Preparation of 2-Carboxy-3-methoxy-N-ethylphenylacetamide

By a method similar to that described in Preparative Example 4, Step 4 above but starting from 2-carboxy-3-methoxyphenylacetic acid (1.25g), the product was obtained as a pale yellow solid, yield 0.40g.

Step 2 Preparation of N-Ethyl-8-methoxy Homophthalimide

By a method similar to that described in Preparative Example 4, Step δ but using 2-carboxy-3-methoxy-N-ethylphenylacetamide (prepared as described in

step 1 above) (0.40g), the title compound was obtained as a buff coloured solid, yield 0.23g.

^nmr data (CDC1 ₃ ): δl.20 (3H, t) , 3.99 (2H, q) , 4.01 (5H, s), 6.83 (IH, d), 6.96 (IH, d), 7.60 (IH, dd)

Preparative Example 7 - Preparation of N-Ethyl-7-methoxy Homophthalimide

Step 1 Preparation of 2-Carboxy-4-methoxyphenylacetic acid

A stirred slurry of 2-bromo-δ-methoxybenzoic acid (11.56g) and cuprous bromide (O.δOg) in ethyl acetoacetate (74ml) was treated portionwise with a

60% dispersion of sodium hydride in oil ^" (4.80g). The resulting pale green slurry was heated to 80-90°C for 3.6 hours before being cooled and quenched with water (ca 200ml). The mixture was extracted with diethyl ether

(4x70ml), and the combined extracts were discarded. The aqueous phase was acidified to pHl using concentrated hydrochloric acid, and extracted with ether (2x70ml). The combined ether layers were evaporated in vacuo, and the wet, oily residue was dissolved in 2M potassium hydroxide solution

(100ml). This was left to stand for 4δ minutes, then acidified to pHl using concentrated hydrochloric acid and left to stand for 16 hours.

Dichloromethane (30ml) was added to break up the sticky precipitate which had formed, and the insoluble material was filtered off, washed and dried to afford the product as a pale yellow crystalline solid, yield δ.βlg.

Step 2 Preparation of 2-Carboxy-4-methoxy-N-ethylphenylacetamide

By a method similar to that described in Preparative Example 4, Step 4 above but starting from 2-carboxy-4-methoxyphenylacetic acid (prepared as described in step 1 above) (2.50g), the product was obtained as a pale yellow solid, yield 1.08g.

Step 3 Preparation of N-Ethyl-7-methoxy homophthalimide

By a method similar to that described in Preparative Example 4, Step δ but using 2-carboxy-4-methoxy-N-ethylphenylacetamide (prepared as described in step 2 above) (l.Oδg), the title compound was obtained as a white crystalline solid, yield 0.73g.

^X Hnmr data (CDC1 ₃ ): δl.17 (3H, t) , 3.80 (3H, s), 3.89 (2H, s), 3.9δ (2H, q), 7.00-7.10 (2H, m) , 7.60 (IH, d)

Preparative Example 8 - Preparation of 7-Chloro-N-ethyl Homophthalimide

Step 1 Preparation of 2-Carboxy-4-chlorophenylacetic acid

By a method similar to that described in Preparative Example 7, Step 1 but using 2-bromo-5-chlorobenzoic acid (δ.87g), sodium hydride (2.40g of a 60%

- 62 -

dispersion in oil), cuprous bromide (0.40g) and ethyl acetoacetate (37ml), the product was obtained as a pale yellow crystalline solid, yield 3.91g.

Step 2 Preparation of 2-Carboxy-4-chloro-N-ethylphenylacetamide

By a method similar to that described in Preparative Example 4, Step 4 above but starting from 2-carboxy-4-chlorophenylacetic acid (prepared as described in step 1 above) (3.δ0g), and recrystalusing from ethyl acetate/hexane, the product was obtained as a pale yellow solid, yield

O.δδg.

Step 3 Preparation of 7-Chloro-N-ethyl homophthalimide

By a method similar to that described in Preparative Example 4, Step S but using 2-carboxy-4-chloro-N-ethylphenylacetamide (prepared as described in step 2 above) (O.θδg), the title compound was obtained as a white crystalline solid, yield 0.2βg.

^X Hnmr data (CDCI3) : δl.22 (3H, t) , 4.00 (2H, s), 4.0δ (2H, q), 7.23 (IH, d), 7.55 (IH, dd), 6.19 (IH, d)

Preparative Example 9 - Preparation of N-Ethyl-3,4,5-trimethoxybenzamide

3,4,δ-Trimethoxy benzoic acid (δ.OOg) was dissolved in thionyl chloride

(lO.OOg) and the solution was heated under reflux for 6 hours, then cooled.

Excess thionyl chloride was removed in vacuo, and the solid residue was treated with a little water (10ml), followed by a 70%w/v solution of ethylamine in water (2.51g - in two portions), and the solution was heated under reflux until reaction was complete as monitored by gc. The mixture was allowed to cool, when the product crystallised out. This was filtered off and dried, affording the title compound as a white crystalline compound, yield 2.84g.

^X Hnmr data (CDCl ₃ /dg_DMSO) : δl.25 (3H, t) , 3.43 (2H, q) , 3.83 (3H, s) , 3.90

(6H, s), 7.18 (2H, s), 7.66 (IH, broad s)

Preparative Example 10 - Preparation of N-Methyl-3,4,5-trimethoxybenzamide

This compound was prepared by a method similar to that described in

Preparative Example 9 but using 3,4,6-trimethoxy benzoic acid (δ.OOg), thionyl chloride (lO.OOg) and and a 40%w/v solution of methylamine in water

(1.66g). The reaction mixture was extracted with ethyl acetate (x3), and the combined extracts were washed with brine, dried (MgSO and evaporated in vacuo to afford the pure title compound as white solid, yield 2.20g.

