RU2038351C1 - Benzene derivatives containing heterocycle, methods of their synthesis, and herbicide agent - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: derivatives of benzene containing heterocycle of the formula (I) C₃-C₈ where R C_1-5-cycloalkyl which can be substituted with

-alkyl; Z a group of the formula (II)

or (III)

Description

Z (1) где R циклоалкильная группа, имеющая 3-8 атомов углерода;
Х атом галогена;
Z группа формулы
-N

или -N

в которой циклоалкильная группа может быть замещена алкильной группой, имеющей 1-6 атомов углерода, к процессу их получения и к гербициду, содержащему их в качестве активного ингредиента. Более конкретно, изобретение относится к N-замещенным 3,4,5,6-тетрагидрофталимидным производным и N-замещенным фенил-4,5,6,7-тетрагидро-2Н-индазоль- ным производным, характеризующимся наличием циклоалкилоксигруппы в 5-положении фенильного кольца у атома азота.The invention relates to benzene derivatives substituted with a heterocyclic ring represented by the general formula
X

Z (1) where R is a cycloalkyl group having 3-8 carbon atoms;
X is a halogen atom;
Z group of the formula
-N

or -N

in which the cycloalkyl group may be substituted by an alkyl group having 1-6 carbon atoms, to the process for their preparation and to a herbicide containing them as an active ingredient. More specifically, the invention relates to an N-substituted 3,4,5,6-tetrahydrophthalimide derivative and an N-substituted phenyl-4,5,6,7-tetrahydro-2H-indazole derivative characterized by the presence of a cycloalkyloxy group at the 5-position of the phenyl rings at the nitrogen atom.

 So far, as derivatives of N-substituted phenyl-3,4,5,6-tetrahydrophthalimide having herbicidal activity, for example, N- (2-fluoro-4-chloro-5-isopropoxyphenyl) -3,4, 5,6-tetrahydrophthalimide (Japan Patent No. 63-20428) or N-2-fluoro-4-chloro-5-alkyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (Japan Patent No. 58-72563), but were not Compounds having a cycloalkyloxy group at the 5-position of the phenyl ring at a nitrogen atom are known.

 Japanese patent applications (Cocai) NN 63-68562, 63-68563 and 63-280060 disclose, for example, compounds that differ from the compounds of the present invention in that they have a methyl group in the tetrahydrophthalimido moiety and in which the phenyl ring at the nitrogen atom is substituted 2,4-dagaloid-5-cycloalkoxy group, but detailed examples of the preparation and testing of their activity are not known.

 Japanese Patent Application (Cocai) N 55-139359 discloses compounds that differ from the compounds of the present invention in that the substituent at the 2-position of the phenyl ring is a chlorine atom.

 Derivatives of tetrahydrophthalimide known in the art exhibit herbicidal activity, but these compounds are not considered sufficient for use as active ingredients used in the practice of herbicidal agents.

 Turning to a 2N-substituted phenyl-4,5,6,7-tetrahydro-2H-indazole derivative, for example, it is known that 2N- (2-fluoro-4-chloro-5-isopropoxyphenyl) -4,5,6,7 -tetrahydro-2H-indazole (Japanese patent application Kokai N 59-59666) or 2N- (2,4-dichloro-5-methoxyphenyl) -4,5,6,7-terahydro-2H-indazole (Japanese patent application Coca N 52-51365) have herbicidal activity. However, these compounds are not considered sufficient for use as an active ingredient in practical herbicidal agents.

 In a recent search and study of new agricultural agents, new types of agricultural agents have been developed that can replace conventional agricultural agents that require high doses in processing to avoid environmental pollution and environmental damage. For this purpose, it is important to research and study new compounds that exhibit superior effects in low doses. In addition, an important problem is the search for new compounds that exhibit selective herbicidal activity only against weeds and exhibit excellent performance with significantly reduced harmful effects on important crops.

Z (1) где R циклоалкильная группа, имеющая 3-8 атомов углерода;
Х атом галогена;
Z группа
-N

или -N

в которых циклоалкильная группа может быть замещена алкильной группой, имеющей 1-6 атомов углерода, обладают высоким гербицидным эффектом в отношении сорняков при обработке при низкой дозе и оказывают заметно уменьшенное вредное действие на основные культуры.The proposed derivatives of benzene substituted by a heterocyclic ring and represented by the formula
X

Z (1) where R is a cycloalkyl group having 3-8 carbon atoms;
X is a halogen atom;
Z group
-N

or -N

in which the cycloalkyl group can be replaced by an alkyl group having 1-6 carbon atoms, have a high herbicidal effect on weeds when processed at a low dose, and have a markedly reduced harmful effect on the main crops.

 The compounds of the present invention have excellent herbicidal activity when used in low doses against a variety of harmful weeds, for example broad-leaved weeds, such as common white gauze, slightly stalked amaranth, limnocharis, medium asterisk, etc., and grassy weeds, such as blackberries and green bristles, etc. when applied on foliage and soil in the field and do not reveal any herbicidal damage that would cause problems associated with the main crops, for example, wide olistnymi crops such as soybeans, cotton, et al. and grassy crops such as maize and others.

 The compounds of the present invention also exhibit excellent activity against various destructive weeds in rice fields, for example herbaceous species such as creeping polemouth and other broadleaf weeds, such as the common false full-time color, Indian rotala, marmoset or insect weed and other sedge weeds, such like Japanese reed, lake, needle swamp, etc., and Sigitarria pygmaea Mig, etc. when used in low doses, and the damage caused by the herbicide to transplanted rice is very slight. The high selectivity of the compounds of the present invention with respect to rice plants is completely unpredictable given the conventional tetrahydrophthalimide derivatives and tetrahydroindazole derivatives. This characteristic is obviously a consequence of the cycloalkoxy group introduced at the 5-position of the phenyl ring.

 The following describes methods for producing compounds of the present invention and intermediates for them.

NH₂ (2) где R циклоалкильная группа, имеющая 3-8 атомов углерода;
Х атом галогена, в которой циклоалкильная группа может замещаться алкильной группой, имеющей 1-6 атомов углерода, с 3,4,5,6-тетрагидрофталевым ангидридом в инертном растворителе. В качестве инертных растворителей могут использоваться такие растворители, как бензол, толуол, ксилол, хлорбензол, уксусная кислота и др. или смешанные растворители из указанных. Температура реакции выбирается из интервала между комнатной температурой и 150^оС, реакция предпочтительно осуществляется при 50-120^оС. После реакции требуемое соединение может легко выделяться с помощью приемов обработки в чистом виде и с помощью перекристаллизации из растворителя спиртового типа, такого как метанол и др.The N-substituted phenyl-3,4,5,6-tetrahydrophthalimide derivatives of the present invention can be easily obtained by reacting an aniline derivative represented by the formula
X

NH ₂ (2) where R is a cycloalkyl group having 3-8 carbon atoms;
X is a halogen atom in which the cycloalkyl group can be replaced by an alkyl group having 1-6 carbon atoms, with 3,4,5,6-tetrahydrophthalic anhydride in an inert solvent. As inert solvents, solvents such as benzene, toluene, xylene, chlorobenzene, acetic acid, etc., or mixed solvents of these can be used. The reaction temperature is selected from the range between room temperature and 150 ^{° C,} the reaction is preferably carried out at 50-120 ° ^C. After the reaction, the desired compound can be easily isolated using processing techniques and in pure form by recrystallisation from an alcohol type solvent such as methanol and other

 The aniline derivative represented by the general formula (2), which is an intermediate product, can be obtained, for example, using the following alternative synthetic methods.

NH

______→
X

N

R²

OR² ______→

N

где R и Х указаны выше;
R¹ алкильная группа, имеющая 1-6 атомов углерода;
R²- алкильная группа с 1-6 атомами углерода, алкильная группа с 3-4 атомами углерода или аралкильная группа, имеющая 7-8 атомов углерода;
Y атом хлора, брома или иода, метилсульфонилоксигруппа или n-толилсульфонилоксигруппа.Synthesis Method I

NH

______ →
X

N

R ²

OR ² ______ →

N

where R and X are indicated above;
R ^{1 is an} alkyl group having 1-6 carbon atoms;
R ² is an alkyl group with 1-6 carbon atoms, an alkyl group with 3-4 carbon atoms or an aralkyl group having 7-8 carbon atoms;
Y is a chlorine, bromine or iodine atom, a methylsulfonyloxy group or an n-tolylsulfonyloxy group.

N

где R, X и Y значения, указанные выше.Synthesis Method II

N

where R, X and Y are the values indicated above.

More specifically, according to the synthesis method I, the aniline derivative (3) is reacted with a chloroformate ester in the presence of a base such as potassium carbonate, sodium carbonate, magnesium oxide and others in a solvent such as acetonitrile, acetone, N, N-dimethylformamide, etc. with its conversion into a carbamate derivative (4). The carbamate derivative (4) is then converted to the phenolic derivative (5) by selective hydrolysis of the carbonate group by treatment in a flowing solvent in the presence of a base such as sodium hydroxide or potassium hydroxide. The resulting phenolic derivative (5) is reacted with a compound represented by the general formula RY (6) in the presence of a base such as potassium carbonate, sodium carbonate, magnesium oxide, etc. whereby the cycloalkyloxy group can be introduced at the 5-position of the phenyl ring . The reaction is preferably carried out in an appropriate solvent, in addition, a solvent such as acetonitrile, acetone, methanol, ethanol, N, N-dimethylformamide, etc. can be used. The caryamate derivative (7) thus obtained can be converted to the aniline derivative represented by the general formula ( 2) by the reaction in an aqueous solution of sodium hydroxide by hydrolysis of a carbamate ester, or in the case where R ² in the general formula (7) represents, for example, a benzyl group by hydrogenolysis using catalytic The reaction with palladium on carbon.

 Aniline derivatives represented by the general formula (3), which are starting materials, are described in Japanese Patent Application (Cocai) N 62-174065 and can be obtained using the process shown in the examples described below. The compounds represented by formula (6) are industrially available or can be easily obtained from industrially available compounds.

 According to synthesis method II, the nitrophenol derivative (8) described in Japanese Patent Publication No. 1-61099 is converted to the nitrobenzene derivative represented by the general formula (9) by reacting it with a compound represented by the formula RY (6) in the presence of a base such such as potassium carbonate, sodium carbonate, magnesium oxide, potassium hydroxide, sodium hydride, sodium methylate, etc. and then the resulting nitrobenzene derivative can be converted to the aniline derivative (2) using the procedure usually used to reduce the formation of an aromatic nitro compound into an amino group, for example, a process using sodium sulfite, reducing iron, zinc powder, or a catalytic reduction process using platinum oxide or palladium on carbon.

N

(10) где Х имеет те же значения, с соединением, представленным формулой (6). Реакция предпочтительно проводится в растворителе, таком как ацетонитрил, N,N-диметилформамид, ацетон, метанол и др. в присутствии основания, такого как карбонат калия, карбонат натрия, окись магния, метилат натрия и др.The N-substituted phenyl-3,4,5,6-tetrahydrophthalimide derivative of the present invention can be prepared by the reaction of a phenolic derivative represented by the general formula
X

N

(10) where X has the same meanings, with the compound represented by formula (6). The reaction is preferably carried out in a solvent such as acetonitrile, N, N-dimethylformamide, acetone, methanol and others in the presence of a base such as potassium carbonate, sodium carbonate, magnesium oxide, sodium methylate, etc.

 Phenolic derivatives of the general formula (10) as starting materials for this reaction are described in Japanese Patent Application (Cocai) N 58-83672 and can be obtained by the synthesis method III.

+ O

______→

N

_____→ X

N

где Х и R¹ имеют значения, определенные выше.Synthesis Method III

+ O

______ →

N

_____ → X

N

where X and R ¹ have the meanings given above.

More specifically, the aniline derivative represented by formula (3) is reacted with 3,4,5,6-tetrahydrophthalic anhydride in an inert solvent such as benzene, toluene, acetic acid, etc. to convert it to a tetrahydrophthalimide derivative (11 ), and then the carbonate group at the 5-position of the phenyl ring selectively hydrolyzes it in the presence of a base, with the help of which the phenolic derivative represented by the general formula (10) can be obtained. Examples of bases which may be used include potassium carbonate, potassium hydroxide, sodium hydroxide, etc., And the reaction is preferably carried out in a protic solvent such as methanol, ethanol, water and others. At a temperature from ambient to about 100 ^{° C} for reasons of quality indicators product release.

 2N-substituted derivatives of phenyl-4,5,6,7-tetrahydro-2H-indazole of the present invention can be obtained, for example, according to the synthesis method.

