JPH0240659B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to compounds having biological activity, particularly compounds having herbicidal activity, methods for producing such compounds, intermediate compounds useful in producing such compounds, herbicidal compositions utilizing these compounds, and It relates to methods of utilizing those compounds. The present inventors have discovered novel isoquinolines that have biological activity, particularly herbicidal activity. According to the present invention, a compound represented by the following general formula or a salt thereof is provided: {In the formula, A, B, D, E, and J are hydrogen, halogen,
independently selected from the group consisting of nitro, cyano, _C1 - _C6 alkyl, _{C1 - C6} haloalkyl, C1- _C6 alkoxy, _C1 - _C2 alkylthio; U and V are independently selected from hydrogen and halogen; R ¹ and R ² are independently selected from hydrogen and C ₁ -C ₆ alkyl; W is

[Formula] (wherein, G is hydroxy, C ₁ to C ₁₀ alkoxy, C ₁ to _{C 10} alkylthio, N,
N-di(C ₁ -C ₆ alkyl)amino, and N,
C _{1 -} substituted with a substituent selected from the group consisting of N,N-tri(C ₁ -C ₆ alkyl)ammonio
C ₆ alkoxy group, group -NR ⁴ R ⁵ (in the formula, R ⁴ and
R ⁵ is independently selected from C ₁ to C ₆ alkyl),
and the group -O-N=R ¹⁰ , where R ¹⁰ is a C ₁ -C ₁₀ alkylidene group; and Z is halogen; X is oxygen; Y is oxygen , and the group NR ⁶ , where R ⁶ is hydrogen and C ₁ -C ₁₀ alkyl; k is selected from 0 and 1. } The compounds of the formula (wherein R ¹ and R ² are not the same) are optically active, and the present invention also covers individual stereoisomers of such compounds, as well as racemic mixtures of stereoisomers. Also includes mixtures of these stereoisomers. Preferred organic bases have the formula NR ⁷ R ⁸ R ⁹ , where R ⁷ ,
R ⁸ and R ⁹ are hydrogen, C ₁ -C ₂ alkyl, C ₁ -
(independently selected from C ₆ hydroxyalkyl, phenyl and benzyl). Preferred A, B, D, E, J, U and V include hydrogen, halogen, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy, and _C1 - _C6 alkoxy. Includes alkylthio, nitro and cyano. Preferred R ¹ and R ² include hydrogen and C ₁ -C ₆ alkyl. Preferable W is a group

[Formula]. The specific properties of G are not narrowly defined and therefore the group

The formula may be the free carboxylic acid or a derivative such as a salt of the acid, an acid ester, an acid amide, an acid sulfonamide or an acid oxime ester. Preferred G includes hydroxy, _C1 - _C10 alkoxy, _C1
-C ₁₀ alkylthio, N,N-di(C ₁ -C ₆ alkyl)amino, and N,N,N-tri(C ₁ -
C ₁ to C ₁₀ alkoxy group substituted with a substituent selected from the group consisting of C ₆ alkyl) ammonio;
The group ^-NR4R5 (wherein ^R4 and ^R5 are independently selected from _C1 - _C6 alkyl), the group OM {wherein M is ^an alkali metal ion}, the group _-NHSO2R ³ (wherein R ³ is C ₁ -C ₆ alkyl) and the group -
O—N=R ¹⁰ (wherein R ¹⁰ is a C ₁ to C ₁₀ alkylidene group). A more preferable G is
Hydroxy, _C1 - _C10 alkoxy, C2 _{- C10} alkenyloxy, _C2 - _C10 alkynyloxy, _C1-
Included are C ₁₀ alkylthio and groups OM, where M is an alkali metal ion or an alkaline earth metal ion. Preferred X is oxygen. Preferred Y includes oxygen and the group NR ⁶ (wherein R ⁶
is selected from hydrogen, _C1 - _C6 alkyl, _C2 - _C10 alkenyl and C2 _{- C10} alkynyl). Preferable n includes 0 or 2. Examples of compounds encompassed by this invention include the following compounds: Specific compounds of the invention are listed below in Tables 1 and 2.
Details are given in Table and Table 3.

【table】

【table】

【table】

【table】

[Table] Preferred compounds represented by the formula are 3-isoquinolyl compounds in which the phenyl ring is 1,4-substituted, that is, the following formula: (However, n is 0) It is a compound represented by the following. The compounds of the invention can be made in a variety of ways, and in another aspect the invention provides methods for making compounds of formula. Formula a (W in the formula is

[Formula] and G in formula a is not hydroxy) A compound represented by formula b (in which W is -CO ₂ H) can be prepared by using a base to obtain a salt of the acid, for example. By neutralizing the acid, by esterifying the acid with an alcohol, thiol, phenol or thiophenol to obtain an acid ester, or by reacting the acid (or acid halide derivative) with an amine to obtain an amide. (Scheme A). Methods known to those skilled in the art for preparing acid salts, acid esters, acid halides and acid amides can be employed without undue experimentation to form the formula b.
The compound of the present invention represented by formula a can be obtained from the compound of the present invention. (However, in the above formulas b and a, n is 0.) The nitriles of the present invention represented by the formula c (in the formula, W is -C≡N) are, for example, is _-CONH2 ). However, in the above formulas d and c, n is 0) The alcohol of the present invention represented by the formula e (in the formula, W is -CH ₂ OH) has the formula f {in the formula,
W is

[Formula G is OH or O-alkyl] Methods known in the art for reducing acids or acid esters to alcohols, such as reduction methods using lithium aluminum hydride, can be employed without unnecessary experimentation to convert esters of compounds of formula f to alcohols of formula e. The alcohol of the represented compound can be obtained. However, in the above f and e, n is 0) Formula g (wherein, W is _-CH2 -halogen)
The alkyl halide of the present invention represented by is obtained by halogenating an alcohol represented by formula e (wherein W is -CH ₂ OH). Known methods for converting alcohols into alkyl halides, such as halogenation with reagents such as thionyl chloride, can be employed without unnecessary experimentation to convert alcohols of formula e to alkyl halides of formula g. Inventive alkyl halides can be obtained. Ethers of the present invention of formula h (wherein W is _-CH2OR ) are of the formula e (wherein W is -CH2OR).
is -CH ₂ OH). Known methods for converting alcohols into ethers, such as reduction with alkyl halides using Williamson's ether synthesis method, can be employed without unnecessary experimentation to convert alcohols of the invention of formula e to ethers of formula h.
of the ether of the invention can be obtained. Formula h(i) [where W is -CH ₂ OR (-
The ether ( _thioether ) of the present invention represented by the formula g (wherein W is
It can be obtained by alkoxylating (thioalkoxylating) an alkyl halide represented by CH ₂ -halogen. Known methods for converting alkyl halides into ethers (thioethers), such as reaction with alcohols (thiols) using Williamson's ether synthesis method, are employed without unnecessary experimentation, and the alkyl halides of the invention of formula g The ethers (thioethers) of the invention of formula h(i) can be obtained from the halides. An amine of formula j (wherein W is CH ₂ NR ⁴ R ⁵ ) is an amine of formula g (where W is -CH ₂
- halogen) or by aminating an alkyl halide of the formula k (wherein W is