^X Hnmr data (CDCl ₃ /dg_DMS0) : δ3.0δ (3H, d) , 3.69 (3H, s), 3.90 (6H, s), 6.16

(IH, broad s) , 7.00 (2H, s)

Preparative Example 11 - Preparation of 5-Chloro-N-ethyl-l-isoquinolone A stirred mixture of δ-chloroisoquinoline (prepared as described in Preparative Example 14, Step 1 below) (l.OOg) and ethyl iodide (0.96g) in water (20ml) was heated under reflux for 2 hours, before being cooled in an ice bath and simultaneously treated dropwise with solutions of potassium ferricyanide (2.02g) in water (10 ml) and sodium hydroxide (O.Slδg) in water (δml), at such a rate that the reaction temperature did not exceed 10°C. A further quantity of potassium ferricyanide (2.02g) was then added portionwise, and the reaction mixture was stirred at room temperature for 2 hours. This was then extracted with ethyl acetate (x3), and the combined extracts were washed with brine, dried (MgSO and evaporated in vacuo. The residue was purified by chromatography on silica gel, eluting with chloroform, to afford the title compound as a solid which was about 90% pure, yield 0.49g, which was used in Example 12 above without further purification.

^! Hnmr data (CDC1 ₃ ): inter alia 81.39 (3H, t) , 4.06 (2H, q) , 6.87 (IH, d) , 7.17 (IH, d), 7.39 (IH, dd) , 7.68 (IH, d) , 8.37 (IH, d) Preparative Example 12 - Preparation of N-Ethyl-l-isoquinolone-5-N- ethylcarboxamide

N-Ethyl-1-isoquinolone-δ-carboxylic acid (prepared as described in Preparative Example 17 below) (0.30g) was dissolved in thionyl chloride (δml) and the solution was heated under reflux for 30 minutes. Excess thionyl chloride was evaporated in vacuo, and the residue was treated dropwise with a 70%w/v solution of ethyla ine in water (10ml). The resultant mixture was heated under reflux for 3 hours before being cooled and extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO and evaporated in vacuo to afford the solid title compound, yield 0.26g.

^nmr data (CDCI3): δl.30(3H, t) , 1.39 (3H, t), 3.60-3.62 (2H, ), 4.08 (2H, q), 6.03 (IH, broad s) , 7.03 (IH, d) , 7.15 (IH, d) , 7.45 (IH, dd) , 7.73 (IH, dd), 8.52 (IH, dd)

Preparative Example 13 - Preparation of Ethyl N-ethyl-1-isoquinolone-S- carboxylate

N-Ethyl-l-isoquinolone-5-carboxylic acid (prepared as described in Preparative Example 17 below) (O.lδδg) was dissolved in thionyl chloride (δml) and the solution was heated under reflux for 30 minutes. Excess

thionyl chloride was evaporated in vacuo, and the residue was treated dropwise with ethanol (10ml). The resultant mixture was heated under reflux for 3 hours before being cooled, poured into water and extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO and evaporated in vacuo to afford the solid title compound, yield 0.165g.

^X Hnmr data (CDC1 ₃ ): δl.38 (3H, t) , 1.46 (3H, t) , 4.09 (2H, q) , 4.44 (3H, q), 7.18 (IH, d), 7.51 (IH, dd) , 7.66 (IH, d) , 8.32 (IH, d) , 8.69 (IH, d)

Preparative Example 14 - Preparation of 5-Cyano-N-ethyl-l-isoquinolone

Step 1 Preparation of 5-Cyanoisoquinoline and δ-Chloroisoquinoline

A stirred solution of δ-aminoisoquinoline (20.00g) in 6M hydrochloric acid

(150ml) was cooled in an ice/salt bath and treated dropwise with a saturated aqueous solution of sodium nitrite (9.56g) at such a rate that the reaction temperature did not exceed 0°C. Stirring was continued for a further 20 minutes, and the mixture was then added to a solution of cuprous cyanide (12.36g), sodium cyanide (17.29g) and sodium bicarbonate (72.96g) in water (82ml). This mixture was stirred for a further 2.6 hours, then extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO^) and evaporated in vacuo to leave a yellow solid, which was separated by chromatography on silica gel, eluting with ethyl acetate/hexane mixtures to give firstly δ-chloroisoquinoline:

^J Hnmr data (CDC1 ₃ ): δ7.δ4 (IH, m) , 7.78 (IH, ) , 7.90 (IH, d) , 8.02 (IH, d), 8.65 (IH, d), 9.26 (IH, s) followed by 5-cyanoisoquinoline:

^X Hnmr data (CDCI3): 87.71 (IH, ), 8.03 (IH, d), 8.14 (IH, d), 8.26 (IH, d), 6.77 (IH, d), 9.39 (IH, s)

Step 2 Preparation of 5-Cyano-N-ethyl-l-isoquinolone

By a method similar to that described in Preparative Example 11 but using δ-cyanoisoquinoline (prepared as described in Step 1 above) (2.40g), ethyl iodide (2.43g), potassium ferricyanide (6.13g+6.13g) and sodium hydroxide

(1.31g), and purifying the crude product by recrystallisation from ethyl acetate, the title compound was obtained as a crystalline solid, yield

1.34g.