где R и Х имеют значения, указанные выше;
Y атом хлора, атом брома, иода, метилсульфонилоксигруппа или n-толуолсульфонилоксигруппа.Synthesis Method IV
X

where R and X have the meanings indicated above;
Y is a chlorine atom, a bromine atom, iodine, a methylsulfonyloxy group or an n-toluenesulfonyloxy group.

More specifically, the indazole derivative of the present invention can be obtained by chlorinating an indazolinone derivative represented by the general formula (12) using a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, etc. The reaction can be carried out in an organic solvent, but preferably it is carried out without solvent for good exits. The reaction temperature is selected in the range of 100-200 ^about C. In addition, the indazole derivative of the present invention can be obtained using the interaction of 3-chloro-2N- (2-fluoro-4-halogen-5-hydroxyphenyl) -4,5,6, 7 tetragid- ro-2H-indazole represented by the general formula (13), with a compound represented by the general formula (6) in an appropriate solvent in the presence of a base at a temperature from room temperature to under heating, preferably at 30-100 ° ^C. The solvent was which can be used includes a solvent such as acetonitrile, aceto n, tetrahydrofuran, dioxane, dimethyl sulfoxide, N, N-dimethylformamide, methanol, etc. and mixed solvents of the above. Potassium carbonate, sodium carbonate, magnesium oxide, sodium methylate, sodium ethylate, sodium hydride, etc. can be used as a base.

 The indazole derivative represented by the general formula (13) as starting material is known from Japanese Patent Application (Cocai) N 59-170071 and Japanese Application N 62-30761.

 The indazolone derivative represented by the general formula (12) can be obtained according to the synthesis method V.

NH₂

X

N

где Х, R и Y имеют те же значения, что определены выше;
R³ алкильная группа, имеющая 1-6 атомов углерода.Synthesis Method V
X

NH ₂

X

N

where X, R and Y have the same meanings as defined above;
R ^{3 is an} alkyl group having 1-6 carbon atoms.

 The aniline derivative (2), which can be obtained using the process shown in the scheme of the synthesis method I or II, is reacted with sodium nitrite under acidic conditions using hydrochloric acid, sulfuric or borofluoric acid to obtain the diazonium salt, then reducing the diazonium salt with a reducing an agent, such as tin chloride, to turn it into a hydrazine derivative (14). In the described reaction, acetone, acetonitrile, etc., which are used in the preparation of diazonium salts, can be used without any problems.

 The resulting hydrazine derivative (14) can be converted to 2N-substituted phenyl-1,2,4,5,6,7-hexahydro-3H-indazol-3-one (12) by subjecting it to a cyclization-condensation reaction with 2 -alkoxycarbonylcyclohexanone represented by the formula (15). The reaction is preferably carried out in an organic solvent such as benzene, toluene, xylene, chlorobenzene, acetic acid, etc. The reaction temperature is preferably higher than the azeotropic temperature of the solvent and water used due to the good reaction efficiency, and the reaction is preferably carried out using a water removal device, such as the Dean-Stark apparatus. The reaction proceeds sufficiently without the use of a catalyst, but preferably it is carried out in the presence of a basic compound such as triethylamine, pyridine, etc. since the reaction can be effectively promoted.

 Examples of compounds (1) of the present invention include the compounds shown below.

(1) Соединение Х R Соединения, где Z -N

1 F Циклопропильная группа
2 F Циклопентильная группа
3 F 2-Метилциклопентильная
4 F 3-Метилциклопентильная
5 F Циклогексильная группа
6 F 2-Метилциклогексильная
7 F Циклогептильная группа
8 F Циклооктильная группа
9 Cl Циклопропильная группа
10 Cl Циклопентильная группа
11 Cl 2-Метилциклопентильная
12 Cl 3-Метилциклопентильная
13 Cl Циклогексильная группа
14 Cl 2-Метилциклогексильная
15 Cl Циклогептильная группа
16 Cl Циклооктильная группа
17 Br Циклопропильная группа
18 Br Циклопентильная группа
19 Br 2-Метилциклопентильная группа
20 Br 3-Метилциклопентильная группа
21 Br Циклогексильная группа
22 Br 2-Метилциклогексильная группа
23 Br Циклогептильная группа
24 Br Циклооктильная группа
Соединения, где Z -N

25 Сl Циклопропильная группа
26 Cl Циклопентильная группа
27 Cl 2-Метилциклопентильная группа
28 Cl 3-Метилциклопентильная группа
29 Cl Циклогексильная группа
30 Сl 2-Метилциклогексильная группа
31 Cl Циклогептильная группа
32 Cl Циклооктильная группа
33 Cl 2-Метилциклооктильная группа
34 F Циклопропильная группа
35 F Циклопентильная группа
36 F 2-Метилциклопентильная группа
37 F 3-Метилциклопентильная группа
38 F Циклогексильная группа
39 F 2-Метилциклогексильная группа
40 F Циклогептильная группа
41 F Циклооктильная группа
42 F 2-Метилциклооктильная группа
43 Br Циклопропильная группа
44 Br Циклопентильная группа
45 Br 2-Метилциклопентильная группа
46 Br 3-Метилциклопентильная группа
47 Br Циклогексильная группа
48 Br 2-Метилциклогексильная группа
49 Br Циклогептильная группа
50 Br Циклооктильная группа
51 Br 2-Метилциклооктильная группа
Соединения настоящего изобретения обладают отличительными эксплуатационными характеристиками в качестве гербицидного агента.

(1) Compound X R Compounds where Z —N

1 F Cyclopropyl group
2 F Cyclopentyl group
3 F 2-Methylcyclopentyl
4 F 3-Methylcyclopentyl
5 F Cyclohexyl group
6 F 2-Methylcyclohexyl
7 F Cycloheptyl group
8 F Cyclooctyl group
9 Cl Cyclopropyl group
10 Cl Cyclopentyl group
11 Cl 2-Methylcyclopentyl
12 Cl 3-Methylcyclopentyl
13 Cl cyclohexyl group
14 Cl 2-Methylcyclohexyl
15 Cl Cycloheptyl group
16 Cl Cyclooctyl group
17 Br Cyclopropyl group
18 Br Cyclopentyl group
19 Br 2-Methylcyclopentyl group
20 Br 3-Methylcyclopentyl group
21 Br Cyclohexyl group
22 Br 2-Methylcyclohexyl group
23 Br Cycloheptyl group
24 Br Cyclooctyl group
Compounds where Z is N

25 Cl Cyclopropyl group
26 Cl Cyclopentyl group
27 Cl 2-Methylcyclopentyl group
28 Cl 3-Methylcyclopentyl group
29 Cl Cyclohexyl Group
30 Cl 2-Methylcyclohexyl group
31 Cl Cycloheptyl group
32 Cl Cyclooctyl group
33 Cl 2-Methylcyclooctyl group
34 F Cyclopropyl group
35 F Cyclopentyl group
36 F 2-Methylcyclopentyl group
37 F 3-Methylcyclopentyl group
38 F Cyclohexyl group
39 F 2-Methylcyclohexyl group
40 F Cycloheptyl group
41 F Cyclooctyl group
42 F 2-Methylcyclooctyl group
43 Br Cyclopropyl group
44 Br Cyclopentyl group
45 Br 2-Methylcyclopentyl group
46 Br 3-Methylcyclopentyl group
47 Br Cyclohexyl group
48 Br 2-Methylcyclohexyl group
49 Br Cycloheptyl group
50 Br Cyclooctyl group
51 Br 2-Methylcyclooctyl group
The compounds of the present invention have distinctive performance as a herbicidal agent.

 When using the compounds of the present invention as a herbicidal agent, the compounds can be used on their own, but they can usually be used as a herbicidal agent in admixture with one or more auxiliary agents. Typically, the compounds can preferably be used in the form of preparations, for example, wettable powders, emulsifiable agents, powders, granules, flowable preparations, etc. in a known manner by converting the compounds into finished formulations with various carriers, diluents, solvents, surfactants, stabilizers and others as auxiliary agents.

 Solvents as one of the auxiliary agents in the herbicidal composition comprising a compound of the present invention as an active ingredient include, for example, water, alcohols, ketones, ethers, aliphatic and aromatic hydrocarbons, halogenated hydrocarbons, acid amides, esters, nitriles. The solvent may be used alone or in a mixture of two or more solvents.

 Diluents that can be used include mineral powders, for example clays, such as kaolin and bentonite, talc, such as talc or pyrophyllite, oxides, such as diatomaceous earth and white soot, and vegetable powders, such as soy flour and SMS. In addition, the surfactant can be used as a distribution agent, dispersing agent, emulsifying agent and penetration promoting agent. Surfactants include, for example, nonionic surfactants, cationic and amphoteric surfactants. These surfactants can be used singly or as a mixture of two or more agents, depending on utility.

 A preferred method of using a herbicidal agent containing a compound of the present invention as an active ingredient includes soil treatment, water-surface treatment and foliage application and the like. A particularly excellent effect can be obtained by application before germination or at the stage of germination of the weeds to be destroyed.

 A herbicidal preparation comprising a compound of the present invention as an active ingredient can be used in a mixture or in combination with other active ingredients that do not adversely affect the herbicidal activity of the active ingredients of the present invention, for example, other herbicidal agents, insecticides, antimicrobial agents, growth regulators plants and others

 The invention is illustrated using the following examples.

 PRI me R 1.

C

NH₂ + O

C

N

Раствор 2-фтор-4-хлор-5-циклопентилоксианилина (0,50 г, 2,18 ммоль) и 3,4,5,6-тетрагидрофталевого ангидрида (0,398 г, 2,61 ммоль) в уксусной кислоте (3,0 мл) перемешивался в течение 3 ч в условиях дефлегмации. Добавляли воду (20 мл) к получающейся реакционной смеси и смесь экстрагировали этилацетатом (20 мл х 3 раза). Органический слой сушили, а растворитель отгоняли при пониженном давлении. Получающееся в результате желтое маслянистое вещество очищалось с помощью хроматографии на силикагельной колонке (проявляющий растворитель: гексан/этил ацетат 8/1) с получением N-(2-фтор-4-хлор-5-циклопентилоксифенил)-3,4,5,6-тет- рагидрофталимида в виде бесцветного прозрачного маслянистого вещества (0,513 г, 1,41 ммоль, 65% выход). К нему добавлялся этанол (1,0 л) для перекристаллизации с получением продукта в виде белого твердого вещества. Т.пл. 69,0-75,2^оС.

C

NH ₂ + O

C

N

A solution of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (0.50 g, 2.18 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (0.398 g, 2.61 mmol) in acetic acid (3.0 ml) was stirred for 3 hours under reflux. Water (20 ml) was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic layer was dried, and the solvent was distilled off under reduced pressure. The resulting yellow oily substance was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate 8/1) to obtain N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6 Tetrahydrophthalimide as a colorless transparent oily substance (0.513 g, 1.41 mmol, 65% yield). Ethanol (1.0 L) was added thereto to recrystallize to give the product as a white solid. Mp 69.0-75.2 ^about C.

¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.30-2.10 (12H, m), 2.40 (4H, m), 4.68 (1H, m), 6.75 (1H, d, I _HF 7.0 Hz), 7.20 (1H, d. I _HF 9.0 Hz), IR spectrum (KBr disk, cm ^-1 ): 1725, 1505, 1430, 1385, 1200.

 PRI me R 2.

N

+

_ Br

C

N

Циклопентилбромид (1,2 г, 8,1 ммоль) добавляли к раствору N-(2-фтор-4-хлор-5-гидроксифенил)-3,4,5,6-тетрагидрофталими- да (2,0 г, 6,76 ммоль) и карбоната калия (0,60 г, 4,34 ммоль) в ацетонитриле (50 мл) с последующим перемешиванием в течение 2 ч при температуре дефлегмации. После завершения реакции к полученной в результате смеси добавляли 1 н. соляную кислоту (20 мл) и смесь экстрагировали этилацетатом (20 мл х 3 раза). Органический слой промывали водой, сушили над безводным сульфатом магния и растворитель отгоняли при пониженном давлении. К полученному в результате реакции бледно-желтому маслянистому веществу добавляли этанол (5 мл). Выпавший в осадок N-(2-фтор-4-хлор-5-циклопентилоксифенил)-3,4,5,6-тетрагидрофталимид в виде белого твердого вещества (0,75 г, 2,06 ммоль, 30,5% выход) отделяли фильтрованием. Данные спектрального анализа и другие данные являются такими, как показаны в примере 1.Cl

N

+

_ Br

C

N

Cyclopentyl bromide (1.2 g, 8.1 mmol) was added to a solution of N- (2-fluoro-4-chloro-5-hydroxyphenyl) -3,4,5,6-tetrahydrophthalimide (2.0 g, 6, 76 mmol) and potassium carbonate (0.60 g, 4.34 mmol) in acetonitrile (50 ml), followed by stirring for 2 hours at reflux temperature. After completion of the reaction, 1N was added to the resulting mixture. hydrochloric acid (20 ml) and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (5 ml) was added to the resulting pale yellow oily substance. Precipitated N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide as a white solid (0.75 g, 2.06 mmol, 30.5% yield) separated by filtration. Spectral analysis data and other data are as shown in example 1.