It can be obtained by reducing the amide represented by the following formula. Known methods of converting alkyl halides to amines, such as reaction with amines, as well as known methods of converting amides to amines, such as reduction with reagents such as lithium aluminum hydride, can be used without undue experimentation to form the formula The amines of the invention of the formula j can be obtained from the alkyl halides of the invention of g and from the amides of the invention of the formula k, respectively. The N-oxides of the invention of the formula (wherein k is 1) are obtained by oxidizing compounds of the formula (wherein k is 0). Known techniques for converting isoquinoline to isoquinoline N-oxide, such as oxidation methods using persulfates, peroxides, peracids or peresters, can be employed without unnecessary experimentation to convert the N-oxide of the present invention. Obtainable. The compounds of the present invention of the formula {wherein Y is a group NR ⁶ (wherein R ⁶ is not hydrogen)} are:
The compounds of the invention of the formula {wherein Y is a group NR ⁶ in which R ⁶ is hydrogen} can be obtained, for example, by alkylation or acylation. Known methods for preparing secondary amine derivatives, such as alkylation with alkyl halides and acylation with acyl halides, produce the novel compounds of the invention (wherein R ¹ is not hydrogen) without unnecessary experimentation. can do. Formula (where A, B, D, E, U, V, Y,
X, R ¹ , R ² , J, W, k and n have the meanings defined below), a phenol or thiophenol of the formula iodine) according to scheme D, preferably in the presence of an alkaline substance. However, the above formula and the compound represented by the formula in which n is 0 can be obtained by the following method a) or b) or c): a) Formula {wherein L is a leaving group (e.g. alkylsulfonyl, chlorine, bromine or iodine) is condensed with a suitable compound of the formula according to scheme E. b) The following sequential steps: (i) a suitable compound of the formula (wherein L is a leaving group such as alkylsulfonyl, chlorine, bromine or iodine); Isoquinoline derivatives are represented by the formula (wherein Q is hydroxy, mercapto, C ₁ - C ₆
is hydroxy _{, mercapto, C1-C6 alkoxy or C1 - C6} alkylthio. ) is obtained, (ii) the formula obtained in step (i) above (wherein Q is
_C1 - _C6 alkoxy or _C1 - _C6 alkylthio) to give a compound of formula; then (iii) the formula obtained in step (i) and step (ii) above; is condensed with a compound of formula according to the method shown in Scheme D (steps (i) and (ii) are shown in Scheme F), c) The following sequential steps: (i) converting a suitable isoquinoline derivative of formula XI to formula Mercapto,
_C1 - _C6 alkoxy or _C1 - _C6 alkylthio} to obtain a compound represented by the formula (wherein Q has the meaning defined above); (ii) The formula obtained in step (i) above (where Q is
C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkylthio) according to the method described in step (ii) of Scheme F above; then (iii) above step ( The product of formula obtained in i) and (ii) is condensed with a compound of formula according to the method shown in Scheme D above {step (i) is shown in Scheme G}. The condensation reactions shown in schemes D and E to G (where Y is oxygen or sulfur) and outlined above are preferably carried out in the presence of an alkaline material. Preferred alkaline materials include alkali metal and alkaline earth metal hydroxides and carbonates such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. The condensation reactions shown in Schemes D to G and outlined above are also preferably carried out in the presence of a solvent.
Preferred solvents include ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, as well as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N
-Dipolar aprotic solvents such as methylpyrrolidone, hexamethylphosphoramide and sulfolane. The reaction conditions necessary to carry out the condensation reactions shown in Schemes G, E, F and G and outlined above will vary according to the nature of the reactants and solvents used.
Generally, the reaction is accelerated by heating, between 40° and
Reaction temperatures in the range of 150°C and reaction times of 0.5 to 20 hours are sufficient. However, higher or lower reaction temperatures and/or shorter or longer reaction times may be used as desired. The dealkylation reactions shown in Schemes F and G and outlined in section b) (ii) and section c) (ii) are carried out using a variety of known reagents. For example, aryl-alkyl ethers include pyridine, hydriodic acid, hydrobromic acid, sodium triethoxide in dimethylformamide, acetyl P-toluenesulfonate, sodium or potassium iodide in formic or acetic acid, 2,4,6-
Decomposed using reagents such as lithium iodide and boron tribromide in uridine. Reaction times and conditions vary widely depending on the dealkylating agent used and the ether to be cracked. The reaction conditions generally employed when using the above "ether-cleaving" reagents are known to those skilled in the art and, without undue experimentation, are shown in Schemes F and G and described in (ii) of section b) above. and employed to carry out the "ether decomposition" reaction outlined in section c) (ii). Intermediates useful in the preparation of compounds of the formula: The compound represented by is a new compound. Accordingly, in another aspect of the present invention, the present invention is represented by the formula: provide a compound. The compounds of the formula exhibit activity as herbicides and therefore in another aspect of the invention the invention provides a method of significantly damaging or killing undesirable plants, the method comprising: or by applying to the growth medium of the plant an effective amount of a compound of the formula defined above. Compounds of the general formula are effective as herbicides against a wide variety of plants. However, certain compounds of the present invention have beneficial effects on monocotyledonous plants and on dicotyledonous plants, which are relatively unaffected by application rates of the compounds of the present invention that significantly damage or kill other species of plants. Shows selective activity. Additionally, certain compounds of the formula are selectively active within a group of monocots and are sufficient to kill or significantly damage monocot weeds in monocot grains. used in proportion. Accordingly, in yet another aspect, the present invention provides a method for selectively inhibiting the growth of weeds in crops, which method comprises applying a compound of the formula as defined above to or on grains. to the growth medium in an amount sufficient to significantly damage or kill the weeds but not substantially damage the grain. The compound of the formula is applied either directly to the plant (post-problem application) or to the soil of the plant before the problem occurs (pre-problem application). However, compounds are generally more effective when applied after the problem occurs. Although the compounds of the formula can be used on their own to inhibit the growth of plants, severely damage or kill them, they are preferably used in combination with a carrier comprising a solid or liquid diluent. It can be used in the form of a composition comprising the compounds of the invention in a mixture. Accordingly, in another aspect, the present invention provides a composition for inhibiting plant growth, damaging or killing plants, which composition comprises a compound of the formula defined above and an inert compound thereto. It comprises a carrier. Compositions according to the invention include both diluted compositions that are ready for use as well as concentrated compositions that usually require dilution with water before use.
Preferably, the composition contains from 0.01% to 90% by weight of active ingredient. Dilute compositions prepared for use preferably contain from 0.01 to 2% by weight of active ingredient, while concentrated compositions typically contain from 20 to 90% of active ingredient.
The content is preferably 20 to 70%. The solid compositions may be in the form of granules or powder, in which the active ingredient is present in a finely divided diluent, such as kaolin, bentonite, diatomaceous earth, dolomite, calcium carbonate, talc, powdered magnesia, Fuller's earth, Mixed with plaster. They may be in the form of dispersible powders or particles and comprise wetting agents to facilitate the dispersion of the powder or particles in the liquid. Solid compositions in powder form can be applied as foliar fines. Liquid compositions may comprise a solution or dispersion of the active ingredient dissolved or dispersed in water, optionally containing a surfactant, or the active ingredient may be dispersed as droplets in water in a water-miscible organic solvent. It comprises a dissolved or dispersed solution or dispersion. Surfactants may be of cationic, anionic or nonionic type. Cationic surfactants are, for example, quaternary ammonium compounds (eg cetyltrimethylammonium bromide).
Suitable anionic surfactants are soaps; aliphatic monoester salts of sulfuric acid, such as sodium lauryl sulfate; and salts of sulfonated aromatic compounds, such as sodium dodecylbenzenesulfonate, sodium, calcium lignosulfonic acid and butylnaphthalenesulfonic acid. and ammonium salts,
and a mixture of the sodium salts of diisopropyl and triisopropylnaphthalene sulfonic acids. Preferred nonionic surfactants are condensation products of ethylene oxide and fatty alcohols such as oleyl alcohol and cetyl alcohol, or of alkylphenols such as octyl- or nonyl-phenol or octyl-cresol. Other nonionic surfactants are partially esterified products derived from long chain fatty acids and hexitol anhydrides, such as sorbitan monooleate; condensation products of partially esterified products with ethylene oxide; and lecithin. Aqueous liquids or dispersions are prepared by dissolving the active ingredient in water or in an organic solvent, optionally containing a wetting or dispersing agent, and then adding the resulting mixture to water, optionally containing a wetting or dispersing agent. It can be obtained by adding to. Suitable organic solvents include, for example, ethylene dichloride, isopropyl alcohol, propylene glycol, diacetone alcohol, toluene, kerosene, methylnaphthalene, xylene and trichloroethylene. Compositions used in the form of aqueous solutions or dispersions are provided in the form of concentrates containing a high proportion of the active ingredient, which concentrates are diluted with water before use. The concentrate is usually required to withstand long-term storage and is an aqueous preparation such that after such storage it can be diluted with water and maintain homogeneity for a sufficient period of time to apply it using conventional spray equipment. It is required to be able to form objects. The concentrate is conveniently 20 to 90
%, preferably from 20 to 70% by weight of active ingredient. Dilute preparations prepared for use may contain varying amounts of active ingredient depending on the intended purpose, but up to 0.01