^X Hnmr data (CDC1 ₃ ): δl.42 (3H, t), 4.09 (2H, q) , 6.86 (IH, d), 7.29 (IH, d), 7.56 (IH, dd), 7.98 (IH, d) , 8.66 (IH, d)

Preparative Example 15 - Preparation of N-Ethyl-l-isoquinolone-5-

- 65 -

carboxamide

A solution of δ-cyano-N-ethyl-1-isoquinolone (prepared as described in

Preparative Example 14 above) (0.200g) in 2M sodium hydroxide solution

(δml) was treated with a few drops of a 30%w/v solution of hydrogen peroxide, and the mixture was heated to 60-70°C for 3 hours. The precipitate which formed was filtered off, washed with water and hexane, dried and recrystallised from ethyl acetate to give the title compound as a cream solid, yield 0.075g.

^X Hnmr data (CDCI3): δl.31 (3H, t), 4.05 (2H, q) , 7.02 (IH, d) , 7.68 (2H, m), 7.67 (IH, broad s), 7.86 (IH, d) , 8.06 (IH, broad s), 8.37 (IH, d)

Preparative Example 16 - Preparation of N-Ethyl-5-nitro-l-isoquinolone

By a method similar to that described in Preparative Example 11 but using δ-nitroisoquinoline (3.00g), ethyl iodide (δ.38g), potassium ferricyanide

(5.67g+5.67g) and sodium hydroxide (1.45g), and purifying the crude product by chromatography on silica gel (eluting with ethyl acetate) followed by trituration with hexane, the pure title compound was obtained, yield 0.44g.

^X Hnmr data (CDCI3): δl.41 (3H, t), 4.10 (2H, q), 7.27-7.37 (2H, m), 7.57

(IH, dd), 8.42 (IH, d), 8.80 (IH, d)

Preparative Example 17 - Preparation of N-Ethyl-1-isoquinolone-δ-carboxylic

Acid

A solution of 5-cyano-N-ethyl-l-isoquinolone (prepared as described in

Preparative Example 14 above) (0.280g) in 2M sodium hydroxide solution

(28ml) was treated with a 30%w/v solution of hydrogen peroxide (10ml), and the mixture was heated under reflux for 6 hours. The mixture was allowed to cool, and was acidified to pHl using 2M hydrochloric acid. This was extracted with chloroform (x3). The combined extracts were washed with brine, dried (MgSO and evaporated in vacuo to afford the solid title compound, yield 0.220g.

^n r data (CDC dg _^ DMSO) : δl.34 (3H, t) , 4.04 (2H, q), 7.47 (IH, d) , 7.54

(IH, dd), 7.65 (IH, d), 8.30 (IH, d) , 8.50 (IH, d)

Preparative Example 18 - Preparation of N-Ethyl-l-isoquinolone-N,N-diethyl- δ-carboxamide

N-Ethyl-1-isoquinolone-δ-carboxylic acid (prepared as described in

Preparative Example 17 above) (0.220g) was dissolved in thionyl chloride

(δml) and the solution was heated under reflux for 30 minutes. Excess thionyl chloride was evaporated in vacuo, and the residue was treated

dropwise with diethylamine (δml). The resultant mixture was heated under reflux for 3 hours before being cooled, quenched with water and extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO and evaporated in vacuo to afford the solid title compound, yield 0.190g.

^nmr data (CDCI3): δl.OS (3H, t) , 1.30-1.45 (6H, m) , 2.98-3.18 (2H, m) ,

3.45 (2H, m), 4.05 (2H, q), 6.46 (IH, d) , 7.10 (IH, d) , 7.45-7.53 (2H, m) ,

8.46(1H, dd)

Preparative Example 19 - Preparation of 5-Acetamido-N-ethyl-l-isoquinolone

Step 1 Preparation of 5-Amino-N-ethyl-l-isoquinolone

A stirred solution of N-ethyl-δ-nitro-1-isoquinolone (prepared as described in Preparative Example 16 above) (δ.4δg) in a 1:1 mixture of ethanol and water was treated with iron powder (4.20g), followed by a few drops of concentrated hydrochloric acid. The nixture was heated under reflux for 4 hours, then cooled and filtered through hyflo. The filtrate was extracted with ethyl acetate (x3), and the combined extracts were washed with brine, dried (MgSO and evaporated in vacuo to leave a solid residue.

Recrystallisation from ethyl acetate/ethanol afforded the product, yield

0.75g.

Step 2 Preparation of 5-Acetamido-N-ethyl-l-isoquinolone

A stirred solution of δ-amino-N-ethyl-1-isoquinolone (prepared as described in Step 1 above) (0.200g) in chloroform (10ml) was treated with triethylamine (O.llδg), followed by acetyl chloride (0.091g). The mixture was stirred for 30 minutes, before being quenched with water, and extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO and evaporated in vacuo to afford the solid title compound, yield 0.06βg.