 PRI me R 3.

N

+

_ OTs

C

N

К раствору N-(2-фтор-4-хлор-5-гидроксифенил)-3,4,5,6-тетрагидрофталимида (2,0 г, 6,76 ммоль) и карбоната калия (0,60 г, 4,34 ммоль) в ацетонитриле (50 мл) добавляли циклопентил п-толуолсульфонат (1,90 г, 8,11 ммоль) с последующим перемешиванием в течение 2 ч при 80^оС. По завершении реакции к полученной в результате смеси добавляли 1 н. соляную кислоту (20 мл) и смесь экстрагировали этилацетатом (20 мл х 3 раза). Органический слой промывали водой, сушили над безводным сульфатом магния и растворитель отгоняли при пониженном давлении. К полученному бледно-желтому маслянистому веществу добавляли этанол (5 мл) и выпавший в осадок N-(2-фтор-4-хлор-5-циклопентилоксифенил)-3,4,5,6-тетрагидрофталимид в виде белого твердого вещества (0,77 г, 2,12 ммоль, 31,4% выход) отделяли фильтрованием. Данные спектрального анализа и другие данные являются такими, как описаны в примере 1.Cl

N

+

_ OTs

C

N

To a solution of N- (2-fluoro-4-chloro-5-hydroxyphenyl) -3,4,5,6-tetrahydrophthalimide (2.0 g, 6.76 mmol) and potassium carbonate (0.60 g, 4.34 mmol) in acetonitrile (50 mL) was added cyclopentyl p-toluenesulfonate (1.90 g, 8.11 mmol) followed by stirring for 2 hours at 80 ° ^C. Upon completion of the reaction, the resulting mixture was added 1N. hydrochloric acid (20 ml) and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (5 ml) and N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide precipitated as a white solid were added to the resulting pale yellow oily substance (0, 77 g, 2.12 mmol, 31.4% yield) were separated by filtration. Spectral analysis data and other data are as described in example 1.

 PRI me R 4.

Раствор 2-фтор-4-хлор-5-(3-метилциклопентил)оксианилина (1,76 г, 7,22 ммоль) и 3,4,5,6-тетрагидрофталевого ангидрида (1,32 г, 8,68 ммоль) в уксусной кислоте (15 мл) перемешивался в течение 4 ч при пониженном давлении. Полученная в результате реакции смесь добавлялась к 1 н.соляной кислоте (50 мл) и экстрагировалась эфиром (3 порциями по 50 мл). Органический слой сушили, растворитель отгоняли и полученное в результате красно-коричневое маслянистое вещество очищали с помощью хроматографии на силикагельной колонке (проявляющий растворитель: гексан/этилацетат8/1). Полученный в результате N-(2-фтор-4-хлор-5)3-метилциклопентил (оксифенил)-3,4,5,6-тетрагидрофталимид в виде бесцветного прозрачного маслянистого вещества перекристаллизовывался из метанола, давая белое твердое вещество (0,93 г, 2,38 ммоль, 33,0% выход).Me

A solution of 2-fluoro-4-chloro-5- (3-methylcyclopentyl) hydroxyaniline (1.76 g, 7.22 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (1.32 g, 8.68 mmol) in acetic acid (15 ml) was stirred for 4 hours under reduced pressure. The resulting mixture was added to 1 N hydrochloric acid (50 ml) and extracted with ether (3 portions of 50 ml). The organic layer was dried, the solvent was distilled off, and the resulting red-brown oily substance was purified by chromatography on a silica gel column (developing solvent: hexane / ethyl acetate 8/1). The resulting N- (2-fluoro-4-chloro-5) 3-methylcyclopentyl (hydroxyphenyl) -3,4,5,6-tetrahydrophthalimide as a colorless transparent oily substance was recrystallized from methanol to give a white solid (0.93 g, 2.38 mmol, 33.0% yield).

Mp 68.0-70.0 ^about S.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.01 and 1.08 (total 3H, each d.I 6.0 Hz), 1.25-2.20 (11H, m), 2.49 (4H, m), 4.70 (1H, m), 6.72 (1H, d. I _HF 6.0 Hz), 7.20 (1H, d. I _HF 9 , 0 Hz).

IR spectrum (KBr disk, cm ^-1 ): 1720, 1500, 1430, 1375, 1195.

 PRI me R 5.

2-Фтор-4-хлор-5-(2-метилциклопентил) оксианилин (660 мг, 2,71 ммоль), 3,4,5,6-тетрагидрофталевый ангидрид (503 мг, 3,31 ммоль) и уксусная кислота (10 мл) загружали в круглодонную колбу (50 мл), нагревали в течение 5 ч при температуре дефлегмации. По завершении реакции реакционный раствор охлаждали до комнатной температуры и выливали в ледяную воду (100 мл). Смесь экстрагировали этилацетатом (30 мл х 3), органические слои объединяли, промывали водой и насыщенным водным раствором хлористого натрия и сушили над безводным сульфатом магния.

2-Fluoro-4-chloro-5- (2-methylcyclopentyl) hydroxyaniline (660 mg, 2.71 mmol), 3,4,5,6-tetrahydrophthalic anhydride (503 mg, 3.31 mmol) and acetic acid (10 ml) was loaded into a round bottom flask (50 ml), heated for 5 h at reflux temperature. Upon completion of the reaction, the reaction solution was cooled to room temperature and poured into ice water (100 ml). The mixture was extracted with ethyl acetate (30 ml x 3), the organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate.

 The dried agent was separated by filtration, the solvent was distilled off under reduced pressure, the resulting pale brown oily substance was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate 9/1), and N- (2-fluoro-4-chloro- 5-) 2-methylcyclopentyl (hydroxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00 g, 2.65 mmol, 98% yield).

 Colorless transparent oily substance.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): 1.13 (3H, d. I 7.0 Hz), 1.40-2.15 (10H, m), 2.25 -2.50 (4H, m.), 4.25 (1H, m.), 4.52 (1H, m.), 6.72 (1H, d. I _HF 7.3 Hz), 7.30 (1H, d. I _HF 10.2 Hz).

IR (neat, cm ^-1 ): 2970, 1725, 1500, 1425, 1375, 1195.

 PRI me R 6.

NH₂+ O

N

2-Фтор-4-хлор-5-циклогексилоксиани- лин (213 мг, 0,874 ммоль), 3,4,5,6-тетрагидрофталевый ангидрид (134 мл, 0,874 ммоль) и уксусная кислота (10 мл) загружали в круглодонную колбу (50 мл) и нагревали при температуре дефлегмации в течение 15 ч. После завершения реакции реакционный раствор охлаждался до комнатной температуры, к нему добавляли воду (50 мл) и смесь экстрагировали этилацетатом (20 мл х 3). Органические слои объединяли, промывали водой и насыщенным водным раствором хлористого натрия и сушили над безводным сульфатом магния. Осушающий агент отделяли фильтрованием и растворитель отгоняли при пониженном давлении с получением неочищенного продукта (332 мг). Продукт очищали хроматографией на силикагельной колонке (проявляющий растворитель: гексан/этилацетат 19/1), в результате N-(2-фтор- 4-хлор-5-циклогексилоксифенил)-3,4,5,6-тетра- гидрофталимид в виде белого твердого вещества (230 мг, 0,609 ммоль, 70% выход). Путем перекристаллизации из смеси гексан/хлороформ продукт выделяли в виде бесцветных игольчатых кристаллов. Т.пл. 102-103^оС.

NH ₂ + O

N

2-Fluoro-4-chloro-5-cyclohexyloxyaniline (213 mg, 0.874 mmol), 3,4,5,6-tetrahydrophthalic anhydride (134 ml, 0.874 mmol) and acetic acid (10 ml) were charged into a round bottom flask ( 50 ml) and heated at reflux for 15 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water (50 ml) was added to it, and the mixture was extracted with ethyl acetate (20 ml x 3). The organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the solvent was distilled off under reduced pressure to obtain a crude product (332 mg). The product was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate 19/1), resulting in N- (2-fluoro-4-chloro-5-cyclohexyloxyphenyl) -3,4,5,6-tetrahydrophthalimide as white solid (230 mg, 0.609 mmol, 70% yield). By recrystallization from hexane / chloroform, the product was isolated as colorless needle crystals. Mp 102-103 ^about S.

¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.20-2.50 (4H, m), 4.18 (1H, m), 6.79 (1H, d . I _HF 7.3 Hz), 7.23 (1H, d. I _HF 10.2 Hz).

IR spectrum (KBr disk, cm ^-1 ): 2950, 1715, 1495, 1425, 1375, 1190.

 PRI me R 7.

C

N

2-Фтор-4-хлор-5-циклопентилоксифе-нилгидразин (24,5 г, 0,10 моль), 2-этоксикарбонилциклогексанон (17,0 г, 0,10 моль) растворяли в уксусной кислоте (200 мл) и перемешивали в течение 2 ч при температуре дефлегмации. По завершении реакции растворитель отгоняли, при этом получали неочищенный продукт (37 г). Продукт промывали смешанным растворителем бензол/гексан, при этом получали 2N-(2-фтор-4-хлор-5-циклопентилоксифе- нил)-1,2,4,5,6,7-гексагидро-3Н-индазол-3-он в виде белого твердого вещества (25,3 г, 72,3% выход). Т.пл. 151-152^оС.

C

N

2-Fluoro-4-chloro-5-cyclopentyloxyphenylhydrazine (24.5 g, 0.10 mol), 2-ethoxycarbonylcyclohexanone (17.0 g, 0.10 mol) was dissolved in acetic acid (200 ml) and stirred in for 2 hours at reflux temperature. Upon completion of the reaction, the solvent was distilled off, and a crude product (37 g) was obtained. The product was washed with a mixed benzene / hexane solvent to give 2N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -1,2,4,5,6,7-hexahydro-3H-indazol-3-one as a white solid (25.3 g, 72.3% yield). Mp 151-152 ^about S.

¹ H-NMR spectrum (CDCl ₃ CF ₃ CO ₂ H, TMS, ppm): δ 1.40-2.03 (12H, m), 2.37 (2H, m), 2, 55 (2H, m.), 4.65 (1H, m.), 6.97 (1H, d. I _HF = 9.0 Hz).

IR spectrum (KBr, disk, cm ^-1 ): 2950, 2400, 1770, 1600, 1505, 880.

MS spectrum (m / e): 352 (M ⁺ , 6%), 350 (M ⁺ , 18%), 284 (100%), 81 (38%), 41 (66%).

Phosphorus oxychloride (6.6 g, 43.0 mol) was added to the resulting 2N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -1,2,4,5, 6, 7-hexahydro-3H- idazol-3-one (15.0 g, 42.8 mmol), followed by stirring for 30 minutes under heating at 160 ^C. After cooling, the reaction mixture was ice-cooled dilute aqueous solution of sodium hydroxide (50 ml) was added to the resulting mixture and the mixture was extracted with methylene chloride (200 ml x 4). The extract was washed with dilute aqueous sodium hydroxide (400 ml) and saturated aqueous sodium chloride (400 ml), dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane 1/9 1/5), whereby 3-chloro-2N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) - 4,5,6,7-tetrahydro-2H-indazol as a white solid (4.3 g, 26.5% yield). Mp 88-91 ^about S.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.05-2.10 (12H, m), 2.30-2.85 (4H, m), 4.73 (1H, m), 6.95 (1H, d. I _HF 6.0 Hz), 7.23 (1H, d. I _HF 9.0 Hz).

 IR spectrum (KBr disk, cm-1): 2960, 1510, 1195.

MS spectrum (m / e): 372 (M ⁺ , 12.1%), 370 (M ⁺ , 11.6%), 368 (M ⁺ , 17.0%), 300 (100%), 265 ( 52.7%), 41 (64%).

Elemental analysis (calculated values: C ₁₈ H ₁₉ N ₂ OClF,): C 58.39 (58.55); H 5.04 (5.19); N, 7.49 (7.59).

 PRI me R 8.