% to 10.0% by weight, preferably 0.1 to 2% by weight of active ingredient are usually used. A preferred form of concentrated composition is one containing the active ingredient finely divided and dispersed in water in the presence of surfactants and suspending agents. Suitable suspending agents are hydrophilic colloids and include, for example, polyvinylpyrrolidone and sodium carboxymethylcellulose, as well as vegetable gums such as gum arabic and gum tragacanth.
Preferred suspending agents are those that impart thixotropic properties and increase the viscosity of the concentrate. Examples of preferred suspending agents include hydrated colloidal mineral silicates such as montmorillonite, beedelite, nontronite, hectorite, saponite and saucolite. Bentonite is particularly preferred. Other suspending agents include cellulose derivatives and polyvinyl alcohol. The rate at which the compounds of the invention are applied depends on, for example, the compound selected for use, the identity of the plant whose growth is to be inhibited, the formulation selected for use and whether the compound is applied to the leaves or to the roots. It depends on a number of factors, including whether the Generally, a ratio of 0.005 to 20 kg per hectare is appropriate;
0.1 to 10 kg per hectare is preferred. Compositions of the invention may contain, in addition to one or more compounds of the invention, one or more compounds with biological activity other than the invention.
For example, the compounds of the invention as defined above are generally substantially more effective against monocots or herbaceous plants than against dicots or broad-leaved plants. Consequently, in some applications, the use of compounds of the invention alone as herbicides is sufficient to protect crops. In yet another aspect, the invention provides a composition comprising a mixture of at least one herbicidal compound of the formula defined above and at least one herbicide. Other herbicides may be any herbicides that do not have a formula. The herbicides are generally herbicides with complementary action. For example, one preferred class consists of mixtures having herbicidal action against broad-leaved weeds. A second preferred type consists of mixtures containing contact herbicides. Examples of useful complementary herbicides include the following herbicides: A benzo-2 such as 3-isopropylbenzo-2,1,3-thiadiazin-4-one-2,2-dioxide (common name bentozone) ,1,3
-Thiadiazin-4-one-2,2-dioxide B Hormonal herbicides as well as e.g. 4-chloro-2
-Methylphenoxyacetic acid (common name MCPA),
2-(2,4-dichlorophenoxy)propionic acid {common name dichlorprop}, 2,4,5-trichlorophenoxyacetic acid (common name 2,4,5-T), 4-
(4-chloro-2-methylphenoxy)butyric acid (common name MCPB), 2,4-dichlorophenoxyacetic acid (common name 2,4-D), 4-(2,
4-dichlorophenoxy)butyric acid (common name mecoprop) and their derivatives (e.g. salts,
3-[4-(4-) such as C 3-[4-(4-chlorophenoxy)phenyl]-1,1-dimethylurea (common name chloroxerone); halophenoxy)phenyl]-1,1-dialkylurea; D 2-methyl-4,6-dinitrophenol (common name DNOC, 2-tert-butyl-4,6-
Dinitrophenols and derivatives thereof, such as dinitrophenol (common name dinoterb), sec-butyl-4,6-dinitrophenol (dinoseb) and its dinoceb acetate ester; E N', N'- diethyl-2,6-dinitro-4
-Trifluoromethyl-m-phenylenediamine (common name dinitramine), 2,6-dinitro-N,N-dipropyl-4-trifluoromethylaniline (common name trifluralin) and 4-methylsulfonyl-2,6-dinitro ―
Dinitroaniline herbicides such as N,N-dipropylaniline (common name nitraline); F N'-(3,4-dichloro-phenyl)-N,
Phenylurea herbicides such as N-dimethylurea (common name diuron) and N,N-dimethyl-N'-[3-(trifluoromethyl)phenyl]urea (common name fluorometuron); G 3-[(methoxycarbonyl)amino phenylcarbomonol phenyl carbamates such as phenyl (3-methylphenyl)-carbamate {common name phenmedipham} and 3[(ethoxycarbonyl)amino]phenyl phenyl carbamate (common name demimediphum); H 2-phenylpyridazin-3-ones such as 5-amino-4-chloro-2-phenylpyridazin-3-one (common name pyrazone); I 3-cyclohexyl-5,6-trimethyleneuracil (common name Renasil), 5-bromo-
Uracil herbicides such as 3-tert-butyl-6-methyluracil (common name Bromacil) and 3-tert-butyl-5-chloro-6-methyluracil (common name Turbacil); J 2-chloro-4-ethylamino -6-(iso-propylamino)-1,3,5-triazine (common name atrazine), 2-chloro-4,6-
Di(ethylamino)-1,3,5-triazine (common name simazine) and 2-azido-4-
(iso-propylamino)-6-methylthio-
Triazine herbicides such as 1,3,5-triazine (common name aziprothrin); K 3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea (common name linuron), 3-(4- 1-alkoxy-1- such as chlorophenyl)-1-methoxy-1-methylurea (common name monolinuron) and 3-(4-bromo-4-chlorophenyl)-1-methoxy-1-methylurea (common name chlorobromulon) Alkyl-3-phenylurea herbicides; L Thiol carbamate herbicides such as S-propyldipropyl-thiocarbamate (common name Verorate); M 4-amino-4,5-dihydro-3-methyl-6-phenyl-1, 2,4-triazine-5
-one (common name metamitrone) and 4-amino-6-tert-butyl-4,5-dihydro-
3-methylthio-1,3,4-triazine-5
-1, such as On (common name metribuzin)
2,4-triazin-5-one herbicide; N 2,3,6-trichlorobenzoic acid (common name 2,3,6-TBA), 3,6-dichloro-2-
Benzoic acids such as methoxybenzoic acid (common name dicamba) and 3-amino-2,5-dichlorobenzoic acid (common name chloramben); O N-butoxymethyl-α-chloro-2',6 ′-
Diethylacetanilide (common name butachlor}, the corresponding N-methoxy compound (common name Aracol), the corresponding N-iso-propyl compound (common name propachlor) and 3',4' dichloropropioanilide (common name anilide herbicides such as P 2,6-dichlorobenzonitrile (common name dichlorobenyl), 3,5-dibromo-4-hydroxybenzonitrile (common name bromoxynil) and 3,5-diiod-4-hydroxybenzonitrile Dihalobenzonitrile herbicides such as (common name Ioxynil); Q haloalkanoic acid derivatives such as 2,2-dichloropropionic acid (common name Darapon), trichloroacetic acid (common name TCA) and their salts; R 4-nitrophenyl 2 -Nitro-4-trifluoromethylphenyl ether (common name fluorodiphen), methyl 5-(2,4-dichlorophenoxy)-2-nitrobenzoate (common name bifuenox), 2-nitro-5-
(2-chloro-4-trifluoromethylphenoxy)benzoic acid, 2-chloro-4-trifluoromethylphenyl 3-ethoxy-4-nitrophenyl ether and compounds disclosed in European Patent Publication No. 3416 diphenyl ether herbicides such as S N,N-dimethyl-diphenylacetamide (common name diphenamide), N-(1-naphthyl)phthalamic acid (common name naphthalam) and 3-amino-1,2,4- Mixed herbicide containing triazole. Examples of useful herbicides include the following; agent is 1,
Bipyridium herbicides such as 1'-ethylene-2,2'-dipyridium ion (common name diquate); U monosodium methane arsonate (common name
and amino acid herbicides such as V N-(phospho-1 methyl)-glycine (common name glyphosate) and its salts and esters. The invention is illustrated in a non-limiting manner by the following examples. Example 1 Ethyl 4-(3-chloro-1-isoquinolyloxy) phenoxy acetate (17) Ethyl 4-hydroxy phenoxy acetate (1.0 g), 1,3-dichloroisoquinoline (1.0
g), anhydrous potassium carbonate (0.7 g) and dry dimethylformamide (10 ml) at 120-130 g)
The mixture was heated at a temperature of 0.degree. C. for 3 hours with stirring. The solvent was removed under reduced pressure and the residue was treated with water. The aqueous mixture was extracted with a mixture of acetone and chloroform and the solvent was removed from the organic extract by distillation under reduced pressure. The residue was chromatographed on silica gel using chloroform eluent to obtain ethyl 4-(3-chloro-1-isoquinolyloxy)phenoxy acetate (1.2 g).
A melting point of 97°C is obtained. The assigned structure was confirmed by nuclear magnetic resonance, mass spectrometry, and elemental analysis. Example 2 The following compound was obtained from the appropriate 1-chloroisoquinoline and ethyl 4-hydroxy-phenoxycarboxylate following a method substantially similar to that described in Example 1 above: Ethyl 4-( 1-isoquinolyloxy) phenoxy acetate (18), melting point 70°C; Ethyl 4-(3-methyl-1-isoquinolyloxy) phenoxy acetate (19), melting point 101°C; Ethyl 4-(3-chloro-5- Nitro-1-isoquinolyloxy)-phenoxy acetate (20),
Melting point 129℃; Ethyl 2-[4-(3-chloro-5-nitro-
1-isoquinolyloxy)phenoxy]propionate (21), melting point 103-104°C; and ethyl 2-[4-(3-methyl-5-nitro-1-isoquinolyloxy)phenoxy]propionate (76), melting point 101°C. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Example 3 4-(3-chloro-1-isoquinolyloxy)phenoxyacetic acid (22) was converted into 4-(3-chloro-1-
Isoquinolyloxy) phenoxyethyl acetate (17)
was obtained by alkaline hydrolysis (NaOH aqueous solution), followed by acidification of the alkaline reaction mixture and recovery of the acid. The product has a melting point of 186° C. and its structure was confirmed by nuclear magnetic resonance spectroscopy and mass spectrometry. Example 4 Ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (23) a) 6-nitrophthalide (14.0) dissolved in acetic acid
g; J A Houbion, J A Miles and J A Paton, Organic Preparations and
Proceclures International, 11 (1), 27 (1979))
was hydrogenated over palladium on carbon catalyst to give 6-aminophthalide (12.0 g; W R Vaughan and S L Baird, J. Amer. Chem. Soc., 68 ,
1314 pages (1946)). 6-Aminophthalide (10.0 g) was converted to 6-chlorophthalide (8.5 g; J
Tirouflet.Bull.soc.sci.Bretagne Spc.No26.7,
(1951)). A mixture of 6-chlorophthalide (2.0 g) and potassium cyanide (2.0 g) was stirred at a temperature of 180° C. for 4 hours. The solid was cooled, dissolved in water and the solution acidified with concentrated hydrochloric acid. A dark brown solid was collected, washed with water and dried. The crude solid was dissolved in ethyl acetate, the solution treated with charcoal, filtered and the solvent evaporated to give 4-chloro-2-carboxyphenylacetonitrile (1.70 g) as pale yellow crystals with a melting point of 120°C. A mixture of 4-chloro-2-carboxyphenylacetonitrile (8.0 g), N-methyl-4-hydroxyaniline (10.0 g) and chlorobenzene was heated under reflux for 2 hours. The mixture was cooled and the crystallized product was collected by filtration. Wash the solid several times with acetone and 4-[N-
(7-chloro-1-hydroxyisoquinoline-
3-yl)-N-methylamino]phenol (8.57 g) was obtained with a melting point of 266°C. 4-[N-(7-chloro-1-hydroxyisoquinolin-3-yl)-N-methylamino]
A mixture of phenol (4.0 g) and phosphorous oxychloride was heated to reflux for about 10 minutes, at which point a clear solution was obtained. The mixture was cooled and poured into ice. The precipitated solid was collected and purified by column chromatography using silica gel (eluent dichloromethane/ethyl acetate; 90/10) to obtain 4-[N-(1,7-dichloroisoquinolin-3-yl)-N -Methylaminophenol (2.57g) as a yellow crystalline solid, melting point 124
Obtained as °C. b) Ethyl 2-bromopropionate (1.6g),
4-[N-(1,7-dichloroisoquinoline-
A mixture of 3-yl)-N-methylamino]-phenol (2.76 g), anhydrous potassium carbonate (1.19 g) and methyl ethyl ketone was heated under reflux for 3 hours. The mixture was cooled, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain an oily substance, which was purified by column chromatography using silica gel (eluent dichloromethane).
- Ethyl {4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (3.10 g) is crystallized from ethanol as a yellow oil with a melting point of 86°C. I got it as a thing. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ ; δ value (ppm): 1.3
(3H, t); 1.65 (3H, d); 3.45 (3H, s);
4.25 (2H, q); 4.75 (1H, q); 6.40 (1H,