^X Hnmr data (CDC1 ₃ ): δl.37 (3H, t) , 2.30 (3H, s), 4.05 (2H, q) , 6.46 (IH, d), 7.12 (IH, d), 7.47 (IH, dd) , 7.89 (IH, d) , 8.33 (IH, d)

Preparative Example 20 - Preparation of N-Ethyl-7-hydroxy homophthalimide

A mixture of N-ethyl-7-methoxy homophthalimide (prepared as described in

Preparative Example 7 above) (0.570g) and pyridine hydrochloride (δ.OOg) were melted together at 170-180°C for 2 hours. The mixture was cooled, dissolved in 2M hydrochloric acid (60ml) and extracted with ethyl acetate

(30ml). The ethyl acetate extract was washed with 2M hydrochloric acid

(60ml), water (30ml), saturated sodium bicarbonate solution (2xδ0ml), dried

- 67 -

(MgSO,) and evaporated to dryness in vacuo. The solid residue was recrystal!ised from ethyl acetate/hexane to afford the title compound as a white solid, yield 0.340g.

^nmr data (CDC1 ₃ ): δl.19 (3H, t) , 3.93 (2H, s), 4.00 (2H, q) , 7.04-7.12

(2H, m), 7.62 (IH, m) , 9.37 (IH, s)

Preparative Example 21 - Preparation of N-Ethyl-3,5-dimethoxybenzamide

This compound was prepared by a method similar to that described in

Preparative Example 9 but using 3,δ-dimethoxy benzoic acid (δ.OOg), thionyl chloride (δ.OOg) and and a 70%w/v solution of ethylamine in water (3.00g).

The reaction mixture was extracted with ethyl acetate (x3), and the combined extracts were washed with saturated sodium bicarbonate solution

(x2) , brine, dried (MgSO.) and evaporated in vacuo to afford the pure title compound as an off-white solid, yield δ.07g.

^nmr data (CDCI3) : δl.35 (3H, t) , 3.68 (2H, m) , 3.92 (6H, s), 6.54 (IH, broad s), 6.66 (IH, m) , 7.03 (2H, m)

Preparative Example 22 - Preparation of N-Ethyl-6,7-dimethoxy-l- isoquinolone

A stirred mixture of 6,7-dimethoxy-l-isoquinolone (0.250g), finely powdered sodium hydroxide (0.170g), potassium carbonate (0.340g) and tetra-n- butylammonium sulphate (0.041g) in toluene (20ml) was heated under reflux and treated dropwise with a solution of ethyl iodide (2.85g) in toluene

(δml). Heating was continued for a further 4 hours, then the mixture was allowed to cool, diluted with toluene and quenched with water. The organic phase was separated, washed with water, dried (MgSO.) and evaporated in vacuo to afford the title compound, yield 0.212g.

^! Hnmr data (CDCI3) : δl.27 (3H, t), 3.88 (3H, s), 3.90 (3H, s), 3.92 (2H, m), 6.32 (IH, d), 6.78 (IH, s), 6.91 (IH, d) , 7.72 (IH, s)

Preparative Example 23 - Preparation of N-n-Propyl Homophthalimide

By a method similar to that described in Preparative Example 2 but using homophthalic anhydride (1.62g), n-propylamine (lδml) and water (10ml), the title compound was obtained as a pale yellow solid, yield 0.82g.

^! Hnmr data (CDC1 ₃ ): δθ.87 (3H, t) , 1.69 (2H, m) , 3.86 (2H, t) , 3.96 (2H, s), 7.19 (IH, d), 7.35 (IH, dd) , 7.60 (IH, m) , 8.13 (IH, d)

Preparative Example 24 - Preparation of N-iso-Propyl Homophthalimide

By a method similar to that described in Preparative Example 2 but using homophthalic anhydride (1.62g), iso-propylamine (lδml) and water (10ml),

- 68 -

the title compound was obtained as a pale yellow solid, yield 0.21g.

^X Hnmr data (CDC1 ₃ ): δl.42 (6H, d) , 3.92 (2H, s), 5.13 (IH, m) , 7.17 (IH, d), 7.35 (IH, dd), 7.49 (IH, m) , 8.12 (IH, d)

Preparative Example 25 - Preparation of N-Phenyl Homophthalimide

By a method similar to that described in Preparative Example 2 but using homophthalic anhydride (1.62g), aniline hydrochloride (19.lg) and water

(25ml), and recrystalusing the crude product from ethyl acetate/hexane, the title compound was obtained as a pale yellow solid, yield 0.82g. data (CDCI3) : 64.16 (2H, s), 7.10-7.18 (2H, ) , 7.27 (IH, d), 7.33-

7.48 (4H, m), 7.59 (IH, ) , 8.18 (IH, d)

Preparative Example 26 - Preparation of N-n-Butyl Homophthalimide

By a method similar to that described in Preparative Example 2 but using homophthalic anhydride (2.00g), n-butylamine (16ml) and water (10ml), the title compound was obtained, yield 0.97g.

^X Hnmr data (CDC1 ₃ ): δθ.88 (3H, t) , 1.31 (2H, m) , 1.51 (2H, m) , 3.92 (2H, t), 3.94 (3H, s), 7.19 (IH, d) , 7.35 (IH, dd) , 7.50 (IH, dd) , 8.14 (IH, d)

Preparative Example 27 - Preparation of N-(2-Methylpropyl) Homophthalimide

By a method similar to that described in Preparative Example 2 but using homophthalic anhydride (2.00g), 2-methylpropylamine (lδml) and water

(10ml), the title compound was obtained, yield 0.37g.