Раствор 3-хлор-2N-(2-фтор-4-хлор-5-гидроксифенил)-4,5,6,7-тетрагидро-2Н-ин- дазола (220 мг, 0,731 ммоль), 3-метилциклопентил n-толуолсульфоната (250 мг, 0,999 ммоль) и карбоната калия (120 мг, 0,870 ммоль) в ацетонитриле (25 мл) перемешивали в течение 4 ч при нагревании в условиях дефлегмации. После завершения реакции реакционный раствор выливали в 1 н. соляную кислоту (50 мл) и экстрагировали этилацетатом (50 мл х 3). Органический слой промывали насыщенным водным раствором хлористого натрия (100 мл) и сушили над сульфатом магния. Осушающий агент отделяли с помощью фильтрования и растворитель отгоняли из фильтрата с получением неочищенного продукта (0,29 г). Продукт очищали с помощью хроматографии на силикагельной колонке (проявляющий раствор: этилацетат/гексан 1/9) и получали 3-хлор-2N-(2-фтор-4-хлор-5-)3-метилцикло- пентил(оксифенил)-4,5,6,7-гексагидро-2Н-индазол в виде белого твердого вещества (242 мг, 86,4% выход).

Solution of 3-chloro-2N- (2-fluoro-4-chloro-5-hydroxyphenyl) -4,5,6,7-tetrahydro-2H-indazole (220 mg, 0.731 mmol), 3-methylcyclopentyl n-toluenesulfonate (250 mg, 0.999 mmol) and potassium carbonate (120 mg, 0.870 mmol) in acetonitrile (25 ml) was stirred for 4 hours while heating under reflux. After completion of the reaction, the reaction solution was poured into 1N. hydrochloric acid (50 ml) and was extracted with ethyl acetate (50 ml x 3). The organic layer was washed with a saturated aqueous solution of sodium chloride (100 ml) and dried over magnesium sulfate. A drying agent was separated by filtration, and the solvent was distilled off from the filtrate to obtain a crude product (0.29 g). The product was purified by silica gel column chromatography (developing solution: ethyl acetate / hexane 1/9) to obtain 3-chloro-2N- (2-fluoro-4-chloro-5-) 3-methylcyclopentyl (hydroxyphenyl) -4, 5,6,7-hexahydro-2H-indazole as a white solid (242 mg, 86.4% yield).

¹ H-NMR spectrum (CDCl ₃ , TMS, ppm):
δ 1.03 and 1.08 (total 3H, each d. I 6.0 Hz), 1.17-2.4 (11H, m.), 2.4-2.83 (4H, m.), 4.80 (1H, m), 6.98 (1H, d. I _HF 6.0 Hz), 7.38 (1H, d. I _HF 9.0 Hz).

IR (neat, cm ^-1 ): 2970, 1505, 1200.

 Reference Example 1

NH₂

NH

OEt
_____→ Cl

NH

OEt

C

NH

OEt

C

NH₂
Этилхлорформат (16,3 г, 150 ммоль) добавляли к раствору 2-фтор-4-хлор-5-метоксикарбонилоксианилина (22,0 г, 100 ммоль) и карбоната калия (13,8 г, 100 ммоль) в ацетоне (300 мл) с последующим перемешиванием в течение 5 ч при 60^оС. После завершения реакции растворитель отгоняли при пониженном давлении, остаток подкисляли с помощью добавления 1 н. соляной кислоты (100 мл) и экстрагировали этилацетатом (100 мл х 3). Органический слой промывали водой, сушили и растворитель отгоняли при пониженном давлении. Выпавшее в осадок твердое вещество отделяли фильтрованием.

NH ₂

NH

Oet
_____ → Cl

NH

Oet

C

NH

Oet

C

NH ₂
Ethyl chloroformate (16.3 g, 150 mmol) was added to a solution of 2-fluoro-4-chloro-5-methoxycarbonyloxyaniline (22.0 g, 100 mmol) and potassium carbonate (13.8 g, 100 mmol) in acetone (300 ml ), followed by stirring for 5 hours at 60 ^C. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was acidified by adding 1N. hydrochloric acid (100 ml) and was extracted with ethyl acetate (100 ml x 3). The organic layer was washed with water, dried and the solvent was distilled off under reduced pressure. The precipitated solid was separated by filtration.

 The solid was recrystallized from a mixture of chloroform and hexane to give ethyl N- (2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl) carbamate as white crystals (23.3 g, 80.2% yield).

Mp 143.8-147.2 ^about S.

¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.13 (3H, t. I 6.5 Hz), 3.92 (3H, s), 4.23 (2H, q. I 6.5 Hz), 6.80 (1H, br.s.), 7.15 (1H, d. I _HF 10.5 Hz), 8.12 (1H, d. I _HF 8.0 Hz) .

IR spectrum (KBr disk, cm ^-1 ): 1770, 1730, 1545, 1290, 1235, 1215.

The resulting ethyl N- (2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl) carbamate (45.2 g, 155 mmol) was reacted with potassium carbonate (21.4 g, 155 mmol) and water (100 ml) in for 2 hours when heated for 2 hours at reflux temperature. After completion of the reaction, the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was acidified by adding 1 N. hydrochloric acid (300 ml) and was extracted with ethyl acetate (100 ml x 3 times). The organic layer was washed with water, dried, the solvent was distilled off under reduced pressure, and the precipitated solid was separated by filtration. The solid was recrystallized from chloroform-hexane to give ethyl N- (2-fluoro-4-chloro-5-hydroxyphenyl) carbamate as white crystals (35.2 g, 97% yield). Mp 151.5-154.2 ^about S.

¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.32 (3H, t. I 7.2 Hz), 4.23 (2H, q, I 7.2 Hz), 5 84 (1H, s.), 6.80 (1H, broad s.), 7.04 (1H, I _HF 10.5 Hz), 7.85 (1H, d. I _HF 7.5 Hz) .

IR spectrum (KBr, cm ^-1 ): 3440, 1710, 1560, 1430, 1250.

Then a solution of the resulting ethyl N- (2-fluoro-4-chloro-5-hydroxyphenyl) carbamate (10 g, 42.8 mmol) and potassium carbonate (8.87 g, 64.2 mmol) in acetonitrile (150 ml ) was stirred for one hour at 80 ° ^C. to the mixture is added dropwise cyclopentyl bromide (9.57 g, 84.2 mmol), followed by reacting for 7 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was acidified by adding 1N . hydrochloric acid (100 ml) and was extracted with ethyl acetate (100 ml x 3 times). The organic layer was washed with water, dried and the solvent was distilled off under reduced pressure to obtain N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) carbamate (12.7 g, 98% yield). Mp 92.8-97.8 ^about S.

¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.33 (3H, t. I 7.0 Hz), 1.40-2.10 (8H, m), 4, 32 (2H, q, I 7.0 Hz), 4.88 (1H, m.), 4.32 (2H, q.s.), 7.15 (1H, d. I _HF 10.5 Hz), 7.92 (1H, d. I _HF 7.0 Hz).

IR spectrum (KBr, cm ^-1 ): 1710, 1535, 1495, 1415, 1255.

When using n-tolylsulfonate instead of cyclopentyl bromide in this reaction, N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) carbamate can be obtained in 95% yield
Ethyl alcohol (50 ml) and 2N were added to ethyl N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) carbamate thus obtained. aqueous sodium hydroxide solution (100 ml), followed by stirring for 4 hours while heating in an oil bath at 110 ^C. After completion of the reaction, the solvent was distilled off and the residue was extracted with ethyl acetate (100 ml x 3 times). The organic layer was washed with saturated aqueous sodium chloride, dried and the solvent was distilled off under reduced pressure to obtain 2-fluoro-4-chloro-5-cyclopentyloxyaniline (9.36 g, 40.8 mmol, 97% yield).

¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.40-2.07 (8H, m), 3.72 (2H, br.s), 4.57 (1H , m.), 6.35 (1H, d. I _HF 8.0 Hz), 6.98 (1H, d. I _HF 10.5 Hz).

IR (KBr, disc, cm ^-1 ): 2980, 1635, 1510, 1423, 1250, 1190.

 Reference Example 2

Этил N-(2-фтор-4-хлор-5-метоксикарбонилоксифенил)карбамат (1,45 г, 4,97 ммоль), полученный по ссылочному примеру 1, и раствор карбоната калия (1,03 г, 7,46 ммоль) в этаноле (5,0 мл) перемешивали в течение 1 ч при температуре дефлегмации и затем к смеси добавляли циклопентилбромид (1,11г, 7,46 ммоль) с последующим перемешиванием в течение 2 ч. После завершения реакции смесь выливали в 1 н. соляную кислоту (50 мл) и экстрагировали этилацетатом (50 мл х 3 раза). Органический слой сушили, концентрировали при пониженном давлении с получением этил N-(2-фтор-4-хлор-5-циклопентилоксифенил)карбамата в виде беловато-серых кристаллов (1,41 г, 4,69 ммоль, 94,4% выход). Данные спектрального анализа и другие данные являются такими же, как показаны в ссылочном примере 1.

Ethyl N- (2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl) carbamate (1.45 g, 4.97 mmol) obtained according to Reference Example 1, and a solution of potassium carbonate (1.03 g, 7.46 mmol) in ethanol (5.0 ml) was stirred for 1 h at reflux temperature and then cyclopentyl bromide (1.11 g, 7.46 mmol) was added to the mixture, followed by stirring for 2 hours. After completion of the reaction, the mixture was poured into 1N. hydrochloric acid (50 ml) and was extracted with ethyl acetate (50 ml x 3 times). The organic layer was dried, concentrated under reduced pressure to obtain ethyl N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) carbamate as whitish-gray crystals (1.41 g, 4.69 mmol, 94.4% yield) . Spectral analysis data and other data are the same as shown in Reference Example 1.

 Reference Example 3

NO₂

NH₂

NH

OMe

Cl

NH

OMe

C

NH

OMe

C

NH₂
2-Хлор-4-фторфенол (29,3 г, 0,20 ммоль) загружали в круглодонную колбу (300 ммл), снабженную капельной воронкой, и к нему добавляли водный раствор 2 н. NaOH (100 мл) при охлаждении льдом с последующим перемешиванием в течение 30 мин. Затем к смеси добавляли по каплям изобутилхлорформат (30 мл, d 1,053, 31,6 г, 0,23 моль), смесь перемешивали в течение 2 ч при постепенном повышении температуры до комнатной. После завершения реакции смесь экстрагировали метиленхлоридом (100 мл х 3 раза) и сушили над безводным сульфатом магния. После удаления осушающего агента растворитель отгоняли при пониженном давлении с получением 2-хлор-4-фторфенил (изобутил)карбоната в виде бесцветного прозрачного масла (45,8 г, 0,186 ммоль, 93,0% выход).Cl

NO ₂

NH ₂

NH

Ome

Cl

NH

Ome

C

NH

Ome

C

NH ₂
2-Chloro-4-fluorophenol (29.3 g, 0.20 mmol) was charged into a round bottom flask (300 mml) equipped with a dropping funnel, and an aqueous solution of 2 N was added to it. NaOH (100 ml) under ice-cooling, followed by stirring for 30 minutes. Then, isobutyl chloroformate (30 ml, d 1.053, 31.6 g, 0.23 mol) was added dropwise to the mixture, the mixture was stirred for 2 hours while gradually raising the temperature to room temperature. After completion of the reaction, the mixture was extracted with methylene chloride (100 ml x 3 times) and dried over anhydrous magnesium sulfate. After removal of the drying agent, the solvent was distilled off under reduced pressure to obtain 2-chloro-4-fluorophenyl (isobutyl) carbonate as a colorless transparent oil (45.8 g, 0.186 mmol, 93.0% yield).

¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.00 (6H, d. I 6.9 Hz), 2.05 (1H, t. And sept. I 6.3 and 6 9 Hz), 4.05 (2H, d. I 6.3 Hz), 6.8-7.3 (3H, m.).

Then, fuming nitric acid (100 ml, 98% d 1.52) was poured into a round-bottom flask (200 ml) and 2-chloro-4-fluorophenyl (isobutyl) carbonate (10 g, 40.5 mmol) was slowly added to it under cooling ice. After stirring the mixture for 30 minutes, the reaction mixture was poured onto ice. The 2-fluoro-4-chloro-5-isobutyloxycarbonyloxy nitrobenzene precipitated as a pale yellow solid was filtered off and washed with water. By thorough drying, the desired compound was obtained in the form of white crystals (10.8 g, 36.9 mmol, 91.0% yield). Mp 38.0-49.0 ^about S.

¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.00 (6H, d. I 6.9 Hz), 2.07 (1H, t. And sept. I 6.3 and 6 , 9 Hz), 4.07 (2H, I 6.3 Hz), 7.42 (1H, d. I _HF 10.2 Hz), 8.02 (1H, d. I _HF 6.9 Hz).