s); 6.85-7.35 (6H, m); 8.00 (1H, s). Example 5 Substantially the same as described in Example 4 for ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (23) Following the procedure, the following compounds were prepared: a) Ethyl 2-{4-[N-(1-chloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (25), oil; b) ) Ethyl 2-{4-[N-(1-chloroisoquinolin-3-yl)amino]-phenoxy}propionate (31), oil; c) 2-{4-[N-(7-bromo-1-) chloroisoquinolin-3-yl)-N-methylamino]phenoxy}ethyl propionate (42),
Oily; d) Ethyl 2-{4-[N-(1,6-dichloroisoquinolin-3-yl)-N-methy]phenoxy}propionate (46), oily; e) 2-{4-[N- (1,7-dichloroisoquinolin-3-yl)amino]phenoxy}ethyl propionate (48), melting point 105°C; f) 2-{4-[N-(1-chloro-7-cyanoisoquinolin-3-yl) )-N-methylamino]phenoxy]ethyl propionate (52),
Melting point 134°C; g) Ethyl 2-{4-[N-(1,6,7-trichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (60),
Oily; h) Ethyl 2-{4-[N-(1-chloro-6-fluoroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (63),
Oil; i) 2-{4-[N-(1,7-dichloro-6
-fluoroisoquinolin-3-yl)-N-methylamino]phenoxy}ethyl propionate (67), oil; j) 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)amino]- 2-fluorophenoxy}ethyl propionate (68), oil; k) 2-{4-[N-(1,7-dichloro-6
-cyanoisoquinolin)-3-yl)-N-methylamino]phenoxy}ethyl propionate (69), oil; and l) 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)- Methyl N-methylamino[phenoxy]propionate (75), melting point 85
~86℃. The structure assigned to each compound was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectral data are shown in Table 4 of Example 39. Example 6 2-{4-[N-(7-chloroisoquinoline-
Ethyl 3-yl)-N-methylamino]-phenoxy}propionate (24) a) Zinc powder (0.63 g) was dissolved in a mixture of acetic acid (135 ml) and water (15 ml).
(1,7-dichloroisoquinolin-3-yl)
-N-methylamino]phenol (2.82 g) was added portionwise. After the addition was complete, the mixture was heated to reflux for 1 hour and residual zinc was removed by filtration. The solvent was removed by distillation under reduced pressure to give an oil. The oil was purified by column chromatography using silica gel (eluent dichloromethane/ethyl acetate; 90/10), and 4-[N-(7-chloroisoquinolin-3-yl)-N-methylamino ] Phenol (1.0 g) was obtained as an orange solid, melting point 140°C. b) Ethyl 2-bromopropionate (0.64g),
4-[N-7-chloroisoquinolin-3-yl)-N-methylamino]phenol (0.92
g), anhydrous potassium carbonate (0.49 g), and methyl ethyl ketone were heated under reflux for 5 hours. The solution was cooled, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography using silica gel (eluent dichloromethane) to give 2-{4-[N-(7
Ethyl-chloroisoquinolin-3-yl)-N-methylamine]phenoxy}propionate was obtained as a green oil. The structure attributed to
Confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum data (CDCl ₃ ; δ
Value (ppm): 1.25 (3H, t); 1.60 (3H, d);
3.45 (3H, s); 4.22 (2H, q); 4.75 (1H,
q); 6.52 (1H, s); 6.8-7.4 (6H, m); 7.62
(1H, m); 8.75 (1H, s). Example 7 2-{4-[N-(isoquinolin-3-yl)
-N-methylamino]-ethyl propionate (26) 2-{4-[N-(1-chloroisoquinoline-
Ethyl 3-yl)-N-methylamino]-propionate (2.87 g) was hydrogenated in a solution of potassium hydroxide (0.42 g) in ethanol at atmospheric pressure using a palladium-on-carbon catalyst. After adsorption of the theoretical amount of hydrogen, the solution was filtered, the catalyst was removed and the solvent was removed by distillation under reduced pressure. The product was purified using a column chromatography method using silica gel (eluent dichloromethane/ethyl acetate; 99/1) to obtain 2-{4-[N
-(isoquinolin-3-yl)-N-methylamino]phenoxy}ethyl propionate (0.38g)
was obtained as a green oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ ; δ value (ppm)): 1.20 (3H, t); 1.60 (3H, d); 3.45 (3H, s);
4.20 (2H, q); 4.70 (1H, q); 6.60 (1H, s);
6.8-7.4 (7H, m); 7.65 (1H, d); 8.90 (1H,
s). Example 8 2-{4-[(2-oxide-isoquinoline-
3-yl)oxy]phenoxy}ethyl propionate (27) a) 1,3-dichloroisoquinoline (26.0g;
Obtained by the method of G. Simchem, Angew.
A mixture of Chem.Internat.Ed.5(7), p.663 (1966)), acetic acid (125 ml), hydriodic acid (55 ml) and red phosphorus (9.0 g) was stirred at a temperature of 170°C for 3 hours. while heating. After cooling, the mixture was poured into ice water and the aqueous mixture was neutralized with aqueous sodium hydroxide. The aqueous mixture was extracted with dichloromethane and the organic extracts were dried over anhydrous magnesium sulfate. Evaporation of the solvent gave an oil. The oil was purified by column chromatography using silica gel (eluent: dichloromethane) to obtain 3-chloroisoquinoline (18.23 g), melting point less than 50°C. 3-chloroisoquinoline (18.23g), m-chloroperbenzoic acid 36.46g and benzene (180g)
ml) mixture was stirred at room temperature for 2.5 days. The mixture was diluted with dichloromethane and the resulting solution was then washed several times with 5% aqueous sodium bicarbonate solution and finally with water. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated to give a solid residue. The solid was recrystallized from ethyl acetate to give 3-chloroisoquinoline-2-oxide (6.53 g) as colorless crystals, melting point 147-151°C. b) 3-chloroisoquinoline-2-oxide (1.0g), 2-[4-hydroxyphenoxy]
A mixture of ethyl propionate (1.0 g), anhydrous potassium carbonate (0.91 g), copper powder (0.20 g) and dimethylformamide was heated under reflux for 7 hours with stirring. The mixture was cooled, filtered and the solvent removed by distillation under reduced pressure to give an oil. The product was purified by column chromatography using silica gel (ethyl acetate as eluent), and ethyl 2-{4-[(2-oxide-isoquinolin-3-yl)oxy]phenoxy}propionate (0.39 g) ) was obtained as a brown oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.25 (3H, t);
1.60 (3H, d); 4.20 (2H, q); 4.68 (1H,
q); 6.65-7.25 (5H, m); 7.25-7.75 (4H,
m); 8.40 (1H, s). Example 9 Ethyl 2-{4-[(7-chloro-2-oxidoisoquinolin-3-yl)oxy]phenoxy}propionate (32), solid, melting point <50°, as described in Example 8 above. was prepared from 3,7-dichloroisoquinoline following substantially the same procedure as 3,7-dichloroisoquinoline. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.27 (3H, t); 1.64
(3H, d); 4.25 (2H, q); 4.75 (1H, q); 6.70
-7.30 (5H, m); 7.30 - 7.90 (3H, m); 8.35
(1H, s). Example 10 Ethyl 2-{4-[(isoquinolin-3-yl)oxy]phenoxy}propionate (28) 2-{4-[( 2-Oxide-
isoquinolin-3-yl)oxy]phenoxy}
Added dropwise to a stirred solution of ethyl propionate (1.50 g). After the addition was complete, the solution was stirred for an additional 20 minutes and extracted with ethyl acetate. The organic phase was washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography using silica gel (eluent dichloromethane/ethyl acetate; 99/1) to obtain 2-{4-[(isoquinoline- 3-il)
Ethyl oxy]phenoxypropionate (0.80
g) was obtained as a brown oil. The assigned structure was confirmed by nuclear magnetic resonance spectroscopy and mass spectrometry. Nuclear magnetic resonance spectrum ( _CDCl3 ,
δ value (ppm): 1.22 (3H, t); 1.60 (3H, d);
4.20 (2H, q); 4.70 (1H, q); 6.7-8.0 (9H,
m); 8.93 (1H, s). Example 11 2-{4-[(1-chloroisoquinoline-3-
yl)oxy]phenoxy}ethyl propionate (29) 2-{4-[(2-oxide-isoquinoline-
A mixture of ethyl 3-yl)oxy]phenoxypropionate (1.69 g) and phosphorus oxychloride was heated to reflux for 10 minutes. The mixture was poured into aqueous ethanol and extracted with dichloromethane.
The organic phase was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography using silica gel (eluent dichloromethane),
Ethyl 2-{4-[(1-chloroisoquinolin-3-yl)oxy]phenoxy}propionate (0.65 g) was obtained as a brown oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum ( _CDCl3 , δ value (ppm)): 1.25 (3H, t); 1.60 (3H, d); 4.20
(2H, q); 4.70 (1H, q); 6.8-7.7 (8H, m);
8.0-8.3 (1H, m). Example 12 Ethyl 2-{4-[(1,7-dichloroisoquinolin-3-yl)oxy]phenoxy}propionate (37), melting point 99°C, was prepared using substantially the same procedure as described in Example 11. Therefore, it was manufactured. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum ( _CDCl3 , δ value (ppm)): 1.25 (3H, t); 1.60 (3H, d); 4.25
(2H, q); 4.75 (1H, q); 6.85 (1H, s); 7.05
(4H, m); 7.65 (2H, m); 8.15 (1H, s). Example 13 2-{4-[N-(3-chloroisoquinoline-
1-yl)amino]phenoxy}ethylpropionate (30) a) 1,3-dichloroisoquinoline (5.0g;
(see Example 8) and P-anisidine (3.1 g)
The mixture was heated at a temperature of 170°C for 2 hours.
After cooling, the product was subjected to column chromatography using silica gel (eluent dichloromethane).
3-chloro-1-[N-(4-methoxyphenyl)amino]isoquinoline (1.32
g), a melting point of 101°C was obtained. A mixture of 3-chloro-1-[N-(4-methoxyphenyl)amino]-isoquinoline (1.90 g), hydrobromic acid (10 ml of 48%) and glacial acetic acid was heated to reflux for 9.5 hours. The reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate.
The organic phase was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and 4-[N-(3
-chloroisoquinolin-1-yl)amino]phenol (1.84 g) as pale yellow crystals, melting point
Obtained at 170°C. b) Ethyl 2-bromopropionate (1.33g),
A mixture of 4-[N-(3-chloroisoquinolin-1-yl)amino]phenol (1.80 g), anhydrous potassium carbonate (1.01 g) and dimethylformamide was heated with stirring at a temperature of 100° C. for 1 hour. The mixture was cooled and poured into dichloromethane, and the resulting mixture was washed repeatedly with water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography using silica gel (eluent: dichloromethane) to obtain ethyl 2-{4-(3-chloroisoquinolin-1-yl)amino]phenoxy}propionate (1.74 g) in yellow. Obtained as an oil.
The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.20 (3H, t); 1.50
(3H, d); 4.12 (2H, q); 4.60 (1H, q);
6.60-8.20 (10H, m). Example 14 Ethyl 2-{4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (45) a) 4-fluoro stirred at -5°C A mixture of aniline (27.75 g), acetone (500 ml) and hydrobromic acid (80 ml, 48%) was treated with a solution of sodium cyanide (21.0 g) in water (50 ml) over 30 minutes. . Methyl acrylate (215g) and copper bromide (0.04g) were added.
The internal temperature was raised in a carefully controlled manner; at 15°C nitrogen evolution was intense. Once the rate of nitrogen evolution decreased, the mixture was stirred at 25° C. for 1 hour to complete the reaction. The mixture was evaporated and the residue was partitioned between water and toluene to give the crude 2-bromo-3-(4-fluorophenyl).
Methyl propionate was obtained. Crude 2-bromo-3 dissolved in acetic acid (330ml)
The methyl -(4-fluorophenyl)propionate was stirred and then treated with zinc powder (32.75 g) in portions over 30 minutes. The mixture was stirred for an additional 30 minutes, then filtered and the filter cake was washed with acetic acid. After evaporation of the filtrate, the residue was partitioned between methylene chloride and water to give crude methyl 3-(4-fluorophenyl)propionate, which was then refluxed with aqueous sodium hydroxide (400 ml, 10%) for 2 hours. Seshime,
Cooled, treated with decolorizing carbon and filtered.
The filtrate was acidified with 5NHCl and then filtered.
Wash the filter cake thoroughly with water,
3-(4-fluorophenyl)propionic acid (20.0 g) was obtained as colorless crystals with a melting point of 90°C. A mixture of 3-(4-fluorophenyl)propionic acid (20.0 g) and polyphosphoric acid (800 g) was stirred and then heated at 100° C. for 2 hours. The mixture is then poured into a mixture of ice and water,