^X Hnmr data (CDCI3): δ0.86 (6H, d), 2.06 (IH, m), 3.79 (2H, d), 3.99 (2H, s), 7.20 (IH, d), 7.37 (IH, dd), 7.52 (IH, m), 8.16 (IH, d)

Preparative Example 28 - Preparation of N-(1,2-Dimethylpropyl)

Homophthalimide

By a method similar to that described in Preparative Example 2 but using homophthalic anhydride (2.60g), 1,2-dimethylpropylamine (18ml) and water

(10ml), the title compound was obtained, yield 0.26g.

^nmr data (CDC1 ₃ ): δ0.78(3H, d) , 1.00 (3H, d), 1.42 (3H, d) , 2.54 (IH, m) ,

4.01 (2H, s), 4.63 (IH, m) , 7.22 (IH, d) , 7.41 (IH, dd) , 7.54 (IH, m) , 8.18

(IH, d)

Preparative Example 29 - Preparation of 5-Methoxy-N-methyl-l-isoquinolone and 5-methoxyisoquinoline

A stirred solution of 5-hydroxyisoquinoline (2.00g) in dimethylformamide

(20ml) was treated portionwise with sodium hydride (0.36g). Stirring was continued for a further 10 minutes before the addition of methyl iodide

(3.92g), and this mixture was stirred for a further 3 hours. The reaction

was quenched with water, and the mixture was extracted with ethyl acetate

(x3). The combined extracts were washed thoroughly with saturated sodium bicarbonate solution, dried (MgSO.) and evaporated in vacuo to leave a green oil, which was separated by chromatography on silica gel (eluting with ethyl acetate/hexane 1:3) to give firstly 5-methoxyisoquinoline

(0.37δg):

^! Hnmr data (CDC1 ₃ ): δ4.10 (3H, s) , 7.08 (IH, m) , 7.68-7.68 (2H, ) , 8.11

(IH, d), 8.66 (IH, d) , 9.31 (IH, s) followed by δ-methoxy-N-methyl-1-isoquinolone (0.138g):

^nmr data (CDClj): δ3.60 (3H, s), 3.96 (3H, s), 6.85 (IH, d) , 7.02-7.09

(2H, m), 7.42 (IH, dd) , 8.02 (IH, d)

Preparative Example 30 - Preparation of N-Ethyl-5-methoxy-l-isoquinolone

By a method similar to that described in Preparative Example 11 but using δ-methoxyisoquinoline (prepared as described in Preparative Example 29 above) (0.363g), ethyl iodide (0.712g), potassium ferricyanide

(0.751g+0.751g) and sodium hydroxide (0.192g), and purifying the crude product by chromatography on silica gel (eluting with ethyl acetate/hexane

1:4), the title compound was obtained, yield 0.163g.

^X Hnmr data (CDCI3): 61.37 (3H, t), 3.94 (3H, s) , 4.06 (2H, q) , 6.88(1H, d) ,

7.03-7.10 (2H, m), 7.41 (IH, dd) , 8.01 (IH, d)

Preparative Example 31 - Nitration of N-Ethyl Isoquinolin-l,3,4-trione

A stirred solution of N-ethyl isoquinolin-l,3,4-trione (prepared as described in Example 1 above) (0.3δg) in fuming nitric acid (3ml) was cooled to 0°C, and concentrated sulphuric acid (3ml) was added. The mixture was allowed to warm to room temperature and was stirred for a further 4 days before being quenched with water (δml). The precipitate which formed was filtered off, washed and dried to afford a 1:1 mixture of

N-ethyl-5-nitro isoquinolin-l,3,4-trione and N-ethyl-8-nitro isoquinolin-

1,3,4-trione (0.348g).

Preparative Example 32 - Preparation of 5-Ethoxycarbonylamino-N-ethyl-l- isoquinolone

A stirred solution of δ-amino-N-ethyl-1-isoquinolone (prepared as described in Preparative Example 19, Step 1 above) (0.200g) in chloroform (10ml) was treated with triethylamine (O.llδg), followed by ethyl chloroformate

(0.126g). stirring was continued for a further 2.5 hours, and the mixture was then evaporated to dryness in vacuo. The residue was purified by

chromatography on silica gel (eluting with ethyl acetate/hexane 1:2) to afford the title compound as a white solid, yield 0.064g.

^X Hnmr data (CDCl _j ): δl.31-1.42 (6H, m) , 4.08 (2H, q) , 4.28 (2H, q) , 6.51

(IH, d), 6.60 (IH, broad s) , 7.13 (IH, d) , 7.48 (IH, dd) , 7.95 (IH, d) ,

8.28 (IH, d)

Preparative Example 33 - Preparation of N-Ethyl-δ-N,N- bis(methanesulphonyl)-l-isoquinolone

A stirred solution of 5-amino-N-ethyl-l-isoquinolone (prepared as described in Preparative Example 19, Step 1 above) (0.200g) in chloroform (10ml) was treated with triethylamine (O.llδg), followed by methanesulphony1 chloride

(0.266g - in two portions). The mixture was left to stand for 72 hours, before being filtered to remove a trace of insoluble material. The filtrate was added to water, and the organic layer was separated, washed with brine, dried (MgSO.) and evaporated in vacuo to afford the title compound as a white solid, yield 0.062g.

^X Hnmr data (CDC1 ₃ ): δl.40 (3H, t) , 3.40 (6H, s), 4.07 (2H, q) , 6.69 (IH, d), 7.24 (IH, d), 7.56 (IH, dd) , 7.67 (IH, d) , 6.90 (IH, d)

Preparative Example 34 - Preparation of N-Ethyl-2,5-dimethoxybenzamide

By a method similar to that described in Preparative Example 9 but using

2,5-dimethoxy benzoic acid (2.00g), thionyl chloride (10ml) and and a

70%w/v solution of ethylamine in water (30ml), the title compound was obtained, yield 2.36g.