Thus obtained 2-fluoro-4-chloro-5-isobutyloxycarbonyloxy quinobenzene (10 g, 34.3 mmol), toluene (100 ml) as solvent and 10% palladium on carbon (1.5 g) were loaded into pressure-resistant glass autoclave (300 ml). After thoroughly displacing the internal contents with hydrogen gas, stirring was started at a hydrogen pressure of 4 atm. As the reaction proceeds generate heat (about 50 ^C) while stirring continued. It was further mixed with the addition of hydrogen from time to time until hydrogen uptake ceased. After completion of the reaction, palladium-carbon was separated by filtration and the released water was removed using a drying agent. The solvent was distilled off under reduced pressure to obtain quantitatively substantially pure 2-chloro-4-fluoro-5-isobutyloxycarbonyloxyaniline (9.42 g) as a yellow oil.

¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.00 (6H, d. I 6.9 Hz), 2.04 (1H, t. And sep. I6.3 and 6 , 9 Hz), 4.04 (2H, d. I 6.3 Hz), 6.97 (1H, d. I _HF 6.9 Hz), 7.24 (1H, d. I _HF 9.0 Hz )

Methyl chloroformate (23.4 g, 0.248 mol) was added to a solution of 2-fluoro-4-chloro-5-isobutyloxycarbonyloxyaniline (65.0 g, 0.248 mol) and potassium carbonate (32 mg, 0.232 mmol) in acetone (300 ml), then the mixture was stirred for 5 hours at reflux temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, 1 N was added to the residue. hydrochloric acid (300 ml) and the precipitated solid was filtered off. The solid was washed thoroughly with water and dried to give methyl N- (2-fluoro-4-chloro-5-isobutyloxycarbonyloxyphenyl) carbamate as white crystals (56.6 g, 71.4% yield). Mp 72.2-78.8 ^about SM.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.00 (6H, d. I 6.5 Hz), 2.05 (1H, t. And sept. I 6.5 Hz) ), 3.78 (3H, s.), 4.03 (2H, d.I 6.5 Hz), 6.85 (1H, broad s.), 7.08 (1H, d. I _HF 10 , 2 Hz), 8.10 (1H, d. I _HF 7.5 Hz).

IR spectrum (KBr, disk, cm ^-1 ): 1773, 1733, 1545, 1285, 1235, 1180.

Methyl N- (2-fluoro-4-chloro-5-isobutyloxycarbonyloxyphenyl) carbamate, prepared as described above, was dissolved in methanol (100 ml), and then sodium carbonate (7.26 g, 52.3 mmol) was added to the mixture. ) followed by reaction ^at 50 ° C for 3 hours. After the reaction, the solvent was distilled off under reduced pressure, the resulting solid was dissolved in acetic acid (20 mL). The solution was poured into ice water and the separated solid was separated by filtration. The solid was washed thoroughly with water and dried to give methyl N- (2-fluoro-4-chloro-5-hydroxyphenyl) carbamate as white crystals (9.60 g, 43.7 mmol, 99.8%). Mp 140.0-141.0 ^about C.

¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.57 (3H, s.), 3.78 (3H, s.), 5.53 (1H, s.), 6 75 (1H, br.s.), 7.05 (1H, d. I _HF 10.5 Hz), 7.82 (1H, d. I _HF 7.5 Hz).

IR spectrum (KBr, disk, cm ^-1 ): 3440, 1717, 1560, 1430, 1250.

A solution of methyl N- (2-fluoro-4-chloro-5-hydroxyphenyl) carbamate (5.0 g, 22.8 mmol) prepared as described above and potassium carbonate (3.89 g, 28.1 mmol) , in acetonitrile (50 ml) was stirred for 1 h at reflux temperature. Then bromocyclopentane (4.07 g, 27.3 mmol) was added dropwise to the mixture, which was then reacted for 3 hours. After completion of the reaction, the solvent was distilled off, the residue was acidified by adding 1N. hydrochloric acid (50 ml) and was extracted with ethyl acetate (100 ml x 3 times). The organic layer was washed with water and the solvent was distilled off under reduced pressure to obtain methyl N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) carbamate (5.56 g, 19.3 mmol, 84.7% yield). Mp 120.0-123.0 ^about C.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.40-2.10 (8H, m), 3.77 (3H, s), 4.77 (1H, m .), 6.82 (1H, br.s.), 7.07 (1H, d.I _HF 10.5 Hz), 7.83 (1H, d.I _HF 7.5 Hz).

IR spectrum (KBr, disk, cm ^-1 ): 1714, 1535, 1500, 1415, 1255, 1190.

Ethyl alcohol (30 ml) and 2N were added to the resulting methyl N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) carbamate. aqueous sodium hydroxide solution (50 ml) and the mixture was stirred for 4 hours while heating in an oil bath at 110 ^C. After completion of the reaction, the solvent was distilled off and the residue was extracted with ethyl acetate (100 ml x x 3 times). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off under reduced pressure to obtain an oily 2-fluoro-4-chloro-5-cyclopentyloxyaniline (4.36 g, 19.0 mol, 95.0% yield). Spectral analysis data and other data are such. as shown in reference example 17.

 Reference Example 4

NO₂ +

- OTs

C

NO₂

C

NH₂
Раствор 2-фтор-4-хлор-5-гидроксинитробензола (7,1 г, 37,1 ммоль) и карбоната калия (5,1 г, 37,1 ммоль) в ацетонитриле (300 мл) перемешивали в течение 2 ч при температуре дефлегмации. К нему добавлялся циклопентил п-толуолсульфонат (10,3 г, 40,8 ммоль) с перемешиванием в течение 2 ч при температуре дефлегмации. После завершения реакции растворитель отгоняли из реакционной смеси при пониженном давлении. К нему добавляли 1 н. соляную кислоту (300 мл) и смесь экстрагировали этилацетатом (100 мл х 3 раза). Органический слой промывали водным раствором бикарбоната натрия и водой, сушили, растворитель удаляли при пониженном давлении, при этом получали 2-фтор-4-хлор-5-циклопентилоксинитро- бензол в виде желтого твердого вещества (8,93 г, 34,3 ммоль, 92,6 выход). Т.пл. 58,0-62,6^оС.Cl

NO ₂ +

- OTs

C

NO ₂

C

NH ₂
A solution of 2-fluoro-4-chloro-5-hydroxy-nitrobenzene (7.1 g, 37.1 mmol) and potassium carbonate (5.1 g, 37.1 mmol) in acetonitrile (300 ml) was stirred for 2 hours at a temperature reflux. Cyclopentyl p-toluenesulfonate (10.3 g, 40.8 mmol) was added to it with stirring for 2 hours at reflux temperature. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure. To it was added 1 N. hydrochloric acid (300 ml) and the mixture was extracted with ethyl acetate (100 ml x 3 times). The organic layer was washed with an aqueous solution of sodium bicarbonate and water, dried, the solvent was removed under reduced pressure, and 2-fluoro-4-chloro-5-cyclopentyloxynitrobenzene was obtained as a yellow solid (8.93 g, 34.3 mmol, 92.6 yield). Mp 58.0-62.6 ^about S.

¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.41-2.26 (8H, m), 4.87 (1H, m), 7.34 (2H, d . I _HF 10.5 Hz), 7.62 (2H, d. I _HF 7.5 Hz).

IR spectrum (KBr, disk, cm ^-1 ): 1535, 1490, 1350, 1205.

The resulting 2-fluoro-4-chloro-5-cyclopentyloxynitrobenzene (13 g, 50.1 mmol) was dissolved in toluene (100 ml), a catalytic amount of 10% palladium on carbon (0.5 g) was added to the mixture, and the mixture was stirred at from room temperature to ⁷⁰ ° C under hydrogen pressure of 3-5 atm in a glass autoclave. After the adsorption of hydrogen gas ceased, the catalyst was removed by filtration, the solvent was distilled off under reduced pressure from the filtrate to obtain an oily 2-fluoro-4-chloro-5-cyclopentyloxyaniline. Spectral analysis data and other data are as described in Reference Example 1.

 Reference Example 5

NH

OMe +

OTs

NH

OMe ____→

NH₂
Раствор метил N-(2-фтор-4-хлор-5-изобутилоксикарбонилоксифенил) карбамата (5,37 г, 16,8 ммоль), приготовленого по способу, показанному в ссылочном примере 3, 3-метилциклопентил п-толуолсульфоната (5 г, 20,2 ммоль) и карбоната калия (2,32 г, 16,8 ммоль) в метаноле (50 мл) перемешивали в течение 5 ч при температуре дефлегмации. После завершения реакции реакционную смесь выливали в 1 н. соляную кислоту (100 мл) и смесь экстрагировали этилацетатом (50 мл х 3 раза). Органический слой сушили, растворитель удаляли при пониженном давлении, при этом получали N-[2-фтор-4-хлор-5-(3-метилциклопентил)оксифенил] карбамат в виде серо-белых кристаллов (3,81 г, 12,6 ммоль, 75,2% выход).

NH

OMe +

OTs

NH

OMe ____ →

NH ₂
A solution of methyl N- (2-fluoro-4-chloro-5-isobutyloxycarbonyloxyphenyl) carbamate (5.37 g, 16.8 mmol) prepared according to the method shown in Reference Example 3, 3-methylcyclopentyl p-toluenesulfonate (5 g, 20.2 mmol) and potassium carbonate (2.32 g, 16.8 mmol) in methanol (50 ml) was stirred for 5 hours at reflux temperature. After completion of the reaction, the reaction mixture was poured into 1N. hydrochloric acid (100 ml) and the mixture was extracted with ethyl acetate (50 ml x 3 times). The organic layer was dried, the solvent was removed under reduced pressure to obtain N- [2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl] carbamate as gray-white crystals (3.81 g, 12.6 mmol 75.2% yield).

¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.02 and 1.08 (total 3H, d. I6.0 Hz), 1.25-2.40 (7H, m. ), 3.77 (3H, s.), 4.75 (1H, m.), 6.68 (1H, br.s.), 7.05 (1H, d. I _HF = 10.5 Hz) 7.75 (1H, d. I _HF 7.5 Hz).

 Then ethyl alcohol (20 ml) and 2 N. an aqueous solution of sodium hydroxide (30 ml) was added to the resulting methyl N- [2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl] carbamate (3.45 g, 11.4 mmol), after which the mixture stirred for 3 hours at reflux temperature. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 ml x 3 times). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried and the solvent was distilled off under reduced pressure, whereby 2-fluoro-4-chloro-5- (3-methylcyclopentyl) -oxyaniline (1.77 g, 7.26 mmol, 63) was obtained 6% yield).

¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.02 and 1.10 (total 3H, d. I6.0 Hz), 1.22-2.58 (7H, m. ), 3.75 (2H, br.s.), 4.65 (1H, m), 6.33 (1H, d. I _HF 8.0 Hz), 6.98 (1H, d. I _HF 10.0 Hz).

 Reference Example 6

₊

_{____→}

N

____→ Cl

N

Раствор 2-фтор-4-хлор-5-метоксикарбонилоксианилина (20 г, 91,1 ммоль) и 3,4,5,6-тетрагидрофталевого ангидрида (14 г, 92,0 ммоль) в уксусной кислоте (200 мл) подвергали реакции в течение 5 ч при нагревании при температуре дефлегмации. После завершения реакции смесь охлаждали до комнатной температуры, к ней добавляли воду (200 мл) и полученную смесь экстрагировали этилацетатом (100 мл х 3 раза). Органический слой промывали водным раствором карбоната натрия и воды, сушили и растворитель отгоняли при пониженном давлении. Полученное в результате маслянистое вещество очищали хроматографией на силикагельной колонке (проявляющий растворитель: этилацетат/гексан 1/5), при этом получали N-(2-фтор-4-хлор-5-метоксикарбонилоксифе- нил)-3,4,5,6-тетрагидрофталимид в виде белого твердого вещества (26,2 г, 72,1 ммоль, 79,2% выход). Т.пл. 138,5-146,2^оС.

₊

_{____ →}

N

____ → Cl

N

A solution of 2-fluoro-4-chloro-5-methoxycarbonyloxyaniline (20 g, 91.1 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (14 g, 92.0 mmol) in acetic acid (200 ml) was reacted for 5 hours when heated at reflux temperature. After completion of the reaction, the mixture was cooled to room temperature, water (200 ml) was added thereto, and the resulting mixture was extracted with ethyl acetate (100 ml x 3 times). The organic layer was washed with an aqueous solution of sodium carbonate and water, dried and the solvent was distilled off under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane 1/5) to obtain N- (2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl) -3,4,5,6 Tetrahydrophthalimide as a white solid (26.2 g, 72.1 mmol, 79.2% yield). Mp 138.5-146.2 ^about S.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.82 (4H, m), 2.42 (4H, m), 3.93 (3H, s), 7 21 (1H, d. I _HF 6.5 Hz), 7.33 (1H, d. I _HF 9.0 Hz).