Extracted with ethyl acetate. The organic phase was washed again with water, dilute sodium bicarbonate solution and water, then dried over magnesium sulphate and evaporated to 6-
Fluoro-1-indanone (17.0 g) was obtained as a crystalline solid with a melting point of 54°C. A solution of 6-fluoro-1-indanone (1.65 g) dissolved in a mixture of 2-methoxyethanol (25 ml) and concentrated hydrochloric acid (5.8 ml) was added with n-
Butylnitrile (1.5ml) was added with stirring. After standing for 2 hours at room temperature, the crystalline slurry was poured into ice water (140ml) and the colorless crystalline precipitate was filtered, washed with cold water and air dried. Recrystallized from an aqueous methanol solution to give 6-fluoro-2-oximino-1-indanone (1.25
g) was obtained as colorless crystals with a melting point (decomposition) of 260°C. Phosphorus pentachloride (2.20g) was mixed with methylene chloride (50g).
ml) of 6-fluoro-2-oximino-1-indanone (1.76 g) in portions to a stirred solution (nitrogen was bubbled through the solution). Nitrogen was continuously bubbled through the solution for 2 hours, then the mixture was filtered, evaporated to dryness, and acetone and water were added. The mixture was stirred at room temperature for 3 hours, concentrated and diluted with water. The colorless precipitate was collected, washed with water, and 4-fluoro-2-
Carboxyphenylacetonitrile (1.17g)
was obtained with a melting point of 140°C. A mixture of 4-fluoro-2-carboxyphenylacetonitrile (2.07 g), N-methyl-4-hydroxyaniline (2.8 g) and chlorobenzene (50 ml) was heated under reflux for 2 hours. The mixture was cooled and the crystallized product was collected by filtration and 4-[N-(7-fluoro-1-hydroxyisoquinolin-3-yl)-N-methylamino]phenol (2.08
g) was obtained at a melting point of 249°C. A mixture of 4-[N-(7-fluoro-1-hydroxyisoquinolin-3-yl)-N-methylamino]phenol (2.08 g) and phosphorus oxychloride was heated to reflux for about 10 minutes, at which point a clear solution appeared. I got it. The mixture was cooled and poured into ice-water. The precipitated solid was collected and subjected to column chromatography using silica gel (eluent dichloromethane/ethyl acetate; 90/10).
to give 4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]phenol (2.00 g) as yellow crystals, melting point
Obtained at 130°C. b) Ethyl 2-bromopropionate (1.12g),
4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]phenol (1.70g), anhydrous potassium carbonate (0.86g)
and methyl ethyl ketone (20 ml) was heated under reflux for 3 hours. The mixture was cooled, diluted with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain an oil, which was purified by column chromatography using silica gel (eluent dichloromethane) to obtain 2-{4-[N-
(1-chloro-7-fluoroisoquinoline-3
Ethyl)-N-methylamino]phenoxy}propionate (2.00 g) was obtained as a yellow oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)); 1.29 (3H,
t); 1.65 (3H, d); 3.47 (3H, s); 4.27 (2H,
q); 4.75 (1H, q); 6.47 (1H, s) 6.85-7.20
(6H, m); 7.30 (1H, d). Example 15 2-{4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]
The following compounds were prepared in substantially the same manner as described in Example 14 for the preparation of ethyl phenoxy}propionate (45): a) 2-{4-[N-(1-chloro-7-methyl) isoquinolin-3-yl)-N-methylamino]phenoxy}ethyl propionate (41),
Oily; b) Ethyl 2-{4-[N-(1-chloro-7-methoxyisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (70),
and c) methyl 2-{4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (71),
Oily. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectral data are shown in Table 4 in Example 39. Example 16 Ethyl 2-{4-[N-(7-fluoroisoquinolin-3-yl)-N-methylamino]phenoxypropionate (72) 2-{4-[N-(7-fluoroisoquinolin-3-yl)-N-methylamino]phenoxypropionate (72) Dissolved in acetic acid (50 ml) N-
(1-chloro-7-fluoroisoquinoline-3-
Zinc powder (4 x 1.63 g) was added portionwise over 2 hours to a stirred solution of ethyl)-N-methylamino]phenoxy}propionate (1.00 g). The mixture was filtered and the filter cake was washed with acetic acid. After evaporating the liquid, the residue was partitioned between methylene chloride and water. The organic phase was washed successively with sodium bicarbonate, water, aqueous ethylenediaminetetraacetic acid (5%) and water, then dried over magnesium sulphate and evaporated to give a green oil. It was purified by column chromatography using silica gel (eluent dichloromethane), and ethyl 2-{4-[N-(7-fluoroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (0.55 g) was obtained as a greenish oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectroscopy. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.28 (3H,
t); 1.64 (3H, d); 3.48 (3H, s); 4.25 (2H,
q); 4.74 (1H, q); 6.62 (1H; s); 6.87-7.37
(7H, m); 8.85 (1H, s). Example 17 2-{4-[N-(7-fluoroisoquinolin-3-yl)-N-methylamino]phenoxy}
Example 16 for the production of ethyl propionate (72)
The following compounds were obtained from the corresponding 1-chloro substituted compounds following substantially the same procedure as described in: a) 2-{4-[N-(4-chloroisoquinolin-3-yl)-N-methyl b) 2-{4-[N-(4,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}ethyl propionate (40), oily;
and c) Ethyl 2-{4-[N-(6-chloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (47), oil. The structure assigned to each compound was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectral data are shown in Table 4 in Example 39. Example 18 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionic acid (50) 2-{4-[N-(1) dissolved in ethanol ，
To the solution of ethyl 7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate was added a slight excess of ethanolic potassium hydroxide at room temperature. The mixture was stirred for 12 hours and then evaporated. The residue was diluted with water, acidified with dilute hydrochloric acid and extracted with dichloromethane.
The dichloromethane extract was dried over sodium sulfate and then evaporated to give 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionic acid as a yellow solid, melting point
Obtained at 136°C. Example 19 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionic acid acetone oxime (55) 2-{4-[N-(1,7 -dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionyl chloride dissolved in dichloromethane to produce 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)N-methylamino]phenoxy }Produced by adding phosphorus pentachloride (1.07 g) little by little to a solution of propionic acid (2.0 g) at room temperature and stirring the reaction mixture for 12 hours. A solution of acetone oxime (0.41 g) in dichloromethane was added to a solution of acid chloride in dichloromethane and the reaction mixture was then stirred at room temperature for 45 minutes. The solution was concentrated and the product was then purified by chromatography on silica gel to give 2-{4-[N-1,7-dichloroisoquinolin-3-yl)-N-methylamino].
Phenoxy}propionate acetone oxime (0.70 g) was obtained as a yellow oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.70 (3H, d); 1.90
(3H, s); 2.00 (3H, s); 3.40 (3H, s); 4.85
(1H, q); 6.33 (1H, s); 6.70-7.30 (6H,
m); 7.90 (1H, s). Example 20 For the production of 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate acetone oxime (55), substantially the same procedure as described in Example 19 was carried out. The following compounds were prepared from the appropriate acid chloride and the appropriate alcohol, thiol or amine following the same procedure. a) 2-(N,N-dimethylamino)ethyl 2
-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (51), oil; b) 2-(N,N-dimethylamino)ethyl 2
-{4-[N-(1,4,7-trichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (53), oil; c) S-n-butyl 2-{4-[N -(1,7
-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (56), oil; and d) N,N-di(n-propyl)2-{4-
[N-(1,7-dichloroisoquinoline-3-
yl)-N-methylamino]phenoxy}propionamide (58), melting point 113°C. The structure assigned to each compound was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectral data are shown in Table 4 in Example 39. Example 21 Ethyl 2-{4-[N-(1,4-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (33) Ethyl 2-bromopropionate (1.36 g), 4
-[N-(1-hydroxyisoquinolin-3-yl)-N-methylamino]phenol (2.00g),
A mixture of anhydrous potassium carbonate (1.04 g) and methyl ethyl ketone (20 ml) was heated under reflux for 3 hours. The mixture was cooled, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain an oil, which was purified by column chromatography using silica gel (eluent dichloromethane) to obtain 2-{4-[N-(1-hydroxyisoquinolin-3-yl). )-N-methylamino]phenoxy}ethyl propionate (1.92 g) was obtained as a brown solid, melting point 96°C. Ethyl 2-{4-[N-(1-hydroxyisoquinolin-3-yl)-N-methylamino]phenoxy}propionate, hydrogen peroxide (0.38g,
30%) and concentrated hydrochloric acid (0.34g) was stirred at room temperature for 90 minutes and then poured into water. The aqueous mixture was extracted with dichloromethane, then dried over magnesium sulphate and evaporated to give a brown oil. Purified by column chromatography using silica gel (eluent dichloromethane), 2-
Ethyl {4-[N-4-chloro-1-hydroxyisoquinolin-3-yl)-N-methylamino]phenoxy}propynate as a brown solid, melting point 136℃
obtained as. A mixture of ethyl 2-{4-[N-(4-chloro-1-hydroxyisoquinolin-3-yl)-N-methylamino]phenoxy}propionate and phosphorus oxychloride is heated to reflux for about 5 minutes, and this step A clear solution was obtained. The mixture was cooled and then poured into ice. This was extracted with dichloromethane, dried over magnesium sulfate, and evaporated to obtain a crude oil. The obtained oil was purified by column chromatography using silica gel (eluent dichloromethane) to obtain 2-{ 4-[N
-(1,4-dichloroisoquinolin-2-yl)
Ethyl -N-methylamino]phenoxy]propionate (0.74 g) was obtained as a yellow oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.20 (3H, t); 1.55
(3H, d); 3.40 (3H, s); 4.15 (2H, q); 4.55
(1H, q); 6.68 (4H, s); 7.10-8.20 (4H, m). Example 22 Following substantially the same procedure as described in Example 21 above, 4-[N-(7-chloro-1-hydroxyisoquinolin-3-yl)-N-methylamino]
From phenol to 2-{4-[N-(1,4,7-
Ethyl trichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (35) was obtained as an oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectroscopy. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.15 (3H, t); 1.60
(3H, d); 3.50 (3H, s); 4.20 (2H, q); 4.70
(1H, q); 6.80 (4H, m); 7.15-8.25 (3H, m). Example 23 2-{4-[N-(1-bromo-7-chloroisoquinolin-3-yl)-N-methylamino]
Phenoxy}ethyl propionate (39) 2-{4-[N-(7-chloro-1-hydroxy-isoquinolin-3-yl)-N-methylamino]phenoxy}ethyl propionate (1.00g)
and phosphorus oxybromide mixture at 120 °C for 10 min.
heated with. Cool the mixture and pour into ice water;
Extraction with dichloromethane, drying over magnesium sulphate and evaporation gave an oil. Purified by column chromatography using silica gel (eluent dichloromethane) to obtain 2-{4-[N-
Ethyl (1-bromo-7-chloroisoquinolin-3-yl)-N-methylaminophenoxy}propionate (0.83 g) was obtained as a yellow oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.25 (3H, t); 1.65
(3H, d); 3.50 (3H, s); 4.30 (2H, q); 4.80
(1H, q); 6.42 (1H, s); 7.10 (4H, m); 7.28
(2H, m); 8.00 (1H, s). Example 24 2-{4-[N-(1-bromoisoquinoline-