^X Hnmr data (CDC1 ₃ ): δl.28 (3H, t) , 3.98 (3H, s), 4.01 (3H, s) , 4.08 (2H, q), 7.26 (IH, s) , 7.33 (IH, d) , 7.46 (IH, d)

Preparative Example 35 - Preparation of 5-Butanamido-N-ethyl-l-isoquinolone

By a method similar to that described in Preparative Example 32 but using δ-amino-N-ethyl-1-isoquinolone (prepared as described in Preparative

Example 19, Step 1 above) (0.200g), triethylamine (O.llδg) and butyryl chloride (0.124g), and purifying the crude product by chromatography on silica gel (eluting with ethyl acetate/hexane 1:1), the title compound was obtained as a white solid, yield 0.202g.

^! Hnmr data (CDC1 ₃ ): δl.Oδ (3H, t) , 1.38 (3H, t) , 1.85 (2H, m) , 2.48 (2H, t), 4.06 (2H, q), 6.45 (IH, d) , 7.12 (IH, d) , 7.21 (IH, broad s) , 7.53 (IH, dd), 7.94 (IH, d) , 8.33 (IH, d)

Preparative Example 36 - Preparation of N-Methyl-5-nitro-l-isoquinolone

By a method similar to that described in Preparative Example 11 but using

5-nitroisoquinoline (3.00g), methyl iodide (12.24g), potassium ferricyanide

(5.67g+δ.67g) and sodium hydroxide (1.45g), the crude title compound was obtained, yield 2.30g.

^! Hnmr data (CDCI3) : inter alia δ3.65 (3H, s), 7.26-7.34 (2H, m) , 7.68 (IH, m), 8.41 (IH, d), 8.78 (IH, d)

Preparative Example 37 - Preparation of 7-cyano-N-ethyl homophthalimide

Step 1 Preparation of 2-carboxy-N-ethyl phenylacetamide

A mixture of homophthalic anhydride (2δ.00g) and 70% w/v aqueous ethylamine

(2δ0ml) was heated under reflux for 2 hours. The clear solution was cooled and acidified with concentrated hydrochloric acid. The white precipitate was filtered off, washed with water and dried to afford the title compound as a white solid, yield 24.60g. ^l W nmr data (dg_DMS0): δθ.94 (3H, t) , 2.98 (2H, m) , 3.72 (2H, s)7.16-7.28

(2H, m), 7.42 (IH, dt) , 7.75 (IH, dd) , 7.86 (IH, broad t) , 12.82 (IH, broad s)

Step 2 Preparation of 2-carboxy-N-ethyl-4-nitro phenylacetamide

A stirred solution of 2-carboxy-N-ethyl phenylacetamide (prepared as in step 1 above) (20.73g) in concentrated sulphuric acid (250ml) was cooled to ca. 10°C and treated with a solution of potassium nitrate (50.50g) in concentrated sulphuric acid (160ml) over 40 minutes. The mixture was then allowed to warm to room temperature, and was stirred for a further 3.6 hours before being poured onto ice (ca. 11). The precipitate was filtered off, washed with water and dried to afford the title compound, yield δ.65g. ^l H nmr data (dg_DMS0) : δθ.94 (3H, t) , 2.99 (2H, m), 3.92 (2H, s) , 7.53 (IH, d), 7.93 (IH, broad t) , 8.27 (IH, dd) , 8.49 (IH, d)

Step 3 Preparation of 4-amino-2-carboxy-N-ethyl phenylacetamide

A solution of 2-carboxy-N-ethyl-4-nitro phenylacetamide (prepared as in step 2 above) (2.30g) in ethanol (150ml) was treated with a 5% palladium on charcoal catalyst (0.12δg) and hydrogenated until 620ml of hydrogen had been taken up. The mixture was filted through hiflo (washing through with more ethanol), and the filtrate was evaporated to dryness in vacuo to leave an oil. Trituration with hexane afforded the title compound as a solid, yield 1.98g. H nmr data (d _β _DMS0) : δθ.90 (3H, t) , 2.96 (2H, ) , 3.30 (2H, broad s) ,

3.50 (2H, s), 6.57 (IH, dd) , 6.82 (IH, d) , 6.97 (IH, d) , 7.69 (IH, broad t)

Step 4 Preparation of 2-carboxy-4-cyano-N-ethyl phenylacetamide

A stirred solution of 4-amino-2-carboxy-N-ethyl phenylacetamide (prepared as in step 3 above) (2.44g) in 6M hydrochloric acid (20ml) was cooled to

0°C, and treated dropwise with a solution of sodium nitrite (0.91g) in water (3ml). The mixture was then stirred at 0°C for a further 30 minutes before being neutralised with sodium carbonate. The resultant mixture was added in portions to a hot (60-70°C) aqueous solution of copper (I) cyanide

(1.18g) and potassium cyanide (1.72g). The resultant mixture was heated under reflux for 1.5 hours, then cooled and extracted with ethyl acetate

(4x40ml). The combined extracts were washed with brine, dried (MgSO^) and evaporated in vacuo to yield the crude title compound as a pale brown solid

(0.44g), which was used directly in step 5.