IR spectrum (KBr, disk, cm ^-1 ): 1765, 1725, 1508, 1500, 1440, 1430, 1260, 1195.

Potassium carbonate (4.6 g, 33.3 mmol) was added to a solution of N- (2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (11.8 g, 33 4 mmol) obtained as described above in methanol (100 ml), followed by stirring for 5 hours at reflux temperature. After completion of the reaction, the mixture was poured into 1N. hydrochloric acid (200 ml) and was extracted with ethyl acetate (100 ml x 3 times). The organic layer was washed with water, dried and the solvent was distilled off under reduced pressure to obtain a crude product (9.4 g). The product was recrystallized from ether / hexane to give N- (2-fluoro-4-chloro-5-hydroxyphenyl) -3,4,5,6-tetrahydrophthalimide as a white solid (6.7 g, 22.7 mmol, 67.8% yield). Mp 145.5-156.4 ^about S.

¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.80 (4H, m.), 2.40 (4H, m.), 6.00 (1H, br.s.), 6.85 (1H, d. I _HF 6.5 Hz), 7.17 (1H, d. I _HF 9.0 Hz).

IR spectrum (KBr, cm ^-1 ): 3440, 1785, 1720, 1530, 1430, 1395, 1185.

 Reference Example 7

_{OH + Me}

_{___→}

_Me
Циклопентанол (50 г, 0,58 ммоль) и n-толуолсульфонилхлорид (120г, 0,629 моль) растворяли в пиридине (200 мл), растор выливали в смесь льда и воды (примерно 1 л) с последующим тщательным перемешиванием. Выпавшее в осадок твердое вещество отфильтро- вывали, сушили и получали циклопентил n-толуолсульфонат в виде белого твердого вещества (94,9 г, 0,390 моль, 68,1% выход).

_{OH + Me}

_{___ →}

_Me
Cyclopentanol (50 g, 0.58 mmol) and n-toluenesulfonyl chloride (120 g, 0.629 mol) were dissolved in pyridine (200 ml), the solution was poured into a mixture of ice and water (about 1 L), followed by thorough stirring. The precipitated solid was filtered off, dried, and cyclopentyl n-toluenesulfonate was obtained as a white solid (94.9 g, 0.390 mol, 68.1% yield).

Mp below 30 ^about C.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.23-2.07 (8H, m), 2.45 (3H, s), 4.98 (1H, m. ), 7.38 (2H, d. I 9.0 Hz), 7.85 (2H, d. I 9.0 Hz).

 Reference Example 8

- OH + Me -

- SO₂Cl ___→

- OSO₂-

- Me
Циклопентанол (10 г, 0,116 моль), n-толуолсульфонилхлорид (24,3 г, 0,128 моль) и простой эфир (100 мл) загружали в круглодонную колбу (200 см³) и растворяли. Затем медлено к раствору при охлаждении ниже 10^оС на водяной бане добавляли гидроокись калия (32,5 г, 0,58 моль) в виде порошка. После добавления смесь перемешивали в течение дополнительных 2 ч. После завершения реакции смесь выливали в ледяную воду (20 мл), органический слой и водный слой разделяли. Органический слой сушили и концентрировали при пониженном давлении, получая циклопентил n-толуолсульфонат в виде бледно-желтой вязкой жидкости (22,0 г, выход 81,8%).

- OH + Me -

- SO ₂ Cl ___ →

- OSO ₂ -

- Me
Cyclopentanol (10 g, 0.116 mol), n-toluenesulfonyl chloride (24.3 g, 0.128 mol) and ether (100 ml) were charged into a round bottom flask (200 cm ³ ) and dissolved. Then, to a solution of lingering on cooling below ^{10 °} C water bath was added potassium hydroxide (32.5 g, 0.58 mol) in powder form. After addition, the mixture was stirred for an additional 2 hours. After completion of the reaction, the mixture was poured into ice water (20 ml), the organic layer and the aqueous layer were separated. The organic layer was dried and concentrated under reduced pressure to give cyclopentyl n-toluenesulfonate as a pale yellow viscous liquid (22.0 g, 81.8% yield).

 Reference Example 9

OH + Me -

- SO₂Cl ___→

OSO₂-

- Me
3-Метилциклопентанол (5,0 г, 49,9 ммоль) подвергали взаимодействию с n-толуолсульфонилхлоридом в пиридине (50 мл) таким же образом, как в ссылочном примере 7, с получением 3-метилциклопентил n-толуолсульфоната (11,7 г, 46,2 ммоль, выход 92,5%).

OH + Me -

- SO ₂ Cl ___ →

OSO ₂ -

- Me
3-Methylcyclopentanol (5.0 g, 49.9 mmol) was reacted with n-toluenesulfonyl chloride in pyridine (50 ml) in the same manner as in Reference Example 7 to give 3-methylcyclopentyl n-toluenesulfonate (11.7 g, 46.2 mmol, yield 92.5%).

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.93 and 1.00 (total 3H, each d. I 6.0 Hz), 1.20-2.30 (7H, m .), 2.48 (3H, s.), 4.97 (1H, m.), 7.38 (1H, d. I 8.0 Hz), 7.85 (1H, d. I 8.0 Hz).

- NHCOOMe +

OTs

- NH₂
Раствор метил N-(2-фтор-4-хлор-5-гидроксифенил)карбамата (1,53 г, 6,98 ммоль), синтезированного с помощью процесса, описанного в ссылочном примере 3, 2-метилциклопентил n-толуолсульфоната (1.78 г, 6,99 ммоль) и N,N-диметилформамида (15мл) загружали в круглодонную колбу, (50 см³), затем к нему добавляли гидроокись калия (400 мг, 7,15 ммоль) в виде порошка с последующим перемешиванием в течение 7 ч при нагревании на масляной бане при 80-100^оС. После завершения реакции реакционный раствор охлаждали до комнатной температуры, к нему добавляли 2 н. соляную кислоту (50 мл) и смесь экстрагировали этилацетатом (20 мл х 3). Органические слои объединяли, промывали насыщенным водным раствором хлористого натрия и сушили над безводным сульфатом магния. Осушающий агент удаляли с помощью фильтрования, растворитель отгоняли при пониженном давлении, давая неочищенный продукт (1,51 г). Продукт очищали с помощью хроматографии на силикагельной колонке (проявляющий растворитель: гексан/этилацетат 17/3), получая 2-фтор-4-хлор-5-(2-метилциклопентил)оксианилин в виде бесцветного маслянистого вещества (666 мг, 2,73 ммоль, выход 40%).Reference Example 10
Cl

- NHCOOMe +

OTs

- NH ₂
A solution of methyl N- (2-fluoro-4-chloro-5-hydroxyphenyl) carbamate (1.53 g, 6.98 mmol) synthesized using the process described in Reference Example 3, 2-methylcyclopentyl n-toluenesulfonate (1.78 g , 6.99 mmol) and N, N-dimethylformamide (15 ml) were loaded into a round bottom flask, (50 cm ³ ), then potassium hydroxide (400 mg, 7.15 mmol) was added to it in powder form, followed by stirring for 7 hours while heating in an oil bath at 80-100 ° ^C. After completion of the reaction, the reaction solution was cooled to room temperature, thereto was added 2N. hydrochloric acid (50 ml) and the mixture was extracted with ethyl acetate (20 ml x 3). The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, the solvent was distilled off under reduced pressure to give a crude product (1.51 g). The product was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate 17/3) to obtain 2-fluoro-4-chloro-5- (2-methylcyclopentyl) hydroxyaniline as a colorless oily substance (666 mg, 2.73 mmol) yield 40%).

 Colorless transparent oily substance.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.04 and 1.15 (total 3H, each d. I 7.0 Hz and 7.0 Hz), 1.40-2, 40 (7H, m), 3.66 (2H, br.s), 4.15 and 4.42 (total 1H, each m), 6.35 (1H, d. I _HF 9.2 Hz ), 6.98 (1H, d. I _HF 11.9 Hz).

IR spectrum (disk, cm ^-1 ): 3425, 2980, 2900, 1630, 1510, 1245, 1190.

 Reference Example 11

- NHCOOMe +

OTs ____→

- NHCOOMe +

- NH₂
Метил N-(2-фтор-4-хлор-5-гидроксифенил)карбамат (1 г, 4,56 ммоль), синтезированный с помощью процесса, описанного в ссылочном примере 3, циклогексил n-толуолсульфоната (1,20 г, 4,73 ммоль), карбонат калия (635 мг, 4,95 ммоль), каталитическое количество йодистого калия и N,N-диметилформамид (20 мл) в качестве растворителя загружали в круглодонную колбу (100 см³) и перемешивали на масляной бане при 80^оС. После завершения реакции реакционный раствор охлаждали до комнатной температуры, к нему добавляли 1 н. соляную кислоту (100 мл), и смесь экстрагировали этилацетатом (20 мл х 3). Органические слои объединяли, промывали водой и насыщенным водным раствором хлористого натрия и сушили над безводным сульфатом магния. Осушающий агент удаляли с помощью фильтрования, растворитель отгоняли при пониженном давлении, давая неочищенный продукт (875 мг). Продукт отделяли и очищали с помощью хроматографии на силикагельной колонке (проявляющий растворитель: гексан/этилацетат 9/1), давая метил N-(2-фтор-4-хлор-5-циклогексилоксифенил)карбамат (12 мг, 0,46 ммоль, выход 8,1%), 2-фтор-4-хлор-5-циклогексилоксианилин (213 мг, 0,87 ммоль, выход 19%) и непрореагировавший исходный материал, метил N-(2-фтор-4-хлор-5-гидроксифенил)карбамат (540 мг, 2,46 ммоль, степень выделения 54%).Cl

- NHCOOMe +

OTs ____ →

- NHCOOMe +

- NH ₂
Methyl N- (2-fluoro-4-chloro-5-hydroxyphenyl) carbamate (1 g, 4.56 mmol) synthesized using the process described in Reference Example 3, cyclohexyl n-toluenesulfonate (1.20 g, 4, 73 mmol), potassium carbonate (635 mg, 4.95 mmol), a catalytic amount of potassium iodide and N, N-dimethylformamide (20 ml) as solvent were loaded into a round bottom flask (100 cm ³ ) and stirred in an oil bath at 80 ^about C. After completion of the reaction, the reaction solution was cooled to room temperature, 1N was added to it. hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate (20 ml x 3). The organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, the solvent was distilled off under reduced pressure to give a crude product (875 mg). The product was separated and purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate 9/1) to give methyl N- (2-fluoro-4-chloro-5-cyclohexyloxyphenyl) carbamate (12 mg, 0.46 mmol, yield) 8.1%), 2-fluoro-4-chloro-5-cyclohexyloxyaniline (213 mg, 0.87 mmol, 19% yield) and unreacted starting material, methyl N- (2-fluoro-4-chloro-5-hydroxyphenyl ) carbamate (540 mg, 2.46 mmol, 54%).

 Methyl N- (2-fluoro-4-chloro-5-cyclohexyloxyphenyl) carbamate.

 White needle crystals.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.03-2.08 (10H, m), 3.80 (3H, s), 4.22 (1H, m. ), 7.10 (1H, d. I _HF 10.5 Hz), 7.88 (1H, d. I _HF = 7.3 Hz).

 2-Fluoro-4-chloro-5-cyclohexyloxyaniline.

 Colorless transparent oily substance.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.15-2.06 (10H, m), 3.46 (2H, br.s.), 4.10 (1H, m.), 6.39 (1H, d. I _HF 9.0 Hz), 6.97 (1H, d. I _HF 11.5 Hz).

IR (neat, cm ^-1 ): 3500, 3400, 2940, 2860, 1630, 1505, 1240, 1190.

 Reference Example 12

- NHCOOMe +

OTs

- NH₂
Метил N-(2-фтор-4-хлор-5-гидроксифенил)карбамат (2,03 г, 9,23 ммоль), циклогексил n-толуолсульфоната (2,51 г, 9,85 ммоль) и N,N-диметилформамид (30 мл) загружали в круглодонную колбу (100 см³). Затем в нее добавляли гидроокись калия (1г, 17,8 ммоль) в виде порошка. Смесь перемешивали в течение 4 ч на масляной бане при 80^оС. После завершения реакции реакционный раствор охлаждали до комнатной температуры, к нему добавляли 1н. соляную кислоту (100 мл) и смесь экстрагировали этилацетатом (20 мл х х 3). Органические слои объединяли, промывали водой и насыщенным раствором хлористого натрия и сушили над безводным сульфатом магния. Осушающий агент удаляли фильтрацией, растворитель отгоняли при пониженном давлении, при этом получали неочищенный продукт. Продукт отделяли, очищали с помощью хроматографии на колонке (проявляющий растворитель:гексан/этилацетат 9/1), получали 2-фтор-4-хлор-5-циклогексилоксианилин (574 мг, 2,36 ммоль, выход 26%) и непрореагировавший исходный материал, метил N-(2-фтор-4-хлор-5-гидроксифенил)карбамат (1,22 г, 5,54 ммоль, соотношение при выделении 60%). Данные спектров и др. показатели являются такими же, как показаны в ссылочном примере 11.Cl

- NHCOOMe +

OTs

- NH ₂
Methyl N- (2-fluoro-4-chloro-5-hydroxyphenyl) carbamate (2.03 g, 9.23 mmol), cyclohexyl n-toluenesulfonate (2.51 g, 9.85 mmol) and N, N-dimethylformamide (30 ml) was loaded into a round bottom flask (100 cm ³ ). Then, potassium hydroxide (1 g, 17.8 mmol) was added in powder form. The mixture was stirred for 4 hours in an oil bath at 80 ^C. After completion of the reaction, the reaction solution was cooled to room temperature, thereto was added 1N. hydrochloric acid (100 ml) and the mixture was extracted with ethyl acetate (20 ml x 3). The organic layers were combined, washed with water and a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and a crude product was obtained. The product was separated, purified by column chromatography (developing solvent: hexane / ethyl acetate 9/1), 2-fluoro-4-chloro-5-cyclohexyloxyaniline (574 mg, 2.36 mmol, 26% yield) and unreacted starting material were obtained. , methyl N- (2-fluoro-4-chloro-5-hydroxyphenyl) carbamate (1.22 g, 5.54 mmol, 60% extraction ratio). Spectrum data and other indicators are the same as shown in reference example 11.

 Reference Example 13

NH₂

NH

OCH₂Ph
____→ Cl

NH

OCH₂Ph

l

-

- NH

OCH₂Ph

l

-

- NH₂
2-Фтор-4-хлор-5-метоксикарбонилокси- анилин (2 г, 6,86 ммоль), карбонат калия (1,42 г, 10,3 ммоль), бензилхлорформат (1,17 г, 6,86 ммоль) и ацетон (20 мл) в качестве растворителя загружали в двухгорлую колбу (100 см³) и нагревали в течение 2 ч в условиях дефлегмации. После завершения реакции смесь добавлялась к 1н. соляной кислоте (50 мл) и экстрагировали этилацетатом (50 мл х 3).После сушки органический слой концентрировали и получали чистый бензил N-(2-фтор-4-хлор-5-метоксикарбонилоксифенил)карбамат в виде твердого вещества (2,21 г, 91,1 выход).

NH ₂

NH

OCH ₂ Ph
____ → Cl

NH

OCH ₂ Ph

l

-

- NH

OCH ₂ Ph

l

-

- NH ₂
2-Fluoro-4-chloro-5-methoxycarbonyloxy-aniline (2 g, 6.86 mmol), potassium carbonate (1.42 g, 10.3 mmol), benzyl chloroformate (1.17 g, 6.86 mmol) and acetone (20 ml) as a solvent was charged into a two-necked flask (100 cm ³ ) and heated for 2 hours under reflux conditions. After completion of the reaction, the mixture was added to 1N. hydrochloric acid (50 ml) and extracted with ethyl acetate (50 ml x 3). After drying, the organic layer was concentrated to give pure benzyl N- (2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl) carbamate as a solid (2.21 g 91.1 yield).

Mp 70-72 ^about S.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 3.62 (3H, s.), 3.96 (2H, s.), 6.59 (1H, d. I 7.5 Hz), 7.01 (1H, d. I 10.0 Hz), 7.20 (1H, br.s.), 7.10-7.50 (5H, s.).

Benzyl N- (2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl) carbamate (1.77 g, 5 mmol), prepared as described above, and potassium carbonate (0.69 g, 5 mmol) were loaded into a flask (50 cm ³⁾ and thereto was added methanol (30ml) as the solvent followed by stirring at 50-60 ^{° C} for 2 hours. After the reaction mixture was cooled to room temperature and poured into cooled 2N. hydrochloric acid (60 ml). The mixture was thoroughly mixed, the precipitated benzyl N- (2-fluoro-4-chloro-5-hydroxyphenyl) carbamate as a white solid (1.36 g, 4.60 mmol, 92% yield) was isolated by filtration and well dried up.

Mp 70-72 ^about S.

Spectrum ¹ H-NMR (CDCl ₃ + DMCO-d ₆ , TMS, ppm):
δ 5.25 (2H), 7.10 (1H. d. I 11.5 Hz), 7.49 (5H, s.), 7.85 (1H, d. I 8.6 Hz), 9, 47 (1H, br.s.).

Then benzyl N- (2-fluoro-4-chloro-5-hydroxyphenyl) carbamate (12.2 g, 41.3 mmol), potassium carbonate (5.97 g, 432.1 mmol), cyclopentyl n-toluenesulfonate (11 , 2 g, 46.4 mmol) and acetone as solvent (150 ml) were loaded into a round-bottom flask (500 cm ³ ) and heated for 9 h under reflux conditions. After completion of the reaction, the reaction mixture was poured into 1N. hydrochloric acid. After thorough mixing, the precipitated benzyl N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) carbamate as a pale yellow solid (14.9 g, 40.9 mmol, 99% yield) was separated by filtration and dried well.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.48-2.07 (8H, m), 4.83 (1H, m), 5.26 ((2H, s .), 6.92 (1H, br.s.), 7.14 (1H, _{d.I HF} 11.5 Hz), 7.47 (5H, s.), 7.93 (1H, d. I _HF 8.3 Hz).

Benzyl N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) carbamate (2 g, 5.51 mmol), synthesized as described above, 5% Rd / C (100 ml) as a catalyst and toluene (15 ml ) as a solvent was loaded into a round-bottom flask (50 cm ³ ), while the inner part of the flask was replaced sufficiently by hydrogen gas. Then, in an atmosphere of hydrogen gas mixture was carefully stirred for 3 h at 50 ^C. After completion of the reaction, the catalyst was separated by filtration, the resulting filtrate was dried with anhydrous magnesium sulfate. After separating the drying agent by filtration, the solvent was distilled off under reduced pressure from the filtrate to obtain 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.26 g) as a pale brown oily substance. Spectral data and other characteristics are as shown in Reference Example 1.

 Reference Example 14

OH + Me -

- SO₂Cl ___→

SO₂-

- Me
2-Метилциклопентанол (21,06 г, 0,210 моль) и n-толуолсульфонилхлорид (48,3 г, 0,252 моль) загружали в трехгорлую колбу, (500 см³), снабженную мешалкой, а затем к смеси при охлаждении льдом добавляли по каплям пиридин (170 мл). Смесь перемешивали в течение 10 ч при постепенном повышении температуры до комнатной. После завершения реакции к реакционной смеси добавляли холодную воду (500 мл) и смесь экстрагировали эфиром (200 мл х x 3). Органические слои объединяли, промывали последовательно 2н. соляной кислотой, водой и насыщенным водным раствором хлористого натрия и сушили безводным сульфатом магния. Осушающий агент отделяли с помощью фильтрования, растворитель отгоняли при пониженном давлении и получали по существу чистый 2-метилциклопентил n-толуолсульфонат в виде бесцветного прозрачного маслянистого вещества (49,7 г, 0,195 моль, выход 93%).

OH + Me -

- SO ₂ Cl ___ →

SO ₂ -

- Me
2-Methylcyclopentanol (21.06 g, 0.210 mol) and n-toluenesulfonyl chloride (48.3 g, 0.252 mol) were charged into a three-necked flask (500 cm ³ ) equipped with a stirrer, and then pyridine was added dropwise to the mixture under ice cooling. (170 ml). The mixture was stirred for 10 hours while gradually raising the temperature to room temperature. After completion of the reaction, cold water (500 ml) was added to the reaction mixture, and the mixture was extracted with ether (200 ml x 3). The organic layers were combined, washed sequentially with 2n. hydrochloric acid, water and a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. The drying agent was separated by filtration, the solvent was distilled off under reduced pressure to obtain essentially pure 2-methylcyclopentyl n-toluenesulfonate as a colorless transparent oily substance (49.7 g, 0.195 mol, 93% yield).

 Colorless transparent oily substance.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.85 (3H, d. I 7.5 Hz), 1.41-2.10 (7H, m), 2.43 (3H, s.), 4.42 and 4.80 (total 1H, each m.), 7.33 (2H, d. I _HF 9.0 Hz), 7.80 (2H, d. I _HF 9 , 0 Hz).

 Reference Example 15

OH + Me -

- SO₂Cl ___→

OSO₂-

- Me
Циклогексанол (5,01 г, 50 ммоль) и n-толуолсульфонилхлорид (10,6 г, 55,6 ммоль) загружали в круглодонную колбу (100см³) и затем к смеси при охлаждении льдом по каплям добавляли пиридин (20 мл). Смесь перемешивали в течение 8 ч при постепенном повышении температуры до комнатной. После завершения реакции к реакционной смеси добавляли холодную воду (500 мл) и смесь экстрагировалась эфиром (100 мл х 3). Органические слои объединяли, промывали последовательно 2н. соляной кислотой, водой и насыщенным водным раствором хлористого натрия и сушили безводным сульфатом магния. Осушающий агент отделяли с помощью фильтрования и растворитель отгоняли при пониженном давлении, при этом получали по существу чистый циклогексил n-толуолсульфонат в виде белого твердого вещества (12,7 г, 49,9 ммоль, выход 99%).

OH + Me -

- SO ₂ Cl ___ →

OSO ₂ -

- Me
Cyclohexanol (5.01 g, 50 mmol) and n-toluenesulfonyl chloride (10.6 g, 55.6 mmol) were charged into a round bottom flask (100 cm ³ ), and then pyridine (20 ml) was added dropwise to the mixture under ice cooling. The mixture was stirred for 8 hours while gradually raising the temperature to room temperature. After completion of the reaction, cold water (500 ml) was added to the reaction mixture, and the mixture was extracted with ether (100 ml x 3). The organic layers were combined, washed sequentially with 2n. hydrochloric acid, water and a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. The drying agent was separated by filtration and the solvent was distilled off under reduced pressure to obtain substantially pure cyclohexyl n-toluenesulfonate as a white solid (12.7 g, 49.9 mmol, 99% yield).

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.00-1.93 (10H, m), 2.43 (3H, s), 4.30-4.64 ( 1H, m.), 7.30 (2H, d. I _HF 9.0 Hz), 7.78 (2H, d. I _HF 9.0 Hz).

 Reference Example 16

l

-

- NH₂

l

-

- N $\genfrac{}{}{0ex}{}{\text{+}}{\text{2}}$ BF $\genfrac{}{}{0ex}{}{\text{-}}{\text{4}}$

l

-

- NHNH₂
2-Фтор-4-хлор-5-циклопентилоксиани- лин (23 г, 0,1 моль), синтезированный с помощью процесса, описанного в ссылочном примере 1, 3, 4 или 13, растворяли в ацетонитриле (50 мл) и к нему добавлялии 42%-ную борфторную кислоту (150 мл). После перемешивания в течение 30 мин при комнатной температуре медленно при 0-5^оС добавляли водный раствор (150 мл) сульфита натрия (20 г, 0,280 моль). После перемешивания в течение 2 ч при данной температуре образовавшееся твердое вещество отделяли с помощью фильтрования и промывали смесью льда и воды, а затем смесью этилацетат/гексан (1/6). С помощью тщательной сушки получали 2-фтор-4-хлор-5-циклопентилоксифенилдиазоний- фторборат в виде серо-белого твердого вещества (29,5 г, выход 89,4%).

l

-

- NH ₂

l

-

- N $\genfrac{}{}{0ex}{}{\text{+}}{\text{2}}$ Bf $\genfrac{}{}{0ex}{}{\text{-}}{\text{4}}$

l

-

- NHNH ₂
2-Fluoro-4-chloro-5-cyclopentyloxyaniline (23 g, 0.1 mol) synthesized using the process described in Reference Example 1, 3, 4 or 13 was dissolved in acetonitrile (50 ml) and 42% borofluoric acid (150 ml) was added. After stirring for 30 minutes at room temperature slowly at 0-5 ^{° C} was added an aqueous solution (150 ml) of sodium sulfite (20 g, 0.280 mol). After stirring for 2 hours at this temperature, the solid formed was separated by filtration and washed with a mixture of ice and water, and then with a mixture of ethyl acetate / hexane (1/6). By careful drying, 2-fluoro-4-chloro-5-cyclopentyloxyphenyldiazonium fluoroborate was obtained as a gray-white solid (29.5 g, 89.4% yield).

Mp 147-150 ^about C (decomposition).

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.38-2.17 (8H, m), 4.88 (1H, m), 7.57 (1H, d. I _HF 9.0 Hz), 8.10 (1H, d. I _HF 5.0 Hz).

IR (neat, cm ^-1 ): 3130, 2975, 2280, 1490, 525.

To a solution of tin (II) chloride monohydrate (200 g, 0.886 mol) dissolved in concentrated hydrochloric acid (200 ml) and THF (200 ml) was added THF (200 ml), a solution of 2-fluoro-4-chloro-5- cyclopentyloxyphenyl-diazoniyftorborata (31.3 g, 0.094 mol) under cooling at 0-5 ^C. After stirring for 8 hours at this temperature, thereto was added an aqueous solution (1000 ml), potassium hydroxide (160 g). The solid that formed was separated by filtration and the filtrate was extracted with ethyl acetate (1000 ml x 3). The extract was washed with a saturated aqueous solution of sodium chloride (1000 ml) and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the solvent was distilled off under reduced pressure to give 2-fluoro-4-chloro-5-cyclopentyloxyphenylhydrazine as brownish crystals (20.9 g, 85.6% yield).

Mp 77-79 ^about S.

Spectrum ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.35-2.1 (8H, m), 3.85 (1H, br s), 4.75 (1H, m.), 6.60 (1H, d. I _HF 8.0 Hz), 6.95 (1H, d. I _HF 14.0 Hz).

IR spectrum (KBr, disk, cm ^-1 ): 3350, 2980, 1610, 1510, 1175, 855.

MS spectrum (m, e): 246 (M ⁺ , 5%), 244 (M ⁺ , 17%), 176 (100%), 41 (61%).

Elemental analysis. The calculated values of C ₁₁ H ₁₄ N ₂ OClF, C 53.80 (53.99); H 5.74 (5.77); N, 11.35 (11.45).

 The invention is further illustrated by way of example preparations of a herbicidal agent comprising a compound of the present invention as an active ingredient, and examples describing the herbicidal effect exerted by the herbicidal agent. Parts are given by weight.

 An example of a preparation 1 (emulsifiable preparation).

 Compound 10 of the present invention (20 parts) xylene (35 parts), cyclohexane (40 parts), and Sorbol 900A (5 parts) [Toho Chemical Co. Ltd. evenly mixed to obtain an emulsifiable preparation. Other compounds of the present invention were also processed as described above to obtain emulsifiable preparations.

 Formulation Example 2 (Wettable Powder)

 A mixture of 50 parts of compound 10 of the present invention, 25 hours diatomaceous earth, 22 parts of clay and 3 parts of Lunox P100C (Toho Chemical Co. Ltd.) were uniformly mixed and ground to obtain a wettable powder. Other compounds of the present invention were also processed as described above to obtain wettable powders.

 An example of a preparation 3 (granules).

 A mixture of 5 parts of compound 10 of the present invention, 35 parts of bentonite, 55 parts of talc and 5 parts of lignin sodium sulfonate was evenly mixed and ground, and then mixed with the addition of water. The mixture was granulated by extrusion from a granulator, dried, and granules were obtained by controlling the grain size.

 Production Example 4 (Powdered Agent). A mixture of 3.11 g of compound 10 of the present invention, 5 g of propylene glycol, 5 g of Newcalgen FS-3 (Takemoto Yuxi), 10 g of Newcalgen D-3020 (Takemoto Yuxi), 0.5 g of Kunipia G4 (Kunimayn Industri), 1 g Newcalgen EX-70 (Takemoto Yusi), 0.1 g of Pronal EX-300 (Toho Chemical) and 75.29 g of xanthan gum were ground for 1.5 hours in a small water mill with 100 ml glass beads (diameter 1-2 mm )

The resulting powder was sieved to obtain 86 g of a (flowing) powdery agent. The active ingredient content determined by liquid chromatography was 3.21%
Production Example 5 (0.5% granular agent). To 285.65 g of UA clay (Canto Bentonite Industry) was added a solution prepared by dissolving 1.6 g of compound 10 of the present invention in 20 ml of acetone. The mixture was well mixed and dried at room temperature. Surfactants consisting of 15 g of Newcalgen G-285 (Takemoto Yuxi) and 7.5 g of Newkalgen DR-705 (Takemoto Yuxi) were added to the dried mixture. The resulting mixture was mixed, granulated with a cylindrical small diameter extruder and dried at 50 ° ^C. The obtained grain was treated to obtain 212 g of a granulated agent with a particle size of 16-48 mesh. The active ingredient content determined by liquid chromatography was 0.503%
Production Example 6 (emulsifiable agent). To 56.55 g of compound 10 of the present invention, 66 g of ST-30 Newcalgen, 5.5 ml of 1,3-dimethyl-2-imidazolidinone, 55 ml of dimethyl sulfoxide and 390 ml of Solvesso 150 (aromatic naphtha having a high boiling point) were added. The mixture was completely mixed to obtain an emulsifying agent. The active ingredient content determined by liquid chromatography was 10.3%
To determine the herbicidal activity of the agents, the resulting preparations were tested as follows.

 Test Example 1 (action on weeds in a rice field).

 Wagner’s pots 1/5000 ar were filled with rice field soil and sown with seeds of early field mustard, Monochoria and Japanese reeds and rice plants were planted in them (type: Nihonbare) at the stage of 2-3 leaves. Pots were kept when watering. After 5 days the surface of the water was treated with a dilute solution of the compound of the present invention, converted into the form of a wettable powder or emulsifiable preparation according to examples of preparations in predetermined amounts of 5, 2.5 and 0.5 g / ar. On the 20th day after the treatment, the herbicidal effect on the test weeds and damage to the rice plants was investigated in accordance with the following standard criteria. The results are shown in table. 1 and 2.

 As a control compound, a commercially available compound (A) was used, using the same preparations and processing methods using the indicated standard evaluation criteria, weed control activity and damage to the crop were studied. Its results are also shown.

Контроль, соединение А (Ронстар).

Control, compound A (Ronstar).

 Test example 2 (action when processing field soil).

Tanks having a surface area of 16 x 10 cm ² and a depth of 7 cm were filled with field soil and sown with seeds of South African millet, common white marie, blackberry, soybean and corn. The containers were then covered with a 1 cm thick soil layer. The next day, a dilute solution of the compound of the present invention, converted into a preparative form of a wettable powder or an emulsifiable preparation in accordance with the preparation examples, was added dropwise evenly on the covering soil layer in predetermined quantities of 20, 10 and 5 g / ar On the 20th day after application, as in Test Example 1, herbicidal activity was tested against test weeds and damage to soy and corn. The test results are shown in table. 3.

 Test Example 3 (action when applied on foliage).

Tanks (trays) having a surface area of 16 x 11 cm ² and a depth of 7 cm were filled with field soil and sown with seeds of South African millet, common white marie, blackberry and soy. 15 days later a dilute solution of a compound of the present invention, converted into a wettable powder or emulsifiable formulation, is applied by spraying or spraying at predetermined concentrations in water in an amount of 10 l / ar. On the 20th day after the treatment, the effect of weed control on the tested weeds and soybean damage was studied in the same manner as in test example 1. The results are shown in table. 4.

 Test Example 4 (action on weeds in a rice field).

 Pots with an area of 1/5000 ar were filled with soil from the rice field and then sown with seeds of Echinochlod oryzicola (I), Monochoria Vaginalis (2), Eleocharis acicularis (3), Scirpus jincoides (4) and other annual broad-leaved weeds and rice plants were transplanted into them ( view: Kosihikari) at the stage of 2-3 leaves. Pots were kept under humidification with water. The next day, the treatment was carried out with a dilute solution of a compound of the invention prepared in the form of a wettable powder or an emulsifiable agent, according to examples of their preparation in a predetermined amount per ar.

 On the 15th day after the addition of the solution, the herbicidal effect on the experimental weeds and the damage to the rice plants was examined, using the indicated evaluation criteria.

 A similar test was performed using control composition A.

 The results are shown in table. 5.

 Test Example 5 (action when processing field soil).

Tanks having a surface area of 10 x 10 cm ² and a depth of 7 cm were filled with soil from the field and sown with seeds of Echinochlod crus-galli (6), Digitalia cibiaris (7), Amaranthus viridis (8), Chenopodium albuni (9) and corn. The containers were then covered with a 1 cm thick soil layer. The next day, a diluted solution of a compound of the invention prepared in the form of a wettable powder or an emulsifiable agent according to examples of their preparation was uniformly added dropwise in a predetermined amount onto a coated soil.

 On the 15th day after the application of the solution, the herbicidal activity of the experimental weeds and the damage to the corn were examined. The results are shown in table. 6.

 Test example 6 (action when applied to foliage).

Tanks having a surface area of 16 x 11 cm ² and a depth of 7 cm were filled with soil from the field and sown with seeds of Echinochloa erus-galli (10), Digitalia ciliaris (11), Amaranthus viridis (12), Chenopodium album (13) and corn.

 After 15 days, the leaves of the grown plants were sprayed with a dilute solution of a compound of this invention, prepared as a wettable powder or emulsifiable agent, at predetermined concentrations in 20 l of water per ar.

 On the 10th day after the treatment, the herbicidal effect on the experimental weeds and the damage to the corn was investigated.

 The results are shown in table. 7.

Claims (7)

1. Derivatives of benzene containing a heterocycle of the general formula

where RC ₃ C _{8 is a} cycloalkyl group which may be substituted by a C ₁ C ₆ alkyl group:
X is halogen;
Z group of the formula

2. The compound according to claim 1, characterized in that R is a cyclopentyl group substituted by a C ₁ C ₆ alkyl group. 3. The compound according to claim 1 or 2, characterized in that the Z group of the formula

4. The compound according to claim 1 or 2, characterized in that the Z group of the formula

5. A method for producing an N-substituted phenyl-3,4,5,6-tetrahydrophthalimide derivative of the general formula

where RC ₃ C _{8 is a} cycloalkyl group which may be substituted with a C ₁ C ₆ alkyl group;
X is halogen
characterized in that the aniline derivative of the general formula

where R and X have the indicated meanings,
subjected to interaction with 3, 4, 5, 6-tetrahydrophthalic anhydride. 6. A method of obtaining an N-substituted derivative of phenyl-3, 4, 5, 6-tetrahydrophthalimide of the general formula

where RC ₃ C _{8 is a} cycloalkyl group which may be substituted with a C ₁ C ₆ alkyl group;
X halogen
characterized in that the phenol derivative of the general formula

where X has the indicated meanings,
subjected to reaction with a compound of the General formula
RY,
where R has the indicated meanings;
Y chlorine, bromine, iodine, methylsulfonyloxy group or p-toluenesulfonyloxy group,
in the presence of a base. 7. A method of obtaining a 2N-substituted derivative of phenyl-4,5,6,7-tetrahydro-2H-indazole of the General formula

where RC ₃ C _{8 is a} cycloalkyl group which may be substituted with a C ₁ C ₆ alkyl group;
X halogen
characterized in that the hydrazine derivative of the general formula

where R and X have the indicated meanings,
subjected to reaction with ether cyclohexanone-2-carboxylic acid of the General formula

where R ₃ C ₁ C _{6 is an} alkyl group,
to obtain an indazolone derivative of the general formula

where R and X have the indicated meanings,
and then the named indazolone derivative is chlorinated. 8. The method of obtaining 2N substituted phenyl 4,5,6,7 tetrahydro 2H - indazole derivative of the General formula

where RC ₃ C _{8 is a} cycloalkyl group which may be substituted with a C ₁ C ₆ alkyl group;
X is halogen
characterized in that the reaction of the phenolic derivative of the General formula

where X has the indicated meanings,
with a compound of the general formula
RY,
where R has the indicated meanings;
Y chlorine, bromine, iodine, methylsulfonyloxy group or p-tolylsulfonyloxy group,
in the presence of a base. 9. A herbicidal agent comprising the active ingredient a benzene derivative containing a heterocycle, and target additives, characterized in that it contains a compound of the general formula as a benzene derivative containing a heterocycle

where RC _{3 is a} C ₈ cycloalkyl group, optionally a C ₁ to C ₆ substituted with an alkyl group;
X is halogen;
Z group of the formula

the following content of ingredients, wt. Active ingredient 0.5 50
Target Supplements Else
10. The herbicidal agent according to claim 9, wherein R is a cyclopentyl group substituted with a C ₁ C ₆ alkyl group. 11. The herbicidal agent according to claim 9 or 10, characterized in that the Z group of the formula

12. The herbicidal agent according to claim 9 or 10, characterized in that the Z group of the formula

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