Ethyl 3-yl-N-methylaminophenoxypropionate (38), oil, was prepared from the previous example 23.
Following essentially the same procedure as described in 2-{4
-Produced from ethyl [N-(1-hydroxyisoquinolin-3-yl)-N-methylamino]phenoxypropionate. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.30 (3H, t); 1.65
(3H, d); 3.50 (3H, s); 4.25 (2H, q); 4.75
(1H, q); 6.45 (1H, s); 6.80-7.50 (7H,
m); 8.00 (1H, m). Example 25 Methyl 2-{4-[N-(7-chloro-1-methoxyisoquinolin-3-yl)-N-methylamino]phenoxypropionate (44) (i) 2-{4-[N A mixture of ethyl -(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.25 g), sodium methoxide (0.63 g) and toluene was heated under reflux for 4 hours. The mixture was cooled, poured into water and extracted with ethyl acetate. The organic fraction was dried (with MgSO ₄ ) and then evaporated to 2-{4-[N-(7-chloro-
1-methoxyisoquinolin-3-yl)-N-
Methylamino]phenoxy]propionic acid was obtained. (ii) The above acid was dissolved in methanol containing a few drops of concentrated sulfuric acid. The mixture was refluxed for 1 hour, cooled, concentrated, dissolved in dichloromethane, washed repeatedly with water, dried ( _MgSO4 ) and evaporated. Purified by column chromatography using silica gel (eluent dichloromethane), 2-{4-
Methyl [N-(7-chloro-1-methoxy-isoquinolin-3-yl)-N-methylamino]phenoxy}propionate (0.44 g) was obtained as a yellow oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.60 (3H, d); 3.42
(3H, s); 3.75 (3H, s); 3.97 (3H, s);
4.75 (1H, q); 6.75-7.30 (7H, m); 7.92
(1H, m). Example 26 2-{4-[N-(1-methoxyisoquinolin-3-yl)-N-methylamino]phenoxy}
Propionic acid (43), melting point 50°C, from previous example 25
was prepared following substantially the same procedure as described in part (i) of . The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.65 (3H, d); 3.42
(3H, s); 2.97 (3H, s); 4.75 (1H, q); 6.15
(1H, s); 6.80-7.50 (9H, m); 8.00 (1H, m). Example 27 Ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-ethylamino]phenoxy}propionate (49) 2-{4-[N-(1,7- Ethyl dichloroisoquinolin-3-yl)amino]phenoxy]propionate (0.36g), sodium hydride (0.05g),
g, 60%) and dimethylformamide (10 ml)
The mixture was stirred at room temperature for 15 minutes. Ethyl iodide (0.17g) was added and stirring continued for a further 15 minutes. The mixture was then poured into ethyl acetate, washed with water, dried over magnesium sulphate and evaporated. Ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-ethylamino]phenoxy}propionate was obtained as a yellow oil (0.40 g) by column chromatography using silica gel. Obtained. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.25 (6H, t); 1.60
(3H, d); 3.95 (2H, q); 4.25 (2H, q); 4.75
(1H, q); 6.20 (1H, s); 7.00-7.80 (6H,
m); 7.95 (1H, s). Example 28 2(dimethylamino)ethyl 2-{4-[N-
(1,7-dichloroisoquinolin-3-yl)
-N-methylamino]phenoxy}propionate methyl iodide salt (57) 2-{4-[N-- dissolved in dichloromethane
(1,7-dichloroisoquinolin-3-yl)-
N-methylamino[phenoxy]propionic acid 2
A solution of -(dimethylamino)ethyl was added to a large excess of methyl iodide dissolved in dichloromethane. The mixture was stirred at room temperature for 2 hours and then evaporated to give 2-(dimethylamino)ethyl 2-{4-[N
-(1,7-dichloroisoquinolin-3-yl)
-N-methylamino]phenoxy]propionate methyl iodide salt was obtained as yellow crystals with a melting point of 76°C. Example 29 2-{4-[N-(1-cyanoisoquinoline-
3-yl)-N-methylamino]phenoxy}
Ethyl propionate (59) 2-{4-[N-(1-chloroisoquinoline-
3-yl)-N-methylamino]phenoxy}ethyl propionate (1.00g), copper cyanide (5.0
A mixture of g) and dimethyl sulfoxide (10ml) was stirred at 120°C for 48 hours. The cooled mixture was dissolved in methylene chloride, washed repeatedly with water, then dried over magnesium sulphate and evaporated. 2-
Ethyl {4-[N-(1-cyanoisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (0.30 g) was obtained as a brown oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.30 (3H, t); 1.67
(3H, d); 3.50 (3H, s); 4.27 (2H, q); 4.78
(1H, q); 6.78 (1H, s); 6.90-7.40 (7H,
m); 8.02 (1H, d). Example 30 Ethyl 2-{4-[N-(7-chloro-1-cyanoisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (61) was prepared as described in Example 29 above. 2-{4 using substantially the same procedure
-[N-(1,7-dichloroisoquinoline-3-
yl)-N-methylamino]phenoxy}propionate. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.31 (3H, t); 1.67
(3H, d); 3.49 (3H, s); 4.27 (2H, q); 4.78
(1H, q); 6.73 (1H, s); 7.10 (4H, q); 7.33
(2H, s); 7.29 (1H, s). Example 31 Ethyl 2-{4-[N-(7-chloro-1-fluoroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (66) and 2-{4-[N-(7 -Chloro-1-methylthioisoquinolin-3-yl)-N-methylamino]phenoxy}ethyl propionate (65) 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methyl A mixture of ethyl amino]phenoxypropionate (0.90 g), anhydrous potassium fluoride (1.50 g) and dry dimethyl sulfoxide (10 ml) was stirred at 160°C for 48 hours.
The cooled mixture was dissolved in methylene chloride and washed repeatedly with water, then dried over magnesium sulfate and evaporated to give a crude oil. Purified by column chromatography using silica gel (eluent: methylene chloride/hexane),
Ethyl 2-{4-[N-(7-chloro-1-methylthioisoquilin-3-yl)-N-methylamino]phenoxy}propionate (0.060 g) as a yellow oil and 2-{4-[ N-(7-chloro-1-fluoroisoquinolin-3-yl)N-
Ethyl methylamino]phenoxypropionate (0.180 g) was obtained as a yellow oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum of 1-methylthio substitution product (compound number 65) (CDCl ₃ , δ value (ppm)): 1.28 (3H, t); 1.65
(3H, d); 2.59 (3H, s); 3.51 (3H, s); 4.25
(2H, q); 4.76 (1H, q); 6.23 (1H, s); 6.85
-7.35 (6H, m); 7.91 (1H, s). The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)) of 1-fluoro substitution product (compound number 66): 1.29 (3H, t); 1.65
(3H, d); 3.43 (3H, s); 4.26 (2H, q); 4.76
(1H, q); 6.30 (1H, s); 6.85-7.35 (6H,
m); 7.84 (1H, s). Example 32 2-{4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino] following substantially the same procedure as described in Example 31
From ethyl phenoxy}propionate, 2-{4
-[N-(1,7-difluoroisoquinoline-3
-yl)-N-methylamino[phenoxy]ethylpropionate (62) was produced. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.29 (3H, t); 1.65
(3H, d); 3.43 (3H, s); 4.26 (2H, q); 4.76
(1H, q); 6.37 (1H, s); 6.85-7.60 (7H, m). Example 33 2-{4-[N-(1,7-dichloroisoquilin-3-yl)-N-methylamino]phenoxy}propyl propionate (73) 2-{4-[N-(1, A mixture of ethyl 7-dichloroisoquinolin-3-yl)-N-methylaminophenoxy}propionate (1.04 g), n-propanol, and a trace amount of concentrated sulfuric acid was heated under reflux for 4 hours. The mixture was concentrated and then partitioned between dichloromethane and water. The dichloromethane phase was washed with water, dried over magnesium sulfate and evaporated to give n-propyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate. (0.72g)
was obtained as a yellow oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 0.90 (3H, t); 1.65
(5H, m); 3.40 (3H, s); 4.10 (2H, t); 4.70
(1H, q); 6.30 (1H, s); 6.70-7.40 (6H,
m); 7.90 (1H, s). Example 34 n-butyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (74) was prepared substantially as described in Example 33 above. was prepared by transesterification reaction according to the same procedure. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 0.70-1.90 (10H, m);
3.45 (3H, s); 4.20 (2H, t); 4.75 (1H, q);
6.30 (1H, s); 6.70-7.40 (6H, m); 7.90 (1H,
s). Example 35 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}ethyl acetate (77) 2-bromoethyl acetate (0.23 g), 4-[N ―
(1,7-dichloroisoquinolin-3-yl)-
A mixture of N-methylamino]phenol (0.40 g), anhydrous potassium carbonate (0.19 g) and methyl ethyl ketone was heated under reflux for 12 hours. Cool the mixture, dilute with dichloromethane, wash with water,
It was dried with anhydrous magnesium sulfate. The solvent was evaporated to obtain an oil, which was purified by column chromatography using silica gel (eluent dichloromethane) to obtain 2-{4-[N-(1,7
-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}ethyl acetate (0.52 g) was obtained as a yellow crystalline solid with a melting point of 99°C. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Example 36 Ethyl 2-methyl-2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (78) 2-bromo-2-methylpropionic acid A mixture of ethyl (0.54 g), 4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenol (0.74 g), potassium carbonate (0.38 g) and dimethylformamide was heated at 100°C. Heated for 28 hours. The mixture was cooled, diluted with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain an oil, and this oil was subjected to column chromatography using silica gel (eluent dichloromethane) to obtain 2-methyl-2-{4-[N-(1,7-dichloroisoquinoline-3). Ethyl (-yl)-N-methylamino]phenoxy}propionate (0.55 g) was obtained as a yellow oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.50 (3H, t); 1.65
(6H, s); 3.45 (3H, s); 4.30 (2H, q); 6.90
(1H, s); 7.10 (4H, q); 7.20 (2H, s); 8.00
(1H, s). Example 37 Ethyl 2-{4-[7-chloroisoquinolin-3-yl]phenoxy}propionate (34) a) 3,7-dichloroisoquinoline (5.59 g),
Sodium 4-methoxyphenoxide (4.55
g), potassium carbonate (3.86 g), copper powder (50 mg) and a trace of oxidation were heated at 180°C for 14 hours, then the mixture was cooled and extracted with ethyl acetate, which was washed with water and sulfuric acid Drying over magnesium and evaporation gave a crude brown solid. Purification was performed by column chromatography using silica gel to obtain 7-chloro-3-(4-methoxyphenoxy)isoquinoline (3.70 g) as a yellow solid with a melting point of 77°C. b) 7-chloro-3-(4-methoxyphenoxy)isoquinolone (3.50 g) in acetic acid (25 ml)
and a solution of hydrogen bromide (25 ml, 48%) at reflux for 3 hours. The mixture was cooled, poured into water, neutralized with sodium carbonate and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulphate and evaporated.
[(7-chloroisoquinolin-3-yl)oxy]phenol (3.02 g) as a brown solid, melting point
Obtained at 190°C. c) In the presence of anhydrous potassium carbonate, 4-[(7-
Chloroisoquinolin-3-yl]phenol (2.82 g) and ethyl 2-bromopropionate (2.07 g) were added to methyl ethyl ketone (50 ml).
The mixture was refluxed for 4 hours. The mixture was cooled, poured into dichloromethane, washed with water, dried over magnesium sulphate and evaporated. Purified by column chromatography using silica gel (eluent dichloromethane), 2-{4-
[(7-chloroisoquinolin-3-yl)oxy]phenoxy}ethyl propionate (3.33
g) was obtained as a brown oil. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.15 (3H, t); 1.60
(3H, d); 4.25 (2H, q); 4.75 (1H, q);
6.80-7.90 (7H, m); 8.90 (1H, s). Example 38 Following substantially the same procedure as described in Example 37 above, 3-chloro-7-fluoroisoquinoline was prepared from 2-{4-[7-fluoroisoquinoline-3
-yl)oxy]phenoxy}ethyl propionate (64) was produced. The assigned structure was confirmed by nuclear magnetic resonance and mass spectrometry. Nuclear magnetic resonance spectrum (CDCl ₃ , δ value (ppm)): 1.26 (3H, t); 1.62
(3H, d); 4.23 (2H, q); 4.74 (1H, q); 6.86
-7.45 (8H, m); 8.88 (1H, s). Example 39 Most of the compounds prepared as above in Examples 5, 15, 17 and 20 are oils, characterized by proton magnetic resonance (PMR) spectroscopy, and are also identifiable. For reference, pmr
The spectral data is listed in Table 4 below:

【table】

[Table] Example 40 Concentrate formulations of the compounds of the invention are: a) 7% v/v "Teric" N13 in the case of oils and waxy solids ["Teric" is a registered trademark; Teric' N13 is an ethoxylation product of nonylphenol and is manufactured by ICI Australia Limited.
Limited)] and 3% v/v “Kemmat” SC15B (“Kemmat”
is a registered trademark; "Kemmat" SC15B is a brand of calcium dodecylbenzenesulfonate); or b) in the case of a crystalline solid, 0.25 To 94 parts by weight of an aqueous solution containing % v/v of ``Telik'' N8 (ethoxylated product of nonylphenol) were added 5 parts by weight of the compound of the invention and ``Dyapol'' PT (``Dyapol'' is a registered trademark). Dyapol® PT is an anionic suspending agent) and ball milling the mixture to produce a stable suspension. Thereafter, by diluting the emulsifiable concentrates and suspensions with water, aqueous compositions of desired concentrations suitable for evaluating the pre- and post-emergence herbicide activity of the compounds of the invention are prepared. produced something. Example 41 The pre-emergence herbicide activity of compounds of the invention formulated as described in Example 40 was evaluated by the following procedure. Seeds of plants of the species to be tested were sown in rows in the soil 2 cm deep in seed boxes. Monocots and dicots were sown in separate boxes and after sowing the two boxes were sprayed with the required amount of the composition of the invention. Two duplicate seed boxes were prepared in a similar manner. However, these were used for comparison without being sprayed with the composition of the invention. All boxes were placed in a greenhouse and the seeds were germinated with a small amount of water by spraying from above, followed by subsurface irrigation as required for optimal plant growth. After 3 weeks, the boxes were removed from the greenhouse and the treatment effects were visually evaluated. The results are shown in Tables 5a and 5b. Chapter 5a
In the table, damage to plants was rated on a scale of 0 to 3. 0 represents 0 to 25% damage;
3 represents 75-99% dead, and 3+
indicates 100% dryness. In Table 5b, damage to the plants was rated on a scale of 0 to 5. 0
represents damage from 0 to 10%, and 1 represents damage from 11 to 30%.
2 represents 31 to 60% damage, 3 represents 61 to 80% damage, 4 represents 81 to 99% damage, and 5 represents 100% wilting. A dash (-) means that the experiment was not conducted. The names of the test plants are as follows. Wh Wheat Ot Wild Crow Wheat Rg Japanese Millet P Pea Ip Ipomea Ms Mustard Sf Sunflower