Step 6 Preparation of 7-cyano-N-ethyl homophthalimide

Crude 2-carboxy-4-cyano-N-ethyl phenylacetamide (prepared as in step 4 above) (0.44g) was heated until it melted. Heating was continued for a further 2 hours, then the melt was allowed to cool, and was dissolved in chloroform. This solution was filtered through a plug of silica-gel, and the filtrate was evaporated to dryness in vacuo to leave the title compound as an off-white solid, yield 0.13g. nmr data (CDCI3): δ2.21 (3H, t), 4.06 (2H, q) , 4,16 (2H, s), 7.47 (IH, d), 7.85 (IH, dd), 8.50 (IH, d)

Preparative Example 38 - Preparation of N-ethyl furan-3-carboxamide

A stirred solution of 3-furanoic acid (lO.OOg) in thionyl chloride (lO.OOg) was heated to ca 60°C for 2 hours, then cooled and evaporated to dryness in vacuo. The residue was treated with 70% w/v aqueous ethylamine, and the resulting solution was heated under reflux for 3 hours. The mixture was cooled, and extracted with ethyl acetate. The extracts were washed with saturated sodium bicarbonate and brine, then dried (MgSO.). Evaporation in vacuo gave the title compound as a pale brown solid, yield 4.50g.

1.22 (3H, t), 3.44 (2H, m) , 6.13 (IH, broad s), 6.62 (IH, s), 7.43 (IH, s) ,

7.94 (IH, s)

Preparative Example 39 - Preparation of N-ethyl thiophene-3-carboxamide

By a method similar to that described in Preparative Example 38, but using thiophene-3-carboxylic acid (2.00g), thionyl chloride (3.00g) and 70% w/v aqueous ethylamine (3.00g), the title compound was obtained as a pale yellow solid, yield 0.72g. H nmr data (CDC1 ₃ ): 61.22 (3H, t) , 3.43 (2H, m) , 6.38 (IH, broad s), 7.29

(IH, m), 7.40 (IH, ) , 7.88 (IH, d)

Preparative Example 40 - Preparation of N-methylpyrrole-3-(N- ethyl)carboxamide

By a method similar to that described in Preparative Example 38, but using

N-methylpyrrole-2-carboxylic acid (δ.OOg), thionyl chloride (δml) and 70% w/v aqueous ethylamine (10ml), the title compound was obtained as a pale yellow solid, yield 1.74g. H nmr data (CDCI3) : δl.20 (3H, t) , 3.41 (2H, m) , 3.94 (3H, s), δ.89 (IH, broad), 6.05 (IH, ) , 6.50 (IH, m) , 6.69 (IH, m)

Preparative Example 41 - Preparation of 2-(4-chlorophenyl)-6-ethyl-5,7- dioxo-4,6,6,7-tetrahydrothiazolo[4,5-c]pyridine

2-(4-Chlorophenyl)-5,7-dioxo-4,5,6,7-tetrahydrothiazol0[4 ,δ-c]pyran

(O.OδOg) was added to 70% w/v aqueous ethylamine. After ca 10 minutes, the solution was evaporated to dryness to leave a white foam. This was heated to 170°C for 2 hours, then cooled. The resultant gum was chromatographed on silica-gel, eluting with ethyl acetate/hexane mixtures, to afford the title compound, yield O.OlOg. H nmr data (CDCI3) : δl.24 (3H, t), 4.02 (2H, q), 4.18 (2H, s), 7.46 (2H, ), 7.92 (2H, m)

Preparative Example 42 - preparation of indole-2-(N-ethyl)carboxamide

A stirred solution of ethyl indole-2-carboxylate (1.89g) in 70% w/v aqueous ethylamine (20ml) was heated under reflux for 6 hours, then cooled and left to stand for ca 16 hours, then heated under reflux for a further 2 hours.

The solution was cooled and diluted with water, and the precipitate was filtered off, washed with water and dried to afford the title compound as a white solid, yield 1.63g.

*H nmr data (CDC1 ₃ ): 61.29 (3H, t) , 3.57 (2H, m) , 6.21 (IH, broad t) , 6.82

(IH, ), 7.13 (IH, m) , 7.28 (IH, m) , 7.43 (IH, m) , 7.64 (IH, m)9.64 (IH, broad s)

Biological Data

The herbicidal activity of the compounds was tested as follows: Each chemical was formulated by dissolving it in an appropriate amount, dependent on the final spray volume, of a solvent/surfactant blend which comprised 78.2 gm/litre of Tween 20 and 21.8 gm/litre of Span 80 adjusted to 1 litre using methylcyclohexanone. Tween 20 is a Trade Mark for a surface-active agent comprising a condensate of 20 molar proportions

of ethylene oxide with sorbitan laurate. Span 80 is a Trade Mark for a surface-active agent comprising sorbitan mono-laurate. If the chemical did not dissolve, the volume was made up to δcm with water, glass beads were added and this mixture was then shaken to effect dissolution or suspension of the chemical, after which the beads were removed. In all cases, the mixture was then diluted with water to the required spray volume. If

3 3 sprayed independently, volumes of 25cm and 30cm were required for pre-emergence and post-emergence tests respectively; if sprayed together,

3 4δcm was required. The sprayed aqueous emulsion contained 4% of the initial solvent/surfactant mix and the test chemical at an appropriate concentration.

The spray compositions so prepared were sprayed onto young pot plants (post-emergence test) at a spray volume equivalent to 400 litres per hectare. Damage to plants was assessed 13 days after spraying by comparison with untreated plants, on a scale of 0 to 9 where 0 is 0% damage, 1 is 1-6% damage, 2 is 6-16% damage, 3 is 16-26% damage, 4 is 26-35% damage, 5 is 36-59% damage, 6 is 60-69% damage, 7 is 70-79% damage, 8 is 80-89% damage and 9 is 90-100% damage.

In a test carried out to detect pre-emergence herbicidal activity, seeds were placed on the surface of plastic trays of compost in the case of tests carried out on Compounds Nos. 1-3, or crop seeds were sown at 2 cm depth (i.e. sugar beet, cotton, rape, winter wheat, maize, rice, soya) and weed seeds at 1 cm depth beneath compost, for the remainder. They were then sprayed with the compositions at a spray volume equivalent to 400 litres per hectare. 20 days after spraying, the seedlings in the sprayed plastic trays were compared with the seedlings in unsprayed control trays, the damage being assessed on the same scale of 0 to 9.

The results of the tests are given in Tables III, IV, and V below.

TABLE III

COMPD PRE/ RATE OF NO. POST APPLN kg/ha BV BN GH GM ZM OS TA SU PA CA GA CV AR BP EH PO CO IH IX AT XP XT AF PN AM AE SH SV DS EC CR

1 Post 5 9 9 8 7 6 - 4 9 8 9 - 8 9 - - 9 - - 9 9 9 - 4 8 - 0 9 8 9 7 0

Post δ 6 8 8 8 9 6 6 8 6 8 9 - 9 9 8 - 6 - 6 4 7 9 9 7 6 , U

2 Post δ 4 0 0 7 0 - 0 6 6 8 - 7 9 - - 4 - - 4 0 0 - 0 4 - 0 4 7 9 4 0 Pre δ 0 0 0 6 0 0 0 4 - 0 - - 0 - - 0 - - 0 0 0 - - 0 - 0 0 0 0 0 0

3 Post δ 0 8 4 8 8 δ 0 7 7 8 δ - 9 - - - 5 - 7 δ δ - 4 - δ 0 8 9 7 9 0 Pre δ 0 0 0 0 0 0 0 6 O - 0 - 4 - - - 4 - 7 7 O - 6 - 7 - 4 7 5 5 0

TAPIE IV

BV BN GH GM ZM OS TA PA CA GA CV AR BP EH IH AT XT AF AM AE SH SV DS EC CR CE

0 - 0 0 0 0 0 - 0 - 3 0 0 0 0 0 0 0 0 0 0 2 4 0 6 9 0 0 3 7 6 0 4 - 6 7 6 - 6 0 0 0 - 0 4 - 0 0 2 0 0 0 0 0 0 6 7 0 4 8 0 1 0 0 0 0 4 0 0 2 4 1 2 6 0 0 0 0 0 1 0 0 0

2 δ 3 6 0 1

0 0 - - 0 -

0 0 - - 0 - 1 1 1 2

IΔfiL -V

COMPD PRE/ RATE OF NO. POST APPLN * g/ha BV BN BNW GH GM ZM OS TA PA MI CA GA AR PO CO EH IH AT XT AF AM LR SH SV BP PD EC CE

TABLE V (continued)

COMPD PRE/ RATE OF NO. POST APPLN * g/ha BV BN BNW GH GM ZM OS TA PA MI CA GA AR PO CO EH IH AT XT AF AM LR SH SV BP PD EC CE

- - l O O O O O O O O S l O

- 4 2 3 4 2 0 6 4 3 7 4 2 0

- 6 9 8 4 3 4 4 5 6 6 6 3 0

- 0 0 0 0 1 0 0 1 0 0 0 0 0

- 5 9 3 6 6 1 1 6 0 1 6 5 1

- 0 0 0 0 0 0 1 0 0 0 0 3 0

- 0 2 2 0 0 0 0 2 1 0 2 3 0

- 3 2 0 2 0 2 0 3 3 2 2 3 0

- 7 5 4 7 3 3 3 7 8 2 3 3 0 - 7 9 6 5 3 3 3 6 6 6 4 3 2

Note: For the tests on compounds 20, 22, 23, 25, 26, 30, 42, 44-49, and 51, as additive (Atplus 463) comprising a 60:40 mixture of a paraffinic oil with an emulsifier was included in the spray composition at 10 grams per litre.

TABLE VI Table VI below gives the results of further tests. In thewse tests, the compounds were formulated as previously described and diluted to a volume of 10ml. The compositions so prepared were sprayed on to the test plants and seeds at a spray volume of 1000 litres per hectare.

d

TABLE VII (continued)

Abbreviations used for Test Plants

PD - Panicum dichotvmiflorum

DS - Dioitaria sanαuinalis

EC - Echinochloa crus-oalli

CE - Cvperus esculentus

CR - Cvperus rotundus

LE - Lvcooersicon esculentus (tomato)

BO - Brassica oleracea

CHEMICAL FORMULAE

(IN DESCRIPTION) Naming conventions used in Examples

Isoquinoline

Isoquinolin-1-one

Isoquinolin-l,3,4-trione

Homophthalimide

CHEMICAL FORMULAE

(IN DESCRIPTION)

(I)

(VI)

(V)

(VII) (VIII)

CHEMICAL FORMULAE

(IN DESCRIPTION)

IX)

(X)

( XI) (XII)

CHEMICAL FORMULAE

(IN DESCRIPTION)

(XV) (XVI)

(XVII) m (XVIII)

(XIX)