【table】

【table】

[Table] Example 42 The post-emergence herbicide activity of the compound of the present invention formulated as described in Example 40 was evaluated by the following method. Seeds of plants of the species to be tested were sown in seed boxes in rows in the soil 2 cm deep. Monocots and dicots were sown in separate seed boxes in duplicate. Four seed boxes were placed in a greenhouse and allowed to germinate by watering lightly by spraying from above, followed by sub-irrigation as required for optimal plant growth. After the plants had grown to a height of about 10 to 12.5 cm, one box each of monocots and dicots was removed from the greenhouse and sprayed with the required amount of the composition of the invention. After spraying, the boxes were returned to the greenhouse for an additional 3 weeks, and treatment efficacy was visually evaluated in comparison to an untreated control group. The results are shown in Tables 6a and 6b. In Table 6a,
Damage to plants was rated on a scale of 0 to 3.
0 represents 0-25% damage, 3 represents 75-99% damage
It means withered, and 3+ means 100% withered. In Table 6b, damage to the plants was rated on a scale of 0 to 5. 0 represents 0 to 10% damage, 1 represents 11 to 30% damage, 2 represents 31 to 60% damage, 4
represents 81 to 99% damage and 5 is 100%
Indicates that it has withered. A dash (-) means that the experiment was not performed. The names of the test plants are as follows. Wh Wheat Ot Wild Crow Wheat Rg Hoso Wheat Jm Japanese millet P Pea Ip Ipomea Ms Mustard Sf Sunflower

【table】

[Table] Example 43 Prepared by diluting 160 ml of a solution containing 21.8 g of Span 80 and 78.2 g of Tween 20 with water to 500 ml in methylcyclohexanone. A compound of the invention was formulated for testing by mixing 5 ml of the emulsion obtained with the appropriate amount of the compound of the invention. "Span" 80 is a registered trademark for surfactants containing sorbitan monolaurate. "Tween" 20 is a registered trademark for a surfactant containing a condensate of sorbitan monolaurate and ethylene oxide in a 20 molar ratio. Each 5 ml emulsion containing the test compound was then diluted to 40 ml with water and sprayed onto seedlings of bee plants of the species named in Table 7 below (post-germination test). After 14 days, damage to the test plants was rated on a scale of 0 to 5. 0 is 0 to 20
% withered, and 5 indicates 100% withered. In pre-emergence tests for herbicide activity, seeds of test plants were sown into shallow slits formed in the soil surface in fiber dishes. Afterwards, the soil surface was leveled, the formulation was sprayed on, and then a thin layer of fresh soil was sprinkled on the sprayed surface. After 21 days, herbicide damage was evaluated on a scale of 0 to 5 similar to the post-emergence test. In both tests, the degree of herbicide damage was assessed by comparison with untreated control plants. The results obtained are shown in Table 7 below. A dash (-) means that the test was not conducted. The names of the test plants are as follows. Sb Sugar beet Rp Western oil Ct Cotton Sy Soybean Mz Corn Ww Autumn wheat Rc Rice Sn Senecio vulgaris Ip Ipomea purpurea Am Amaranthus retroflexus Pi Polvgonum aviculare Ca Pigweed Chenopodium album) Po Portulaca oleracea Ga Gallium aparine Cassia obtusifolia) Av Avena fatua Dg Digitaria sanguinalis Al Alopecurus myosuroides St Setaria viridis Ec Echinochloa crus-galli Sh Sogan heilpens (Sorghum halepense) Ag Agropyron repens Ch Sorghum halepense (Cyperus rotundus)

【table】

【table】

Claims (1)

[Claims] 1. The following general formula: {In the formula, A, B, D, E, and J are hydrogen, halogen,
independently selected from the group consisting of nitro, cyano, _C1 - _C6 alkyl, _{C1 - C6} haloalkyl, C1- _C6 alkoxy, _C1 - _C2 alkylthio; U and V are independently selected from hydrogen and halogen; R ¹ and R ² are independently selected from hydrogen and C _{1 -C 6} alkyl; W _is Alkoxy, _C1 - _C10 alkylthio, N,
N-di(C ₁ -C ₆ alkyl)amino, and N,
C _{1 -} substituted with a substituent selected from the group consisting of N,N-tri(C ₁ -C ₆ alkyl)ammonio
C ₆ alkoxy group, group -NR ⁴ R ⁵ (in the formula, R ⁴ and
R ⁵ is independently selected from C ₁ to C ₆ alkyl),
and the group -O-N=R ¹⁰ , where R ¹⁰ is a C ₁ -C ₁₀ alkylidene group; and Z is halogen; X is oxygen; Y is oxygen , and the group NR ⁶ , where R ⁶ is hydrogen and C ₁ -C ₁₀ alkyl; k is selected from 0 and 1. } or a salt thereof. 2 In the above formula, A, B, D, E and J are hydrogen, halogen,
_C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1
~ _C6 alkoxy, _C1 - _C2 alkylthio, nitro and cyano groups; U and V are independently selected from hydrogen and halogen; ^R1 and ^R2 are hydrogen and _C1 - _{C6 W is} independently selected _from alkyl of _the formula
N-di(C ₁ -C ₆ alkyl)amino, and N,
C _{1 -} substituted with a substituent selected from the group consisting of N,N-tri(C ₁ -C ₆ alkyl)ammonio
C ₁₀ alkoxy group, group -NR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are independently selected from C ₁ to C ₆ alkyl),
and the group -O-N=R ¹⁰ , where R ¹⁰ is a C ₁ -C ₁₀ alkylidene group; X is oxygen; Y is oxygen and the group NR ⁶ (wherein R ⁶ is selected from hydrogen and C ₁ -C ₆ alkyl); k is selected from 0 and 1; or a salt thereof. 3 In the above formula, A, B, D, E and J are hydrogen, halogen, nitro, cyano, C1 _{- C6} alkyl and _C1 - _C6
are independently selected from the group consisting of haloalkyl; U and V are independently selected from hydrogen and halogen; R ¹ and R ² are independently selected from hydrogen and C ₁ -C ₆ alkyl; ] {wherein G is selected from hydroxy, _C1 - _C10 alkoxy, and _C1 - _C10 alkylthio}; X is oxygen; Y is oxygen and the group ^NR6 (wherein R ⁶ is hydrogen and
3. The compound according to claim ₁ or ₂ , or a salt thereof, wherein k is selected from 0 and 1. 4 In the above formula, A, B, D, and E are independently selected from hydrogen, halogen, nitro, cyano, and _C1 - _C6 alkyl; J is hydrogen, halogen, cyano, _C1 - _C6 alkyl; alkyl, selected from the group consisting of _C1 - _C6 alkoxy and _C1 - _C2 alkylthio; U and V are independently selected from hydrogen and halogen; ^R1 and ^R2 are hydrogen and _C1 - _C6 independently selected from alkyl; W is selected from the group consisting of [Formula] {wherein G is hydroxy and C ₁ -C ₁₀ alkoxy}; X is oxygen; Y is oxygen and the group NR ⁶ (wherein R ⁶ is hydrogen and
_C1 to _C6 alkyl); and k is selected from 0 and 1, or a salt thereof according to any one of claims 1 to 3. 5 In the above formula, A, E, V and ^R2 are hydrogen; B and D are independently selected from the group consisting of hydrogen, halogen, methyl and cyano; J is selected from hydrogen, halogen and cyano; U is selected from hydrogen and halogen; R ¹ is methyl; W is a group {wherein G is selected from hydroxy and C ₁ -C ₆ alkoxy}; X is oxygen; Claims 1 to 4, wherein Y is selected from oxygen and the group ^NR6 , where ^R6 is selected from hydrogen, methyl and ethyl; and k is 0. or its salt. 6 In the above formula, A, D, E, U, V and R ² are hydrogen; B and J are independently selected from hydrogen and halogen; R ¹ is methyl; W is a group [Formula] {Formula wherein G is selected from the group consisting of hydroxy and _C1 - _C6 alkoxy}; X is oxygen; Y is oxygen and the group ^NR6 (wherein ^R6 is selected from hydrogen or methyl); and k is 0, the compound or salt thereof according to any one of claims 1 to 5. 7 In the formula, A, D, E, J, U, V and R ² are B is selected from fluorine, chlorine and bromine; R ¹ is methyl; W is a group [formula] {wherein G is hydroxy, C ₁ -C ₆ alkoxy and the group OM (in the formula , M is sodium or potassium); X and Y are both oxygen; and k is 0. or a salt thereof. 8 In the above formula, A, D, E, J, U, V and R ² are hydrogen; B is selected from fluorine, chlorine and bromine; R ¹ is methyl; ; W is a group [formula] {wherein G is selected from hydroxy and C ₁ to _{C 6} alkoxy}; X is oxygen; Y is a group NR ⁶ (wherein R ⁶ is methyl); and k is 0, or a salt thereof according to any one of claims 1 to 6. 9 The following general formula: {In the formula, A, B, D, E, and J are hydrogen, halogen,
independently selected from the group consisting of nitro, cyano, _C1 - _C6 alkyl, _{C1 - C6} haloalkyl, C1- _C6 alkoxy, _C1 - _C2 alkylthio; U and V are independently selected from hydrogen and halogen; R ¹ and R ² are independently selected from hydrogen and C ₁ -C ₆ alkyl; W is [formula] and (wherein G is hydroxy, C ₁ -C ₁₀ alkoxy, _C1 - _C10 alkylthio, N,N-di( _C1 - _C6 alkyl)amino, and N,N,N-tri( _C1 - _C6 alkyl)ammonio. C ₁ -C ₆ alkoxy group substituted with a group -NHSO ₂ R ³ (in the formula,
R ³ is C ₁ -C ₁₀ alkyl), the group -NR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are independently selected from C ₁ -C ₆ alkyl), and the group -O- N=R ¹⁰ (in the formula,
R ¹⁰ is a C ₁ -C ₁₀ alkylidene group); and Z is ^a halogen ^; , and _C1 - _C10 alkyl; k is selected from 0 and 1. } A method for producing a compound represented by the following formula: (In the formula, A, B, D, E, J, U, V, X, Y and k have the meanings defined in the formula.) (In the formula, hal is chlorine, bromine or iodine,
R ¹ , R ² and W have the meanings defined in the formula)
The method, which comprises reacting with a compound represented by: