JPS58124758A - Benzenesulfonamide derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI(R<1> is halogen, hydroxy, lower alkyl, lower alkoxy; R<2> is halogen, nitro, amine, cyano; R<3> is halogen; R<4>, R<5> are H, lower alkyl, aralkyl, lower alkanoyl, aryl, heterocyclic group) and its salt. EXAMPLE:2-Chloro-3-nitro-4-phenoxybenzenesulfonamide. USE:Diuretic and hypotensor. PREPARATION:For example, the reaction of a substituted benzenesulfonic halide of formula II (X is halogen) such as 2-chloro-3-nitro-4-phenoxybenzenesulfonyl chloride with an amine of HNR<4>R<5> such as benzylamine is carried out in chloroform in the presence of triethylamine to give the compound of formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel benzene nulphonamide derivative having diuretic and antihypertensive effects, and more particularly, it relates to a novel benzene nulphonamide derivative having diuretic and antihypertensive effects, and more specifically, it has the general formula [wherein R is a halogen atom, a hydroxy group, a lower alkyl group] , amino group, lower alkoxy group, aryloxy group, lower alkenyloxy group, amino (lower) alkyl group, hydroxy (lower) alkyl group, lower alkanoyloxy (lower) alkyl group, lower alkylthio group, arylthio group, aralkylthio group , acyl group, lower alkanoylamino group, carboxy group, N, S-containing 5-membered heterocyclic sothioureido group, cyano group or carbamoyl group, R
is a halogen atom, R and R are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkoxy (lower) alkyl group, an aralkyl group, a lower alkanoyl group, a lower alkylcarbamoyl group, a cycloalkane carbonyl group, an N-containing '6M aromatic hetero Ring-substituted (lower) alkyl group, 0-containing 5
It means a (lower) alkyl group substituted with a 5-membered heterocyclic ring, a (lower) alkanoyl group substituted with a 0-membered heterocyclic ring, an aryl group, an (imino)azidomethyl group, or a 5-membered heterocyclic group containing N, respectively, and the aryl of R The oxy group may be substituted with one or more halogen atoms, lower alkyl groups, carboxy groups, lower alkoxycarbonyl groups, halo(lower) alkyl groups or lower alkoxy groups, and the N of R
, the S-containing 5-membered heterocyclic group may be substituted with a hydroxy group, a lower alkyl group, a lower alkylamino group, or a lower alkylimino group, and the 0-containing heterocyclic group of R1 is It may be substituted with an oxo group and/or a lower alkyl group, the aryl group and aralkyl group of R and R may be substituted with a halogen atom or a nitro group, and R and R5 are may form a 6-membered heterocycle together with the N atom, and this 6-membered heterocycle may be substituted with a hydroxy (lower) alkyl group or an O-containing 5-membered heterocycle-substituted lower alkanoyl group, and R and R5 may be taken together to form a lower alkylidene group optionally substituted with lower alkylamino, and R and R may be combined to form the formula [wherein Z is a carbonyl group or a sulfonyl group, R6
is a lower alkyl group, a halo (lower) alkyl group or a cycloalkyl (lower) alkyl group, R7 is a hydrogen atom, R
8 means a hydrogen atom or an aryl group, respectively, and R
6 and R7 may be combined to form an N-containing 5-membered heterocyclic group, and the aryl group of R8 may be substituted with a halogen atom and/or an aryloxy group. and when R is a halogen atom or an amide group, B2 is not a carbamoyl group] and salts thereof.

Each definition in the above general formula (1) representing the object of this invention will be explained below.

Halogen atoms include fluor, chloro, bromo and iodo.

Examples of the aryl group include phenyl, naphthyl, tolyl, gysylyl, mesityl, cumenyl, and the like. These aryl groups may be substituted with one or more halogen or nitro as described above.

Examples of the aryloxy group include phenoxy, 2-tolyloxy, 3-tolyloxy, 4-tolyloxy, 2,
6-xylyloxy, 2,4-xylyloxy, 2,6
-xylyloxy, 6,4-xylyloxy, 3.5-
Examples include xylyloxy, naphthyloxy, etc., and these aryloxy groups include furoff 1/, chloro, bromo,
Halogen atoms such as iodine, lower alkyl groups, carboxy groups, methoxycarbonyl and ethoxy forces! Lower alkoxycarbonyl groups such as levonyl, chloromethyl,
Halo (lower) 7t such as dichloromethyl, bromomethyl, bromoethyl, fluoromethyl, trifluoromethyl, etc.
The v'p group may be substituted with a lower alkoxy group such as methoxy, ethoxy, or propoxy.

Examples of the arylthio group include phenylthio, tolylthio, xylylthio, and the like.

Examples of lower alkyl groups include linear or branched hydrocarbons having 1 to 7 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, and hexyl. Residues are exemplified.

Examples of the 4j5Jt7tV kylthio group include methylthio, ethylthio, propylthio, butylthio, and isopropylthio.

Examples of lower alkyl groups include methoxy, ethoxy,
Examples include propoxy, isopropoquine, butquin, 1-methylbutoxy, pentyloxy, 1-methylbutoxy, 1-ethylpropoxy, hexyloxy, and the like.

A lower alkylamino group is an amino residue substituted with a lower alkyl group as described above, such as methylamino,
ethylamino, isopropylamino, propylamino,
Butylamino, tertiary butylamino, pentylamino,
Examples include 7-(lower) alkylamino such as hexylamino, and di(lower) alkylamino such as dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino, diethylamino, and diethylamino.

Examples of the lower alkenyl in the lower alkenyloxy group include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 6-butenyl,
1. Straight chain or branched chain hydrocarbon residues having 1 to 2 double bonds such as 3-butadienyl, 1-methyl-1-propenyl, 1-methylrv-2-propenyl, pentenyl, hexenyl, etc. Among these, a preferable example is allyloxy.

The amino (lower) alkyl group is one in which an amino group is substituted at any position on the lower alkyl group defined above, and among them, aminomethyl is a preferable example.

A hydroxy (lower) alkyl group is a lower alkyl group defined above with a hydroxy group substituted at any position, such as hydroxymethyl, 1-hydroxyethyl, 2:hydroxyethyl, 1,2-dihydroxyethyl. , 1-hydroxypropyl, 2-hydroxypropyl, 6-hydroxypropyl, 2.3-dihydroxypropyl, 1-hydroxyisopropyl, 2-hydroxyisopropyl, hydroquinbutyl, hydroxypentyl, hydroxyhexyl, etc., among which preferred examples include Examples include hydroquinemethyl and hydroxyethyl.

As a lower alkanoyloxy (lower) alkyl group,
For example, acetoxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, propionyloxypropyl, propionyloxybutyl, butyryloxymethyl, imbutyryloxymethyl, tertiary butyryloxymethyl, Examples include 39-butyryloxyethyl, 39-butyryloxypropyl, pentanoyloxymethyl, hexanoyloxymethyl, and the like.

Examples of aralkyl groups include benzyl, phenethyl,
Examples include phenylpropyl, phenylbutyl, phenylhentyl, phenylhentyl, diphenylmethyl, trityl, tolylmethyl, xylylmethyl, naphthylmethyl, and the like. The aryl moiety in these aralkyl groups may be substituted with the above-mentioned halogen atom or nitro group, such examples include 2-chlorobenzyl, 3-chlorobenzyl, 4-10 lobenzyl, 4-fluorobenzyl. , 4-nitrobenzyl, 4-tolylmethyl, and the like.

Examples of the aralkylthio group include benzylthio, phenethylthio, tolylmethylthio, tolylethylthio, and xylylmethylthio.

A halo(lower) alkyl group is a lower alkyl group defined above substituted with 1 to 3 halogen atoms, such as trifluoromethyl, trichloromethyl, dichloromethyl, dibromomethyl, short methyl, chloroethyl, bromoethyl. , iodoethyl, chloropropyl, bromopropyl, iodopropyl and the like.

Examples of lower alkoxy (lower) alkyl groups include:
Methoxymethyl, ethoxymethyl, propoxymethyl,
Isopropoquine methyl, butoxymethyl, benzyloxymethyl, hexyloxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, poxyethyl,
Examples include bencholeoxyethyl, hexyloxyethyl, methoxypropylene, methoxybutyl, methoxybenzene, methoxyhexyl, and the like.

Examples of lower alkanoyl groups include formyl acetyl, propionyl, butyryl, isobutyryl, valeryl,
Examples include isovaleryl, pivalyl, lauroyl, and pivalyl.

Examples of the lower alkanoylamino group include formamide, acetamide, propionamide, butyramide, pentanamide, hexaneamide, and the like.

Examples of the lower argylcarbamoyl group include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, prophylactic carbamoyl, and isopropylic carbamoyl.
Lebamoyl, methyl ethyl lecarmoyl, butylka! Levamoyl, isobutyl carno! Pencilka! Examples include livermoyl, hexyl-levermoyl, and the like.

The aroylthioureido group is a thioureido group substituted with an aroyl group at the 6-position, and examples thereof include benzoylthioureido, toluoylthioureido, naphthoylthioureido, and gisoylthioureido.

Examples of the cycloalkanecarbonyl group include evacyclopropanecarbonyl, cyclobutafcalevonyl, cyclopentanecarbonyl, cyclohexaS-methylisothioureido, S-ethylisothioureido, S-propylisothioureido, and the like.

Examples of cycloalkyl (lower) alkyl groups include Eva,
Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohebutylmethyl, cyclopentyl-ethyl, cyclobentylpropyl, cyclobentylbutyl, cyclopentylpentyl, cyclopentylhexyl and the like.

The acyl group is an acyl derived from an organic carboxylic acid or an organic sulfonic acid.
There are aliphatic acyl, aromatic acyl, aromatic substituted aliphatic acyl, heterocyclic acyl and heterocyclic substituted aliphatic acyl,
A more detailed example is as follows.

Examples of the aliphatic acyl include alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, and balmitoyl, alkenoyl groups such as acryloyl, methacryloyl, and crotonoyl, sulfo groups, mesyl, ethanesulfonyl, Propanesulfonyl, butanesulfonyl*
:=, /lz, etc. (7) Pi1nylalkaneulfonyl group, ;--sulfonyl, alkenenulfonyl group such as propenesulfonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, Alkoxycarbonyl groups such as tertiary butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl; acid halide groups such as chloroformyl, chlorosulfonyl and bromosulfonyl; acid amide groups such as carbamoyl and sulfo-moyl; methylcarbamoyl and dimethylcarbamoyl; Examples include alkylcarbamoyl groups such as ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, pentylcarbamoyl, and hexylcarbamoyl. These aliphatic acyls may be further substituted with a halogen atom such as chloro, bromine, fluoro, or iodo, a hydroxy group, or a lower alkoxy group. Such groups include, for example, chloroacetyl, bromoacetyl, methoxyacetyl, 2,3-dihydroxypropoxycarbonyl, 1,2-dihydroxyethoxycarbonyl, bis(methoxymethyl)methoxycarbonyl, bis(ethoxymethyl)ethoxycarbonyl. , bis(butoxymethyl)methoxycarbonyl and the like.

Examples of aromatic acyl include aroyl groups such as benzoyl, toluoyl, and xyloyl.

Examples of the aromatic substituted aliphatic acyl include phenylacetyl, tolylacetyl, xylylacetyl, naphthylacetyl, phenylpropionyl, tolylpropionyl,
Arylcarbamoyl groups such as naphthylpropionyl, 2-methyltv-2-phenylpropionyl, phenylbutyryl, tolylbutyryl, arylcarbamoyl groups such as phenylcarbamoyl, tolylcarbamoyl, xylylcarbamoyl, phenylmethyl, tolylmesyl, naphthylmesyl, Aralkanulphonyl such as phenylethanesulfonyl and phenylpropanesulfonyl
Examples include aralkenesulfonyl groups such as tulfonyl, tolylmesylphonyl, and vinylnaphthyl-≠#≠pulfonyl, and aralkycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropoxycarbonyl, and diphenylmethoxycarbonyl. I get vignetted.

The aryl moiety in these aromatic acyl and aromatic-substituted aliphatic acyl groups may be substituted with a halogen atom, nitro group, aryl group, amino group, or aryloxy group, and preferred examples include 0- Chlorophenylcarbamoyl, 〇-chlorophenylacetyl, (0-
phenoxy)phenylcarbamoyl, (3-chloro-2
-phenoxyphenyl)carbamoyl, (0-phenoxy)phenylacetyl, N-(2-phenoxy-5-chlorophenyl)carbamoyl, and the like.

Examples of the heterocyclic acyl include a 5- to 6-membered heterocyclic carbonyl group containing at least one double atom selected from a nitrogen atom and an oxygen atom, and specifically, pyrrole carbonyl, nicotinoyl, isonicotinoyl. , pyrazine carbonyl, piperidine carbonyl, piperazine carbonyl, triazine carbonyl, pyrrolidine carbonyl, imidacillin carbonyl, furoyl, hyran carbonyl, morpholine carbonyl, oxazole carbonyl, furazine carbonyl, inxazole carbonyl, oxadiazole carbonyl, etc. .

The heterocyclic group in these heterocyclic carbonyl groups is substituted with one or more hydroxy groups, lower alkyl groups, aryl groups, halo-substituted aryl groups such as chlorophenyl and bromophenyl, aralkyl groups, hydroxy (lower) alkyl groups, etc. may have been done. The most preferable examples of these substituted heterocyclic carbonyl groups include 4-(4-chlorophenyl)-4-hydroquinepiperidicaflevonyl, 4-(benzhydryl)hiberazinyl, and the like.

As a heterocyclic substituted aliphatic acyl, for example, a nitrogen atom as a heteroatom? and (or) a 5-membered double-substituted aliphatic acyl containing an oxygen atom, examples tJ-j, heterocyclic alkanoyl groups such as furylacetyl, furylpropionyl, tetrahydrofurylacetyl, tetrahydrofurylpropionyl, pyrrolecarbamoyl, imidazole Carbamoyl, pyrazole carbamoyl, hyridine carbamoyl, pyrazine carbamoyl, piperidine carbamoyl, piperazine carbamoyl, pyrimidine carbamoyl, hyridazine carbamoyl, triazole carbamoyl, triazine carbamoyl, imidazolidinylbamoyl
and heterocyclic carbamoyl groups such as furylcarbamoyl, hylancarpamoyl, morpholinecarbamoyl, oxazolecarbamoyl, furylcarbamoyl, isoxazolecarbamoyl, and oxadiazolecarbamoyl; heterocyclicalkylcarbamoyl groups such as furylmethylcarbamoyl and tetrahydrofurylmethylcarbamoyl; furylmethylsulfamoyl, furylethylsulfamoyl,
Examples include heterocyclic alkylsulfamoyl groups such as tetrahydrofurylmethylsulfamoyl and tetrahydrofurylethylsulfamoyl. The heterocyclic moiety in these heterocyclic-substituted aliphatic acyl groups may be substituted with lower alkyl, hydroxy, amino, etc., and the most preferred example is uN-methyl-N-(2-methyl-2-tetrahydrofuryl). methyl) carbamoyl,
N-methyl-N-(2-methyl-2-tetrahydrofurylmethyl)sulfamoyl, 2,6-dimethylpiveridinocarpamoyl, and the like.

Examples of the N, S-containing 5-membered heterocyclic group include thiazolyl, thiazolinyl, thiazolidinyl, thiadiazolyl,
Tetrahydrothiadiazolyl, isothiazolyl, etc. are exemplified, and these N, S-containing 5-membered heterocyclic groups are lower alkyl groups, lower alkylamino groups, or lower alkylimino groups such as methylimino, ethylimino, propylimino, butylimino, etc. may be substituted with a group, a hydroxy group, etc. Suitable examples of the substituted N, S-containing 5-membered heterocyclic group include Ifi2-(methylamino)cy4-thiazolyl, 2-(methylimino)-6-methyl-4-hydroxy-4-thiazolidinyl, etc. .

Examples of the heterocyclic group in the O-containing network heterocyclic oxy group include benzofuryl, 2,3-dihydrobendifuryl, chromenyl, chromanyl, and the like. It may be substituted with an alkyl group or an oxo group, and the most preferred example is 2
-Oxo-5-methyl-2,3-dihydrobenzofuran-7-yloxy group may be mentioned.

Examples of the heterocyclic group in the N-containing 6-membered aromatic heterocycle-substituted C (low R) alkyl group include pyridine group pyrimidinyl,
Examples include pyrazinyl, triazinyl, etc., and preferred examples having such groups include pyridylmethyl, triazinylmethyl, etc.

Examples of the heterocyclic group in the 0-containing 5-membered heterocyclic substituted (lower) alkyl group include furyl, tetrahydrofuryl, etc., and preferred examples include furylmethyl, tetrahydrofurylmethyl, and the like.

Examples of the N-containing 5-membered heterocyclic group include pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolidinyl,
Examples include triazolyl and tetrazolyl.

The 0-containing 5-membered heterocyclic-substituted lower alkanoyl group is a lower alkanoyl group substituted with the 0-containing 5-membered heterocyclic group as described above, and specific examples include furoyl and tetrahydrofurancarbonyl.

Examples of R4 and R forming a 6-membered heterocycle together with the N atom to which they are bonded include piperidino, morpholino, 1
-piperazinyl, etc., and these rings may be substituted with the above-mentioned hydroxy (lower) alkyl group or O-containing 5-membered heterocyclic substituted lower alkanoyl group, and preferable examples include u, 4-(2- hydroxyethyl)
-1-piperazinyl, 4-(2-furoyl)-1-piperazinyl, etc. are exemplified.

Examples of lower alkylidene groups formed by R and R together include methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, hexylidene, etc. It may be substituted with a lower alkylamino group such as methylene, lyaminomethylene, dimethylaminomethylene,
Examples include diethylaminomethylene, methylaminoethylidene, and ethylaminoethylidene.

R1 and R2 combine to form the formula %formula% When the compound is represented by the formula It is expressed as

Examples where the aryl group of R in the above formula is substituted with a halogen atom or an aryloxy group include 1, 2.
Examples include 3- or 4-chlorophenyl, 2-phenoxyphenyl, and 2-phenoxy-5-chlorophenyl. The salts in these benzenesulfonamide derivatives are preferably pharmacologically acceptable salts, specifically alkali metal salts such as sodium 4 and potassium salts, alkaline earth metal rings such as calcium salts, magnesium salts, etc. , salts with inorganic bases or acids such as ammonium salts, hydrochlorides, hydrobromides, sulfates, phosphates, carbonates, inorganic acid salts such as deuterate, trimethylamine salts, triethylamine salts, pyridine. salt, prolactin salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzileethylenediamine LN-methylglucamine salt, jetanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt, Amine salts such as phenethylbenzylamine salts, acetates, maleates, lactates, tartrates, methanulphonates, benzene nulphonates,
Examples include salts with organic bases or acids such as carboxylates or sulfonates such as toluene sulfonate, basic or acidic amino acid salts such as arginine salt, aspartate, glutamine salt, lysine salt, and serine salt. be done.

The outline of the method for producing the target compound of the present invention is shown in the following reaction formula.

Manufacturing method A (1) (13W fn11B Manufacturing method G '19) (l□.) Manufacturing method H (11O) (111) (1□5) (1□6) CIIO) (I17) (I18) (119) Manufacturing method N (12o) (12□) Manufacturing method 0 '' 22 ) (123) 1 Manufacturing method P '124) (I25) Manufacturing method Q '' 21 ) (12,s) Manufacturing method R (127) ( 128) Manufacturing method 5 (129) (13o) Manufacturing method T (13,) (12,) Manufacturing method U '132) (133) Manufacturing method ■ (134) (I35) Manufacturing method W 7 Manufacturing method X - Manufacturing method Z 408- [In the formula, R1, R2, R3, R4, R5, R6, R7 and R8 each have the same meaning as above or a halogen atom, Ra is a hydroxy group, lower alkoxy group, aryloxy group, lower alkenyl an oxy group or an O-containing fused heterocyclic oxy group, in which the aryloxy group and the O-containing fused heterocyclic oxy group may each be substituted with the previously defined substituents, and Rb is a lower alkylthio group,
Arylthio at-t is an aralkylthio group, R1 is an amino group or a lower alkanoylamino group, Ra is a lower alkanoylamino group, Ro is a carboxy group, a carbamoyl group, an amino (lower) alkanoyl group or a hydroxy (lower) alkanoyl group, is a hydroquine (lower) alkyl group or an amino (lower) alkyl group, Rg is a lower alkanoyloxymethyl group, Rh is a residue obtained by removing OH from an organic carboxylic acid, R1 is a carboxy group or a hydroxy (lower) alkanoyl group, Rj is a Haloformyl group or halo (low R) alkanoyl group, R is halos I lephonyl X, R1 is nulfamoyl group HN filJll
Sulfur moyl group, Rm is a lower alkylthio group, aralkylthio group or arylthio group, Rn is an alkoxycarbonyl-substituted aryloxy group, Ro is a poxy-substituted aryloxy group, R1 is a haloformyl group, an imidazole carbonyl group or a lower alkoxycarbonyl group ,R
Ku is a lower alkylamino group, Kano is a thioureido group or aroylthioureido group, Yuzu is an aroylthioureido group, Rg is a thioureido group, R2 is an S-lower alkylisothioureido group, RR is a lower alkanoyl group, a lower alkylcarbamoyl group , cycloalkyl (lower) alkanoyl group, 0-containing 5-membered heterocyclic substituted (lower) alkanoyl group, lower alkyl group, lower alkoxy (lower) alkyl group, aralkyl group, N-containing 6-membered aromatic heterocyclic substituted (lower) alkyl group , aryl group, 0-containing 5-membered heterocycle substitution (lower)
It is an alkyl group or an N-containing 5-membered heterocyclic group, and the aryl group and aralkyl group may be substituted with a halogen atom or a nitro group, R9 is a hydrogen atom or a lower alkylamino group, and R10 and R11 are lower Alkyl group, R and R are lower alkanoyl groups, R is an amine residue or alcohol residue, R15 is an amino group or substituted amino group, R and R17 are hydrogen atoms or lower alkyl groups, then the above production method A-Z will be explained in detail.

Production method A The target compound (1) and its salt are produced by reacting compound (III) with compound (It) or its salt.

This reaction usually proceeds easily by stirring the compound (]) and (III) in an aqueous or organic solvent under water cooling and heating. In addition, as a catalyst, the first to third
grade organic amines, sodium acetate, sodium hydroxide,
When the reaction is carried out in the presence of a base such as potassium hydroxide, the reaction proceeds more easily, but it is also possible to use an excess of liquid compound (II) in place of the solvent or catalyst.

Production method B Target compound (+2) and its salt are prepared by adding alcohol (F/) or its reactive boron to compound (Is) or its salt.
Examples include acid esters, sulfo/acid esters, and ammonium salts. This reaction is generally carried out for the compound (1+
) together with compound (IV) or a reactive derivative thereof, and the reaction proceeds more easily if the reaction is further carried out in the presence of a base such as pyridine or potassium carbonate as a catalyst.

However, heating and catalysts are not essential. Further, it is more convenient to use a liquid compound (l or a reactive derivative thereof) also as a solvent.

Production method C The target compound (I4) and its salt can be obtained by reacting compound (I3) or its salt with aldehyde (V) or a reactive derivative thereof. Acetal is exemplified as a reactive derivative of aldehyde (■). This reaction usually only requires stirring the mixture of compound (I3) and (V) or its reactive derivative, but the reaction is easier if the reaction is carried out in the presence of thionyl halide, phosphorus pentachloride, etc. proceed.

Production method The target compound (16) and its salt can be obtained by reacting the halide (I5) with the compound (■) or its salt. Examples of the salt of compound (M) include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts. Various reaction conditions can be selected depending on the starting material, but if the starting material has low activity, alcohol, acetone, dimethylformamide, dimethyl sulfoxide may be used in the presence of a base such as sodium alcoholade, potassium hydroxide, or sodium hydroxide. Both may be heated under reflux in an organic solvent such as It is also possible to use small amounts of metals such as copper as catalysts.

Production method E The target compound (17) and its salt can be obtained by reacting compound (I5) or its salt with compound (■) or its reactive derivative.

The reaction conditions are the same as the above production method, or the compound (■
) has a slightly higher activity than compound (M) in the production method, so the reaction often proceeds under milder conditions or in a shorter time.

Production method F The target compound (I8) and its salt can be obtained by reacting compound (■) with compound (I5) or its salt. The reaction conditions are similar to those in the above production method, but since the starting compound (■) itself acts as a base, the reaction often proceeds easily without using any other base as a catalyst.

Production method G Target compound (1+o) and its salt are compound (I9)
It can be obtained by reducing by a known method. As the reduction method, any method that converts a nitro group into an amide 7 group can be employed, but the reaction proceeds easily by a chemical reduction method or a catalytic reduction method. Specifically, methods using metals such as iron, zinc, tin, and stannous chloride and acids such as hydrochloric acid and sulfuric acid, ammonium sulfide, ammonium hydrosulfide, sodium sulfide, sodium disulfide, ferrous sulfate, and sulfite. Chemical reduction methods using sulfides such as salts, catalytic reduction methods using metal catalysts such as nickel, cobalt, copper, chromium, iron, tin, platinum, palladium, and rhodium, electrolytic reduction, and strong reduction methods such as alkali metal hydroxides. Examples include reduction with phulkari and reduction with hydrazine.

Production method I (target compound (II+) and its salt are produced by compound (1+o
) with compound (+)F) or a reactive derivative thereof at the hydroxy group.

Examples of reactive derivatives in the hydroxyl group of the compound ψ(l) include those exemplified in Production Method B, but especially when reacting with the hydroxyl group as it is, the presence of an acid such as sulfuric acid or hydrochloric acid When a halide is used, the desired product (In) can be obtained in good yield by reacting it in the presence of a base such as an amine.

Manufacture Pope The target compound (112) and its salt are the compound (1+o
) is obtained by thiocarbamoylation.

Examples of the thiocarbamoylating agent include thiocyanate, aroylisothiocyanate, and the like. This reaction proceeds by heating the compound (+10) and the thiocarbamoylating agent in the presence or absence of an organic solvent.

Production method J Target compound (+14) and its salt are compound (113
) can be obtained by hydrolyzing. The hydrolysis reaction easily proceeds by heating compound (113) in the presence of an acid or base in water or a water-containing organic solvent under conditions that can hydrolyze the usual carboa trido group. The desired product (1x4) can be easily obtained by heating in an organic solvent, preferably with a base such as sodium hydroxide or potassium hydroxide.

However, is it hydrolyzed in the starting material (+13)? When a pancreatic group is present, these groups may also be hydrolyzed at the same time, and such cases are also included in the present invention.

In the production method, the target compound (++a) and its salt are compound (1+s
) with compound (X) or a reactive equivalent thereof. The reactive equivalent of compound (X) may be one that can alkylate a mercapto group, and specific examples include diazoalkanes, alkyl sulfates, and alkyl sulfonic acid esters. This reaction is preferably carried out by heating the compound (ls) and the alkyl halide in an organic solvent such as alcohol.

Production method The target compound (+17) and its salt are the compound (1+o
) can be obtained by the so-called Sandmeyer reaction or Gasoterman reaction, in which a halogen compound is produced by converting the amino group of diazonium salt into a diazonium salt and then decomposing it. Diazonium salts can be obtained by reacting compound (++o) (with nitrite or nitrite ester).This diazonium salt can be easily converted to the desired compound (11?) by adding cupric halide. can.

Production method M The target compound (119) and its salt are the compound (++s
) with compound (XI) or a reactive derivative thereof at the hydroxy group.

Examples of reactive derivatives at the hydroxy group of compound (XI) include halides, active esters, and acid anhydrides. This reaction is carried out by a conventional method of acylating an amine, preferably by heating the compound (l1g) and the reactive derivative of the compound CM) in an organic solvent or in its absence. In addition, when using the free compound CM) as a raw material compound, it is used in the presence of a Riedel-Crafts catalyst such as aluminum chloride, tin chloride, boron fluoride, zinc chloride, hydrogen fluoride, sulfuric acid, phosphoric acid, or a Lewis acid. When the reaction is carried out, the reaction progresses easily.

Production method N The target compound (+21) and its salt are the compound (120
) with an oxidizing agent. Oxidizing agents include potassium permanganate, potassium dichromate,
Nitric acid, gelene, etc. can be used alone or in combination. This reaction is carried out by heating compound (+20) and these oxidizing agents in an aqueous solvent.

Production method Q Target compound (123) and its salt are compound (+22.
) can be obtained by reducing. The reducing agent may be one that can convert a carbonyl group into a methylene group, but if the compound (+22) contains a functional group that is easily reduced such as a nitro group, for example, sodium borohydride and trifluoride may be used. By forming a diborane compound using a boron diethyl ether complex, a carbonyl group can be reduced to a methylene group in good yield without adversely affecting other functional groups G. However, if there is no group in the compound (+22) that is affected by a reducing agent, various methods using commonly used reducing agents such as lithium aluminum hydride, sodium borohydride, sodium metal and alcohol can be used. can be adopted.

Production method P Target compound (+25) and its salt 1 are compound (+2
It can be obtained by reacting 4) with compound (xn) or its reactive derivative at the hydroxy group.

When using free compound (xn) as a raw material in this reaction, acids such as hydrochloric acid, sulfuric acid, toluenesulfonic acid, boron trifluoride, zinc chloride, aluminum chloride, and tin chloride should be used in the presence of metals. Preferably, compound (xi) is heated in an organic solvent. Furthermore, when using a halide as a reactive derivative of compound (xi), it is preferable to carry out the reaction in the presence of a base such as pyridine or an alkali metal hydroxide. When using an acid anhydride as a derivative, it is preferable to carry out the reaction in the presence of the above-mentioned acid or base.

Production method Q The target compound (126) and its salt are the compound (+21
) or a reactive derivative thereof at the carboxy group with compound (xm).

Examples of reactive derivatives at the carboxyl group of compound (XIIl) include acid halides such as acid chlorides and acid bromides, acid anhydrides, salts such as sodium salts and ammonium salts, and active esters.

This reaction can be carried out in various reactions depending on the type of raw material compound, for example, the acid halide of compound (lz+) and the compound (xm).
When reacting with an organic amine, the target compound (lza) can be easily obtained by stirring both raw material compounds in an organic solvent.

This reaction can be carried out in the presence of various organic amines such as pyridine, dimethylamine, and triethylamine, and bases such as potassium carbonate and sodium hydroxide. compound (xm)
When used, it also acts as a catalyst.

For example, when the acid halide of the compound (+21) and the alcohol compound (xm ) can be obtained. In this reaction, weekly alcohol compound (xm) can also be used as a solvent1. Also, for example, when reacting free compound (+21) with organic amine compound (xm), phosphorus trichloride The desired amide compound (+26
) can be obtained.

For example, when reacting the free compound (+21) with the alcohol compound (xm), the desired reaction can be achieved by heating and dehydrating both in an organic solvent in the presence of an acid such as hydrochloric acid, sulfuric acid, or phosphoric acid. The ester compound (+26) can be obtained.

Furthermore, for example, when producing a compound in which the group nlh of the target compound (126) is a lower alkanoyl group, compound (xm) is activated with a metal-alkyl compound G such as sodium, magnesium, lithium, etc. (1
2+) is preferred. Especially the compound (xm)
The magnesium salt of malonic acid diethyl ester was obtained as a metal-alkyl compound of
), and finally alkylation by decarboxylation with an acid or base is simple and advantageous.

Production method R Target compound (+28) and its salt are compound (+27)
Obtained by halogenation. Various methods can be employed for this chlorogenation reaction depending on the type of compound (+27).

For example, when the group in compound (+27) is a carboxy group, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, etc., phosphorus oxyhalide, thionylreno-ride, The desired acid halide compound (
+28) can be obtained. .

For example, when the group RE in compound (lz7) & is a hydroxy (lower) alkanoyl group, halogenation can be easily achieved by using molecular halogens such as bromine, chloro, and iodo in addition to the halogenating agents mentioned above. The target compound (128) having a (lower) alkanoyl group is obtained.

Production method S The target compound (130) and its salt are the compound (+29
) with an amine compound (X+V). This reaction can be carried out in the same manner as in Production Method A described above.

Production method The target compound (129) can be obtained by oxidative cleavage of compound (13+)e in the presence of a halogen. This reaction can be easily carried out by reacting compound (131) with a molecular halogen such as chloro, bromo, or iodo in an organic solvent such as glacial acetic acid or acetolyl.

Production method U The target compound (133) and its salt are the compound (+32
) can be obtained by hydrolyzing. This hydrolysis reaction can be carried out by any method that hydrolyzes an alkyl ester and converts it into a carboxyl group, but preferably the compound (+32) is dissolved in an aqueous solution in the presence of a base such as sodium hydroxide or potassium hydroxide. This can be easily done by heating inside the container.

Production method V The target compound (13sC) can be easily obtained by hydrolyzing compound (+34). The hydrolysis reaction can be carried out in the same manner as in the production method U above, but preferably sodium hydroxide is used. , when compound (+34) is heated to reflux in an aqueous solution in the presence of a base such as potassium hydroxide.

Production method W The target compound (+37') and its salt are the compound (+3
It can be obtained by reacting compound (XV) or a derivative thereof with 6).

This is done by heating the sound object (XV) in an organic solvent such as alcohol, and a small amount of acid expansion such as hydrochloric acid or sulfuric acid or an organic acid such as benzenesulfonic acid or toluenesulfonic acid is added as a catalyst. The reaction then proceeds easily.

Production method X Target compound (+39) and its salt are compound (+38
) and compound (XVI) in the presence or absence of a solvent to easily obtain (C).

The target compound (+41) can be obtained by reacting the compound (+40) with the compound (Jun). This reaction (*) can be carried out in the same manner as in the production method W described above.

Production method 2 The target compound (143) and its salt are obtained from the compound (+42
) with compound (XVI).

This reaction is preferably carried out by stirring both starting materials a in an organic solvent such as acetone or alcohol at room temperature or under heating. Objectives obtained here (+43)
The thiazolidine ring is a tautomer with a compound in which the methylimino group substituted at the 2-position becomes a methylamino group, as represented by the following balanced formula.

Further, the desired product (I43) in which the hydroxy group substituted on the thiazoline ring described above is dehydrated to form a thiazole ring may be obtained, but this case is also included in the present invention.

Among the raw material compounds used in the above production methods A to Z, novel compounds can be produced by the methods shown in the reference examples or by any of the production methods A to Z. Also,
When the target compounds obtained by the above-mentioned various production methods C have free amino groups and/or carboxyl groups, these may be converted into desired salts Q by conventional methods.

Next, the diuretic and antihypertensive effects of the benzenesulfonamide derivative (1) obtained according to the present invention will be explained.

Diuretic effect experimental method After oral loading of 20 ml/Kg of physiological saline to male and female SD rats aged 6 weeks or older who had fasted for 18 to 24 hours, the test drug was suspended in 0.5% methylcellulose.
Administer 5 rnl/Kg orally. (However, control group rats LL received only 0.5% methyl cellulose for 5 r
Collect urine up to 6 hours after administration of the test drug, measure urine volume and electrolyte concentrations of Na4-, K+ and d-. Relative values are shown for rats administered the test drug.

Antihypertensive effect: Experimental method Suspended in oil and administered subcutaneously twice a week (301nf
I/h). At the same time as the start of DOCA administration, 1Φ saline is given instead of drinking water. After 5-7 weeks, the average blood pressure is 15 (~
Select animals with 200 mml and administer the test drug intraperitoneally (
10mg/Kg). To measure blood pressure, a cannula inserted into the femoral artery is connected to a blood pressure transducer, and the average blood pressure is electrically measured. The rate of decrease (%) in average blood pressure 6 hours after administration of the test drug is shown in the table.

]] Gen Zhen Gua □ As is clear from the above test results, the object compound (1) of the present invention is useful as a diuretic and antihypertensive agent. This compound (1) can be administered at a daily dose of 1 to 500 mg, 1 to 4 times a day, such as tablets, granules, powders, cuffs, etc.
It is administered in the form of syrup, injection, and tablets. In addition,
The dosage is adjusted as appropriate depending on the patient's age, body weight, symptoms, etc., or depending on the administration method. The various formulations mentioned above can be manufactured by conventional methods using conventional additives.

Next, the present invention will be explained with reference to examples.

-Example 1-(11; 3-nitro-4-phenoxyaniline (94,5y)
of dioxane (500 m(') solution at room temperature, stirring FN
- A dioxane solution of chlorosuccinimide (65,8y) is added dropwise. After stirring this solution at 60°C for 1 hour, dioxane was distilled off under reduced pressure. Brine was added to the residue, extracted with ethyl acetate, and then exploded with magnesium sulfate. The crude powder obtained by distilling off the ethyl acetate under reduced pressure was purified by silica gel column chromatography (developing solvent: toluene). , 2-chloro-3-nitro-4-phenoxyaniline (55,7y) is obtained as a yellow-orange powder.

mp55-59℃ 1, R (Nujol): 3475. 3375.
1525. 1260°1200cm' IslilR (DMSO-d6.δ): 5.87 (2
H, bs), 6.83-7.48 (7H, m) Elementary analysis: (C, 2) (, C/N 20.) - AL 1st shift: C54, 46, L (3, 43, yt
o,ss.

Ci 13.41) Actual value: C54,86+ H3,42, N10.75
゜CA! 13.75 Reference Example 1-(2) 2-10 Rho 3-21 Rho 4-Fe/Xy7 Niline (50,0y) is added to concentrated hydrochloric acid (127me) and dissolved with stirring at room temperature. To this solution, 15 cl-
Aqueous sodium nitrite solution (97y) was added dropwise, and the mixture was further stirred at the same temperature for 1II4I' minutes. This solution was mixed with acetic acid (1
91+++1')-water (32me) solution under stirring at room temperature. After stirring for 30 minutes, add 1.5 ml of water to obtain a yellowish brown paste. Extract this with ethyl acetate and dry the extract over magnesium sulfate. The residue was distilled off and recrystallized from diisopropyl ether to obtain 2-chloro-3-nitro-4-phenoxybenzene sulfonyl chloride (42,2y) as light brown lumpy crystals.mp 106-109
°CIR (Nujol): 1565. 1535.
1370. 1365°1050㎪-1 tlMR(L)MSO-d6. δ): 7.05(LH
, d, J=9Hz).

7.23-7.67 (5H, m), 8.10 (IH,
d, J-9Hz) Elemental analysis: (C1□H7Ce2N0
5S) Calculated value: C41,40,1 (2°03.H
4,02 actual value: C41,72+) 11.92.
N3.86 Reference example 2-m 4-(2=chlorophenoxy)-3-nitroaniline (
N-chloroconophosphate imide (6,912) was added to a dioxane (loome) solution of 13,7y) at room temperature with stirring.
A solution of 80 mf dioxane is added dropwise. After stirring at 35°C for 1 hour, the mixture is further stirred at 55°C for 11 hours.

After dioxane is distilled off under reduced pressure, brine is added, extracted with ethyl acetate, and dried over magnesium sulfate. Ethyl acetate 11. The distilled residue is powdered with a mixed solvent of n-hexane and diisopropyl ether, and the resulting powder is collected and recrystallized from ethanol to obtain a yellow powder of 8.7y. This was purified by silica gel-ram chromatography 7F (developing solvent: toluene), and 2-chloro-4-(2-chlorophenoxy)-3-nitroaniline (8.0!/-) was obtained as a yellow powder. ). 1n1) 101
~1038C IR (Nujol): 3470, 3380,
1530cIn-1HMR (DMSO-d6, δ):
5.92 (2H, bS), -6.88-7. fl
) (6H, m) Elemental analysis: (C12H8C12N203) Calculated value:
C48.18, H2.70, H9.37 Actual value: C4
8.17, H2, 70, H9.40 Reference example 2 -(
2+ Reference Example 1-(2-chloro-4-(2
-chlorophenoxy)-3-nitroayunone (1 2
, 8y) to a yellowish brown powder of 2-chloro-4-(2-
3-nitrobenzenesulfonyl chloride (3.1') is obtained. mplo.

~110°C Engineering R (Nujol): 1535, 1390,
1370. 1185cm-11t111R (DM
SO-d6, δ): 6.85(1)1, d, J=
9t(z).

7, 03-7.75 (4H, m), 8.03 (I
H, d, J = 9 Hz) Reference Example 3 -11+ In the same manner as Reference Example 1-fl), 4-(4-chlorophanoxy)-3-nitroaniline (ls, 3 y) and 1
1-Chloroconophosphate imide (7,72y) gives yellowish brown needle-like crystals of 2-chloro-4-(4-chlorophenoxy)-
3-nitroaniline (13,7y) is obtained. (Recrystallized from ethanol) mp70-74°C [(Nujol):
3455. 3375. 1530cm '+(MR(
uMso-d6. J): 5.92 (2H, bs),
6.95 (2H.

d, d, J=8Hzl 2Hz), 7.02
(2H1s) + calculated value: C48°18. H2,70
, H9, 37 actual measurement value, C48, 23, H2, 65, H
9,44 Reference Example 3-(2) In the same manner as Reference Example 1-(21), 2-chloro-4-(4
-chlorophenoxy)-3-nitroaniline (10,4
f7) to pale yellow needle-like crystals of 2-chloro-4-(4-1
Obtained (4,35y). mp106~108℃
(Diisopropyl ether color IG Go to table +'n'+
) IR (Nujol): 1550. 1185. 1
165cm-1NMR (DMSO-d6.δ) near, 0
7 (IH, d, J-9Hz).

7.17 (2H, d, J=9Hz), 7.48 (2
H, d, J = 9Hz).

8.01 (IH, d, 9Hz) Elemental analysis': (C,,,H6Cl!3No5S) Calculated value: C37,67+ Hl, 58. N3.66
Actual value: C38, 19, Hl, 54. N3.46 Reference Example 4 Nitro 2-chloro-4-methyl-3-h Shashianiline (372
Add a solution of sodium nitrite (15.2p) in water (30me) to a 35% hydrochloric acid (135mf) suspension of y) at 3-7°C.
Drop in 130 minutes. The resulting diazonicum solution was mixed with cupric chloride dihydrate (1
4,0y), water (10me) and glacial acetic acid (320+++
Add dropwise to the mixture e) at 5 to 8°C for 160 minutes, and
Stir for 30 minutes at °C.

The resulting reaction mixture was poured into crushed ice (t, oKg),
Obtain yellow needle-like crystals that precipitate.

The crude crystals (58,0y) were recrystallized from n-heptane (700me) to give light yellow needle-like crystals of 2-chloro-4-/thyl-3-nitrobenzene l sulfonyl chloride (40
,4! ? ). mp102-105°CIR (Nujol): 1525. 1375. 1180.
1165 cm −1 NMR (DMSO-d6.δ):
2.50 (3H, s) + 7.50 (LH.

d, 1 block - 10,0Hz), 8.17 (IH,
d, J-10,0Hz) Elemental analysis' (C7H1C
Z'2NO4S) Calculated value: C31,13,Hl,8
7. H5,19 actual value: C31,40, Hl, 88
．． H5,24 Reference Example 5 Reference Example 1-(2,4-dichloro-3
2,4-dichloro-3-nitrobenzenesulfonyl chloride F<30.6y> in the form of slightly yellowish brown powder crystals was obtained from -y, 02, 2air, y (37,2P). mp9
5-97°C (recrystallized from a mixed solvent of diisopropyl ether and n-hegisane) IR (:i; (Scholl): 1550. 1360
．． 1180. 1160cm -1NMR (DMSO
dr,'): 7.72 (IH, d, J=8
Hz).

8.07 (IH, d, J=8H7) Elemental analysis: “,C,H,,Ce3N [,1,,3)1
　η　: C24, 81, Ho, 69. H
4,82 Actual value: C25,04, Ho, 69. H4
,73 dioxane (1500me), 4-fluoro-
After dissolving 3-nitroaniline (71,0y) and N-chlorosuccinimide (60,8y), stir at 65°C for 2 hours. After distilling off dioxane under reduced pressure, water was added to the residue,
Extract with ethyl acetate and dry over magnesium sulfate. After ethyl acetate was distilled off under reduced pressure, diisopropyl ether (500me) was added and refluxed for 5 minutes. After removing the insoluble matter, the p-liquid was distilled off under reduced pressure, and the resulting residue was recrystallized from isopropanol to give 2-I'chloro4-fluoro-3-nitroaniline (51 , 6y). Of these, 3.60 f/
was recrystallized twice from ethanol to obtain yellowish brown needle crystals (
1,65y) is obtained. mp 119-1210C engineering R
(Nujol): 3475. 3380. 153
0. 1370cm-1NMR (DMSO-d6.δ)
: 5.92 (2H, bs), 7.03 (IH
.

dldlJ=9H2I6H2)1 7.23(IH, d
, d, J=17Hz+9Hz) Elemental analysis: (C6H, CI F N202) Calculated value:
C37,82,N2.12. N14.70 Actual value: C38.41, N2.08. N14.83 Reference example 6
-(21 2-chloro-4-fluoro-3-nitroaniline (48,01 to 2-chloro-
4-Fluoro-3-nitrobenzenesulfonyl chloride (zs, sy) is obtained. Of these, o and soy were purified by column chromatography packed with silica gel (silica gel; 16yt developing solvent: toluene), and a 0.75y sample obtained from the fraction containing the target product was recrystallized from diisopropyl ether. to obtain white columnar crystals (0,61'). mp87-88°C IR (Nuji: +-#): 1530. 1350. 1170
．． 1150cm -1HMR (DMSOd6.a)
: 7.62 (9Hz in t, J).

s, 23 (d+ d, J -9Hz, 6Hz) Elemental analysis = (C6H2ce2FNo4s) Calculated value: C2
6, 29, Ho, 74. N5.11 actual value: C2
6,75,Ho,81. N5.14N-7 Cetyl 4-
10 rho 3-nitroaniline (35,0y) v2-chlorophenol (26,7y), and potassium carbonate (28
,7y) of N,N-dimethylformamide (150d)
The solution is refluxed for 8 hours. After cooling to room temperature, the solid material is
N,N-dimethylformamide was distilled off from the P solution under reduced pressure, and saturated brine was added, followed by extraction with methyl isobutyl ketone. The extract was washed with a 5% hydroxide solution and a saturated saline solution, and then dried over magnesium sulfate. Methyl isobutyl ketone was distilled off under reduced pressure, and the residue was recrystallized from a silica gel column chromadog n-hexane mixed solvent to give N-acetyl-4 as light reddish brown massive crystals.
-(210lophenoxy)-3-nitroaniline(21
, 3y). mp92-95℃ IR (Nujol): 3380. 1690. 1
540. =1370cTt-1NMR(nMso-C6
, δ)':' 2.17(3H,s), 7.11(
IH, d.

J-9Hz), 7.227.66 (4H, m),
7.80 (IH9d, d.

J = 9 N2I 2Hz ) + 8-51 (I H
9d, J-2Hz).

10.36 (IH,s) Reference Example 7-(2) N-acetyl-4-(2-chlorophenoxy)=3-nitroaniline (20,7y) in ethanol (200++
+e) and dissolved in a mixed solution of concentrated hydrochloric acid (25me),
Reflux for 3.5 hours. After distilling off the solvent under reduced pressure, 226y of aqueous sodium hydroxide solution was added, and the mixture was extracted with methyl isobutyl ketone. The extract was washed with saturated saline, dried over magnesium sulfate, and the methyl isobutyl ketone was distilled off under reduced pressure. The resulting residue was recrystallized from isopropyl alcohol to give yellow flaky crystals of 4-(2-chlorophenoxy). )-3-nitroaniline (14,0y) is obtained. mp1
39-141°C IR (Sujoor): 3470. 3420. 3
375. 3345°1530, 1345crn-1 HMR (DMSO-C6,a): 5.70 (2H,
bs), 6.73-7.40 (6H, m), 7.60 (
lHld, d, J-9H2, 2H2) Reference Example 8-m Reference Example 7-f! In the same manner as in 1, yellow needle-shaped N-acetyl-4-(4-chloro phenoxy)-3-nitroaniline (20,7P) is obtained. mp146~148°C (
Isopropyl alcohol color recrystallization) IR (Nujol): 3275. 1655. 1
530. 1350σ-1HMR (DMSO-d6.δ
): 3.33 (3H, s), 7.03 (IH.

d, J=9Hz), 7.07-7.52 (4H, m
), 7.80 (IH.

d, d, J-9H2, 3H2), 8.45 (IHld,
J=3H7).

10.37 (IH, bs) Reference Example 8-12+ N-acetyl-4-(
4-chlorophenoxy)-3-nitroaniline (23,
49) to obtain 4-(4-chlorophenoxy)-3-nitroaniline (15,7y) in the form of brown scales. mp
H4-116°C (recrystallized from isopropyl alcohol) IR (nuclear): 3430. 3420.33
30.3225°1525, 1365cIn NMR (DMSO-d6.δ): 3.40 (2H,b
s), 6.89 (IH.

d, J=9Hz), 6.80-7.07 (3H,
m), 7.18-7.41 (m), 7.29 (
d, J=9Hz) Reference Example 9-(++ Similarly to Reference Example 7-fi+, from N-acetyl-4-fluoro-3-nitroaniline (28,5y), SuIJ methyl thylate (23,9y) 2-(4-
Methyl acetylamino-2-nitrophenoxy)benzoate (32,09) is obtained. mpH4-116°C (recrystallized from ethanol) IR (nujo yu): 330
0. 1725.1670.1540゜1355cm” NMR (DMSO-d6.δ) + 2.07 (3H+
s), 3.70 (3H2s).

6.94 (IH, d, J-9Hz), 7.16-7
．． 94 (4H, m).

7.69 (IH, dd, J-9Hz, 2Hz),
8.42 (IH, d.

J-9Hz), 10.23 (IH, s) Reference Example 7-
In the same way as +21, 2. -(4-acetylamino-2
- Obtain orange blocky crystals of methyl 2-(4-amino-2-nitrophenoxy)benzoate (20,22) from methyl nitrophenoxy)benzoate (27,6y) o mp
117-119°C (recrystallized from methanol) IR (Nujol): 3440. 3345. 1
710. 1525°1340crn-1 NMR (DMSOd6.a): 3.75 (3H
2s), 5.60 (2H9s).

6.72-7.83 (7H, m) Reference Example 9-(3+ 2-(4-amino-2-
Methyl nitrophenoxy)benzoate (18,9y) gives 2-(4-amino-3-chloro-2) dark yellow-green lumpy crystals.
methyl -nitrophenoxy)benzoate (12,3y) is obtained. mpH 4-116°C (recrystallized from toluene) IR (Nujol): 3425. 3340. 1
725. 1530°1310σ-1 NMR (DMSO-d6.δ)+3.78(31(
, s), 5.83 (2H.

bs), 6.78-7.91 (6H, m) Reference Example 9-+4+ In the same manner as in Reference Example 1-(2), 2-(4-amino-3
-chloro-2-ditrophenoxy)amic acid, methyl(1)
1,6y) to pale yellow powder of 2-(3-chloro-4-1
Methyl 0rosulfonyl-2-nitrophenoxy)benzoate (3,7y) is obtained. mp128-133°C IR (Nujol): 1720. 1540. 1
370. 1185cm' NMR (DMSO-c16
．． δ): 3.69 (3H, s), 6.73 (I
H.

d, J=9Hz), 6.87-7.75 (4H,
m), 7.94 (LH.

d, J = 9Hz) Reference Example 10-[11 Iron powder (26,6gt) and ammonium chloride (3,2
y) ethanol (350mf, water (50rnt')
) The suspension is stirred at reflux and 5-nitro-2-phenoxybenzonitrile (2s, oy) is added in portions. After the addition was complete, continue stirring under reflux for 20 minutes to remove the insoluble solids.
The tear solvent is removed under reduced pressure. A saturated aqueous sodium bicarbonate solution was added to the residue, extracted with ethyl acetate, the extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
A light brown powder of 5-amino-2-phenoxybenzonitrile (21°0y) is obtained. mp55-59°C IR (Nujol): 3425. 3340. 2
225cm-1NMR (DMSO-c16.δ):
5.43 (2H, s), 6.82-7.50 (8H
, m) Reference example 10-12+ 5-amino-2-phenoxybenzonitrile (20, 4
y) and an ethanol (400me) solution of N-chloroconophosphate imide (130y) were stirred at 50°C for 11 hours. During this time, N-chlorosuccinimide (1,,3y) was added 1 hour, 2 hours, 6 hours, and 10 hours after the start of the reaction. After charcoal treatment of the reaction solution, ethanol was distilled off under reduced pressure to obtain a residue (2
s, 2y) was purified by silica gel column chromatography (elution solvent: toluene) to obtain 9.8y.
A crude powder of 3-amino-2-chloro-6-fethoxybenzonitrile (5,2y') f:ml was obtained by recrystallization from diisopropyl ether as pale brown powder crystals.

m956~58°C IR (Nujol): 3380. 3320. 22
25σ-1NMR (DMSO-a6; δ): 5.7
2 ('2L bs).

6.82-7.55 (7H, m) Reference Example 10-+3+ 3-Amino-2-chloro-6-phenoxybenzonitrile (5,20') in the same manner as in Reference Example 1-+2) From this, 2-chloro-3-chlorosulfonyl-6-phenoxybenzonitrile (2,45y) is obtained as a light brown powder. mp95-102°C Engineering R (Nujol): 2240. 1190. 1
1?5. 1165crn”NMR (DMSO-d6.
δ): 6.83 (IH, d, J=9Hz).

7.10-7.65 (5H, m), 8.11 (IH
, d, J=9Hz) Example 1 Ammonia gas saturated chloroform solution (850me)
2-chloro-3-nitro-4-phenoxybenzenesulfonyl chloride (711;') was added little by little with stirring under ice cooling, and stirring was continued for an additional 30 minutes at the same temperature. After chloroform was distilled off under reduced pressure, brine was added, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from benzene to obtain white powdery crystals of 2-chloro-3-nitro-4-phenoxybenzenesulfonamide (4 g, 5P). mp164~1
66°C Engineering R (Nujol): 3425. 3325. 1
535. 1365°1315, 1160σ-1 NMR (DMSO-d6.δ): 7.18 (IH,
d, J=9Hz).

7.18-7.57 (5H, m), 7.90 (2H
,s).

8.21 (IH, d, J=9Hz) Elemental analysis: (C,, H9C1!N20.3) Calculated value: C43,84, N2.76, N8.52 Actual value: C43,75, N2.64. N8.58 Example 2 Benzylamine (0,46y), triethylamine (2
, 18y) in chloroform (20mt'), 2-
Chloro-3-nitro-4-phenoxybenzenesulfonyl chloride F' (1,50y) in chloroform (10me
) The solution is added dropwise over 10 minutes under stirring at room temperature and then stirred for 2 hours at room temperature. Chloroform was distilled off under reduced pressure, the residue was extracted with ethyl acetate, dihydrochloric acid, and saturated hydrogen carbonate).
Wash with J-cum aqueous solution and saturated saline, and dry with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of diisopropyl ether (5mt')-isopropatol (10me) to give pale yellow crystals of 2-chloro-3-nitro-4-phenoxy-N. -(benzyl)benzenesulfonamide (1,0y) is obtained.

m p 134~l 36°C IR (Nujol): 3370. 3110. 3
080. 1555°1365, 1350. 127
0. 1195. 1180゜1150c+++-1 NM'R (DMSO-d6.δ): 4.14 (2H
, s) + 6.90 (IH, d, J-9Hz),
7.05-7.55 (IOH, m).

7.90 (LH, d, J=9Hz), 8.70 (I
H, brs) Elemental analysis: (C, gH,, CI N20
5S) Calculated value: 054.4L N3.61. N6
．． 69 Real Itll I+Ej: C54,47
, N3.66, N6.68 Example 3 In the same manner as in Example 2, 2-chlorobenzylamine (1
. -4-phenoxybenzenesulfonamide (2,0Oy) is obtained.mp162-164℃
(Recrystallized from a mixed solvent of ethyl acetate and chloroform) IR (Nujol): 3275. 154
0. 1325σ-1NMR (DMSO-d6.δ):
3.30 (2H, s), 6.99 (LH.

d, J-9Hz), 7.18-7.68 (9H,
m), 7.99 (IH, d, J=9Hz),
8.78 (bs) Elemental analysis: (C+qH14C12N
205S) Calculated value: C50,34,-N3.11. N
6.18 Actual value: C50, 22, N3.02. N6.
13 Example 4 4-chlorobenzylamine (3,58y) was dissolved in dry methylene chloride (30+++e) and 2-chloro-3-nitro-4-phenoxybenzenesulfonyl chloride (4,00y ) in dry methylene chloride (25me) is added dropwise. It is then stirred at room temperature for 4 hours. The reaction mixture was washed with water, 5% hydrochloric acid, and saturated brine, respectively, and dried over magnesium sulfate.

The powdery residue obtained by distilling off the solvent under reduced pressure was mixed with ethyl diisopropyl ether (15+++e)-11v acid (1
Recrystallization from a mixed solvent of 2-chloro-N-(4-chlorobenzyl)-3-nitro-4-
Phenoxybenzenesulfonamide (2,25,p) is obtained. mp152-155℃ IR (Nujol):
3280. 3070. 1573. 1537°13
59, 1335. 1272. 1189. 117
9°1158 cm-1 NMR (DMSO-d6.δ): 4.15 (2H,
s), 6. ．． 87-7.70 (IOH, m),
7.93 (IH, d, J=9Hz), 8.80 (L
H+ b r s ) Elemental analysis: (C,9H,4Cff2N205S) Calculated value: C50,34, N3.11, N 6.18 Actual value: C50,46, N3.16. N6.26 4-chlorobenzylamine (0,81?) in the same manner as in Example 2.
) and 2-chloro-3-nitro-4-phenoxybenzenesulfonylchloro! J)' (2°0y) to white powder 2-chloro-N-(4-chlorobenzyl)-3
-Nitro-4-phenoxybenzenesulfonamide (1
, 15y) obtain. mp151-153.5°C (recrystallized from a mixed solvent of diisopropyl ether and ethyl acetate) IR (Nujol) + 3280. 3070
．． 1573. 1537°1359, 1335.
1272. 1189. 1179°1158cIn-
1 NMR (DMso-a6.δ): 4.15 (2H, s)
, 6.87-7.70 (101-I, m), 7
．． 93 (IH, d, J=9Hz), 8.80 (IH
,brs) Elemental analysis' (C+c+H14C12N205S) Calculated value: C50,34,N3.11. N6.18 actual value; C50.47, N2.92. N6.21 Example 6 3-chloropenzylamine (1,
06y) and 2-talolo-3-nitro-4-phenoxybenzenesulfonyl chloride (1°30y) to give pale yellow powder of 2-chloro-N-(3-chlorobenzyl)-3
- Nitro 4-7e/xybenzenesulfonamide (1
,0,l is obtained. (Recrystallized from a mixed solvent of diisopropyl ether-isopropanol) mp 146-14
8°CIR (Nujol): 3240. j080.
1580. 1535°1360, 1312. 1
280. 1200. 1178°1151σ-1 NMR (DMSO-a6+a): 4.21 (2H,
s), 7.04(LH, d, J=91(z), 7
．． 15-7.70 (9H, m).

8.04 (IH, d, J=9Hz), 8.90 (
LH, brs) Elemental analysis: (C,9H,4C12N2
05B) Calculated value: C50,34,N3.11.
N6.18 Actual value: C50, 33, N3.15.
N6.15 Example 7 4-fluorobenzylamine (0
,95y) and 2-chloro-3-nitro-4-phenoxybenzenesulfonyl chloride (1,20y) to give pale yellow crystals of 2-chloro-N-(4-fluorobenzyl)-3-nitro-4-phenoxy Obtain 1.2 g of benzenesulfonamide.

(Mixed solvent recrystallization of inpropanol-ethanol) mp 174-176°C IR (Nujol): 3350. 3090. 15
75. 1565°1535, 1365. 1335
．． 1285. 1220°1200, 1180.
1155cIn-1NMR (DMSO-d6.δ):
4.17 (2H, d, J=6Hz).

10H.

6.87-7.72 (#, m), 7.97 (LH,
d, J=9Hz).

8.77 (IH, t, J = 6Hz) Elemental analysis: (
C, 9H, 4CI F N20. S) Calculated value: C52
, 24, N3.23. N6.41 actual value: C51
, 93, N3.32. N6.34 Example 8 4-methylbenzylamine (1,
00y) and 2-chloro-3-nitro-4-phenoxybenzenesulfonyl chloride (1°30y) to give pale yellow crystals of 2-chloro-N-(4-methylbenzyl)-3.
-nitro 4-phenoxybenzenesulfonamide (1
, 25y) IJru.

mp139-141°C (recrystallized from a mixed solvent of diisopropyl ether-isopropanol) IR (Nujol): 3290. 1585. 1545. 13
68°1347, 1325. 1281. 1192
．． 1180°1160a-1 NMR (DMSO-d6.J): 2.27 (3H,
s), 4.14 (2H, brs), 6.93"
7.75 (IOH, m), 7.98 (IH, d,
J-9Hz), 8.72 (IH, brs) Elemental analysis: (C2oH17CeN205S) Calculated value: C55,
49+ H3,96,H6,47 Actual value: C55,5
9,H3,94,H6,48 Example 9 4-Nitrobenzylamine hydrochloride (0,66p) is suspended in methylene chloride (20ml), and triethylamine (1,05y) is added under stirring at room temperature. +'&K
, 2-chloro-3-nitro-4-phenoxybenzenesulfonylchloroIJ)'(1,10y) of methylene chloride (
7me) Add the solution dropwise at room temperature and continue stirring for 1 hour.

Methylene chloride was distilled off under reduced pressure, extracted with ethyl acetate, washed with pentahydrochloric acid and saturated brine, and dried over magnesium sulfate.

The solvent was distilled off under reduced pressure, and the resulting powdery residue was recrystallized from a mixed solvent of improvanol and ayatonitrile.
2-chloro-3-nitro N-(4-nitrobenzyl)-4-phenoxybenzenesulfonamide (0,49) was obtained as pale yellow crystals.

mp 177-179°C IR: 3360. 3070.
1575.1540°1510, 1340. 128
0. 1195. 1180°1160c+++-1 NMR (DMSO-ci6.δ): 4.30 (2H
, s), 6.90-8.17 (IIH, m),
9.00 (IH, brs) Elemental analysis: (C19H34
Cj? N5o7s) Calculated value: C49,20, H3,0
4, N9.06 Actual value: C49,11,, H3,03
, N8.95 Example 10 In the same manner as in Example 2, 2-aminomethylpyridine (0
, 47y) and 2-chloro-3-nitro-4-phenoxybenzenesulfonyl chloride (1,50y). Chloroform (20me) is added to the resulting reaction solution, and the white molten powder (1,4y) is removed and washed with chloroform. The P solution and the washing solution were combined and washed with a 2% aqueous sodium hydroxide solution, then washed with saturated saline,
Dry with magnesium sulfate. The light brown powder (0,4y) obtained by distilling off the solvent under reduced pressure and the white P-removed powder obtained after the reaction were combined to form tetrahydrofuran (35
recrystallized from 2-chloro-3- as a pale yellow powder.
Nitro 4-phenoxy~N-(2-pyridylmethyl)
Benzenesulfonamide F(1,1y)1. mp2
01-207°C IR (Nujol): 3100. 1585. 1
540. 1367°1340, 1284. 120
0. 1180. 1159cm'NMR(LIMS
O-d 6. δ): 4.32 (2H, s), 7
．． 04 (LH, d, J=9Hz), 7.15-7.
85 (8H, m).

8.04 (IH, d, J=9Hz), 8.42 (
IH, dd, J-2 and 5Hz), 8.90 (IH
, brs) 几X analysis: (C18H44CeN305S)
Measured °C value: C51,49, H3,36, N10. O1
Real fil+ Iro 1: C51, 65, H3, 54, N9
．． Sol2 Example 11 2-chloro-3-ditro-4-phenoxybenzenesulfonyl chloride (0,50y),! :, 4-10 loaniline (0,20y) are heated and stirred for a while on an oil bath with a bath temperature of 90°C. Then, heat to the same temperature. After cooling, it is dissolved in ethyl acetate, washed with 5% hydrochloric acid and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of inpropanol and ethanol to obtain a powder of 2-chloro-N-(4-chlorophenyl)-3-nitro-4-phenoxybenzenesulfonamide ( o, 3y) is obtained. mp184~187°
C Engineering R (Nujol): 3300. 1585. 15
50. 1370°1350, 1230. 1200
．． 1185. 1165°965σ-1 NMR (DMSO-d6.δ) near. 00-7.60(
IOH, m).

8.17('1)(,d, J=9Hz), 11.
10 (IH, 8) elemental analysis: (C15H12C12N
205S) Calculated value: C49.22, N2.75.
N6.38 Actual value: C49.11, N2.68. N6.
OO Example 12 To a mixed solution of methanol (53,61 and methylamine methanol solution (30 g) (5,95 g), water-cooled ff,
2-chloro-3-nitro-4-phenoxybenzenesulfonyl chloride (2,00y) was added little by little, and the mixture was further stirred for 15 minutes at the same temperature. Methanol is distilled off under reduced pressure, brine is added, and the mixture is extracted with ethyl acetate. After drying over magnesium sulfate, the solvent is distilled off under reduced pressure and the resulting residue is washed with diethyl ether to obtain 2-chloro-N-methyl-3-nidro-4-phenoxybenzenesulfonamide (1,7zl) as a white powder. .

mp203-205°C IR (Nujol): 3325. 1530. 13
35. 1185°1170cm-1 NMR (DMSOd6, J): 7.17(d,
J=9Hz).

7.177.57 (m), 7.35 (S SO2NH)
.

8.12 (IH, d,, T-9Hz) Elemental analysis: (C,, H,, Ct?N205S) Calculated value: C45,55, N3.23. N8.17 actual value: C44,84, N3.14. N7.47 Example 13 To a methanol (50 g) solution of 50 tidimethylamine aqueous solution (3,11 f/), 2-chloro-3-nitro
-phenoxybenzenesulfonyl chloride (1,20p
) was added under water cooling and stirring, and the mixture was further stirred at the same temperature for 30 minutes. After evaporating the solvent under reduced pressure, the mixture is extracted with ethyl acetate. The extract is washed with saturated saline and dried over magnesium sulfate. When the powdery residue obtained by distilling off the solvent under reduced pressure is recrystallized from a mixed solvent of inpropanol-ethanol, flaky crystals of 2-chloro-N,N-dimethyl-3-nitro-
4-phenoxybenzenesulfonamide (1,0y) is obtained. m, p 130-134° CIR (Nujol): 1532. 1360. 1330. 1272
゜1192, 1165. 1145σ-1HMR (D
MSO-d6. δ): 2.87 (6H, s-)
, 7.05-7.75 (6Hlm), 8-12
(I H+ d, J-9Hz) Elemental analysis'("s*
H+301 N205S) Calculated value: C47,13,N
3.6'7. N7.85 Actual value: C46,85,N
3.59. N7.70 Example 14 2-furfurylamine (0,56
y) and 2-chloro-3-nitro-4-phenoxybenzenesulfonyl chloride (2,00y) to form a white powder of 2-chloro-N-(2-furfuryl)-3-
Nitro 4-7 enoxybenzenesulfonamide (1,
65y) Get it.

mpH 3-123°C (recrystallized from ether) IR (Nujol): 3625; 1540. 1370.
1330°1185, 1170. 1150. 1
145σ-1HMR (DMSOda, J):
4.18 (2H1s), 6.11 (IH9d, J=
3Hz), 6.28 (IH, q+ J=3Hz),
7.06 (IH, d, J-9Hz), 7.27
-7.68 (6H, m).

8.03 (LH, d, J=9Hz), 8.67 (
IH, b, s) Example 15 In the same manner as in Example 2, N-(2-hydroxyethyl)
piperazine (0,75,7) and 2-chloro-3-nitro-4-7 enoxybenzenesulfonyl chloride (2
,0Oy) to form a pale brown powder of 1-[(2-chloro-3-nitro-4-phenoxy)benzenesulfonyl]-4-(2-hydroxyethyl)piperazine (2,6
0y) is obtained.

mp, 129-1318C Engineering R (Nujol): 3520. 1535. 137
0. t36o,'1350, 1190. 118
0. 1160cm-1HMR (CDCe3.δ):
2.40 (IH, s), 2.60 (6H, t.

J=5Hz), 3.37(4H,t, J=5Hz
) + 3.67 (2H, t, J=5Hz), 6.
86 (IH, d, J=9Hz).

7.02-7.50 (5H, m), 7.93 (IH
, d, J=9Hz) Example 16 In the same manner as in Example 2, 1-(2-furoyl)piperazine (2,17y) and 2-chloro-3-nitro-4-
Phenoxybenzenesulfonyl chloride (4,00y)
1-[(2-chloro-
3-nitro-4-phenoxy)henzensulfonyl]-
4-(2-furoyl)piperazine (3,70y) is obtained. mp171-173°C (recrystallized from ethyl acetate) IR (Nujol): 1625. 1540
．． 1350cm'NMR (DMSO-d6.δ):
3.30-3.43 (4H, m), 3.73-3.
82 (4H, m), 6.63 (IH, dd, J=3
Hz).

7.03 (IH, d, J=3Hz), 7.11 (
IH, d, J=9Hz).

7.18-7.68 (5H, m), 7.82-7.
85 (IH, m).

8.13 (IH, d, J=9Hz) 3 Elemental analysis: (CnH7BC1 璋o, s) Calculated value: C5
1,27,H3,69,H8,54 Actual value: C50,
72,H3,50,H8,31 Example 17 1H-tetrazol-5-amine (0,86y) was dissolved in pyridine (14me) and 2-chloro-3-nitro-4-phenoxybenzenesulfonyl chloride (3, 5!
1 was added over 40 minutes under stirring at room temperature. After the reaction solution was allowed to stand at room temperature overnight, 120 m(') of water (120 m(')) was added under stirring at room temperature. After the resulting powder was collected, ethyl acetate (
Dissolve in 100mf and 0. Wash twice each with IN hydrochloric acid and saturated saline, and dry with magnesium sulfate.

When the solvent is distilled off under reduced pressure, N[(azido)iminomethyl]-2-chloro-3-nitro-4-phenoxybenzenesulfonamide is obtained. mp156-170℃ (decomposition) IR (Nujol): 3420. 3330. 32
50. 3100°2200, 2140. 1635
．． 1550. 1405°1300, 1200.
1150. 1135. ．． 1105σ-1NMR (DM
SO-d6. δ): 7.04-7.65 (6H, m)
, 7.95 (LH, brs), 8.24 (IH
, d, J=9 Hz), 9.10 (IH, brs) The obtained crude powder is refluxed with pyridine (0.3 mf') in ethanol (70 ml?) for 20 hours. After cooling, the solvent is distilled off under reduced pressure and the resulting oily residue is extracted with ethyl acetate (70rne). 0. Wash with IN hydrochloric acid and saturated saline, and dry with magnesium sulfate. The oily residue obtained by distilling off the solvent under reduced pressure is powdered with chloroform. This powder was collected as P, washed with chloroform, and a white powder of 2-chloro-3-nitro 4-7 was obtained.
Enoxy N-(IH-tetrazol-5-yl)benzenesulfonamide (1,6y) is obtained. mp205.
5'c (decomposition) IR (KBr tablet): 3110.3010.2920.2
830°1615, 1582. 1550. 138
2. 1363°1285, 1196. 1180c
In”NMR (DMS 0-cl 6.δ): 7.
10-7.70 (6H, m), 8.28 (IH, d
, J=9Hz), 10.80 (2H, brs)
Quality analysis (m/e): 396 (M”), 312.
139 elemental analysis: (C+3HgCj' N605S
) Calculated values: C39, 35, H2, 29, N21.1
8 Actual measurement value: C3 is also 22. H2, 18, N20.4
5 Example 18 2-chloro-4-(2-10rophe/xy)-3-nitrobenzenesulfonyl-(1,50y) was dissolved in chloroform (20me), stirred with water cooling, and ammonia gas was added. Infuse for 10 minutes. After stirring for an additional 20 minutes at the same temperature, the reaction solution was washed with brine and dried over magnesium sulfate. The residue obtained by distilling off chloroform under reduced pressure (
1,30y) is washed with diisopropyl ether to obtain a pale yellow powder (1,00y). This powder is purified by silica gel column chromatography (developing solvent: chloroform:methanol-20:1) to obtain a white powder (0.8P) from 7-lactone containing the target compound. When recrystallized from toluene, 2-chloro-4-(2-
10lophenoxy)-3-nitrobenzenesulfonamide (0,65y) is obtained. mp168-171℃ Engineering R (Nujol): 3700. 3550. 153
5. 1360°1330, 1218. 1180.
1160. 1150c+++'NMR (DMSO
-d6. δ) Near. 03 (IH, d, J=9Hz).

7.33-7.82 (4H, m), 7.90 (2H
, bs), 8.14 (IH, d, J = 9Hz
) Elemental analysis = (C1°H8Cl2N20., S) Calculated value:
, C39,69,, H2,22, H7,71 actual measurements:
C39,59, H2,33, H7,67 Example 19 2-chloro-4-(
2-chlorophenoxy)-3-nitrobenzenesulfonyl chloride (2,00y) (7) Chloroform (lOm
e) Drop the solution. After the dropwise addition was completed, the reaction solution was stirred for an additional hour at room temperature, and then washed with water and dried over magnesium sulfate. Chloroform was distilled off under reduced pressure, and the resulting residue was
Purified by silica gel column chromatography (developing solvent: toluene), and from the fraction containing the target product, 1
．． 402 oily product is obtained. This oil was powdered with a mixed solvent of n-hexane and diethyl ether, and then recrystallized with a mixed solvent of toluene and n-hexane. )-N-(4-10 lobenzyl)-3-nitrobenzenesulfonamide (1,10y) o mp 13
4-137°C IR (nudicol): 3275. 1535. 1
360. 1175°1155σ-1 NMR (DMSO-d6.δ): 4.15 (2H, s
), 6.84 (IH.

d, J-9I (z), 7.11-7.77 (8H,
m), 7.94 element analysis: (C+, H+sCI!
aNgOsS・0.12 C, H8) calculated value, C47,
83, H2, 82, H5, 62 actual measurement value: C47, 79,
H2,85,H5,74 Example 20 White scaly crystals were prepared from 2-chloro-4-(4-chlorophenoxy)-3-nitrobenzenesulfonyl chloride (2,001;') in the same manner as in Example 18. , 2-chloro-
4-(4-chlorophenoxy)-3-nitrobenzenesulfonamyl'(0,80y) is obtained. mp230
~232°C (recrystallized from ethanol) IR (Nujol): 3430. 3340. 1
535. 1370°1320, 1185. 116
5. 1150cln'NMR (DMSOd6, J
): 7.25 (IH+d, J=9H2).

7.23-7.67 (4H, m), 7.92 (2H
, bs), 8.17 (LH2cL J-9Hz) Original powder analysis: (C□2H8C1!2N20.S) Calculated value: C39,69, H2,22, H7,71 Actual value:
C39,69,H2,13,H7,63 Example 21 4-chlorobenzylamine (1
, 55y) and 2-chloro-4-(4-chlorophenoxy)-3-nitrobenzenesulfonyl chloride (2,
2-chloro-4-(2-chloro-4-(
4-chlorophenoxy) -N-(4-10lopenzyl)-3-nitrobenzenesulfonamide (1,05y)
get. mp173-175°C (recrystallized from ethanol) IR (Nujol): 3330. 1540.
1350. 1180°1160m' NMR (DMSO-d6.δ): 4.13 (2H,
s), 7.03 (IH, d, J=9Hz), 7
．． 20 (2H, d, J=9Hz).

7.20 (4H, s), 7.57 (2H, d, J
= 9Hz), 7.93 (IH, d, J = 9Hz),
8.75 (LH, bs, NH) elemental analysis: (Cn
) Eta (J?, 1N2058) Calculated value: C46,
79, I (2,69, N 5.74 Actual value: C46°6
7, I(2,61,H5,58 Example 22 2-chloro-3-nitro-4-methylbenzene
) and water (150 tnl) was added dropwise to a mixture of 150 tnl over 60 minutes while cooling to 3-6°C with stirring, and the mixture was further stirred at 2-3°C for 60 minutes.

The pale yellow needle crystals precipitated were collected and washed with water (50 mff), and the resulting crude crystals ('27.0y) were dissolved in methanol (
Recrystallization from a mixed solvent of 100 me) and water (200 me) gives pale yellow needle-like crystals of 2-chloro-3-nitro-4-methyl chlorabensenesulfonamide F (21°7y). mp186-187℃ IR (Nujol): 3340. 3260. 15
25. 1365°1340, 1180. 1160
σ-1NMR (DMSO-d6.δ): 2.36 (
3H, s ), 7.66 (I Hr d, J = 8
-OHz), 7.86 (2Hls), 8.07
(IH, d, J=8.0Hz) Elemental analysis: (CyH7ClN204S) Calculated value-C
33,54,H2,82,N11.18 Actual value: C33
,65,H2,82,N11.44Example 23 LH-tetrazol-5-amine-water salt (1°52y
) in pyridine (15me) and stirred at room temperature. After further stirring for 2 hours at room temperature, diluted with 150 me of water,
Count the amount of powder that precipitates. After washing with water, this was dissolved in ethyl acetate, washed with dilute hydrochloric acid and water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give N-[
(azido)iminomethyl]-2-chloro4-methyl-
A light brown coarse powder of 3-nitrobenzenesulfonamide (2,10y) is obtained. mp154℃ (decomposition) IR (Nujol): 3430. 3325. 21
95. 2145°1635, 1525. 1370
．． 1130cm-1HMR (DMSO-d6.-δ)
: 2.38 (3H, s, CHr), 7.72 (IH
, d, J=8Hz), 7.95 (IH, bs),
8.23 (IH, d, J=8Hz), 9.1
2 (IH, bs) The obtained coarse powder was mixed with pyridine (0,30
me) and hydrochloric acid 50- are added, and extraction is performed with acetic acid ethyl ester. The extract was reduced to 0. IN hydrochloric acid (50+++
j'), washed with saturated saline and dried with magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was washed with chloroform in the center, and then recrystallized from acetone to obtain 2-chloro-4-methyl-3-nitro-N as a white powder crystal.
-(IH-tetrazol-5-yl)benzenesulfonamide (0,75y). mp201℃ (decomposition) Engineering R (Nujol): 3260. 163 cram school 15
30. 1360°1175, 1155cm' NMR (DMSO-d6, δ): 2.38 (3H
, s), 7.73 (IH, d, J=8Hz),
8.28 (IH, d, J=8Hz).

10.72 (2H, bs, NH) Elemental analysis: (C8H, CI N604S) calculated value, C
30, 15, N2.21. N26.37 Actual value: C3
0.05, N2.30. N26.48 Example 24 3-chloropenzylamine (1,57y) and triethylamine (4,62me) were dissolved in tetrahydrofuran (1
2-chloro-3-nitro-4-methyl-benzenesulfonyl chloride (3,0
0y) in tetrahydrofuran (10me) is added dropwise. After the addition is complete, the mixture is further stirred at the same temperature for 30 minutes.

Sweep away the precipitated powder.

The resulting residue was washed with a small amount of diethyl ether and then recrystallized from ethanol to give 2-chloro-N-(3-chlorobenzyl)-3-nitro 4 as slightly brown lumpy crystals. -Methyl benzenesulfonamide (2,50
y) is obtained. mp138-416C IR (Nujol): 3295. 1540. 1
330. 1175°1160cm-1 7,62 (IH, d, J-9Hz), 8.05 (
IH, d, J = 9Hz).

8.83 (IH, bs, NH) Elemental analysis = (C14H72Ce2N204S) Calculated value:
C44,81,N3.22. N7.47 actual value: C4
5゜24. H3,07,N 7.44 Example 25 In the same manner as in Example 12, 50 tidimethylamine aqueous solution (
3,00y) and 2-chloro-3-nitro-4-methylbenzenesulfonylchloroIJ)” (3°00
y) to produce light brown needle-like crystals of 2-chloro-N,
N-dimethyl-3-nitro-4-methyll benzenesulfonamide (2,35y)l#=l.

mp123-124℃ (recrystallized from ethanol) IR (
Nujol): 1540. 1345. 1180.
1160σ-1HMR (DMSO-d6.δ): 2
．． 40 (3H, s), 2.52 (3H.

s), 7.73 (d, J=9Hz), 8.0
8(d, J=9Hz) Elemental analysis: (C9HHCI
N204S) Calculated value: C38.78, N3.98.
N10.05 actual value: C38.78, N3.79. N1
0.08 Example 26 2,4-dichloro-
3-nitrobenzenesulfonyl chloride (20,0y)
Add to the center one by one. After the addition was completed, the mixture was stirred for an additional 15 minutes at the same temperature, and the solvent was distilled off under reduced pressure.

A saturated aqueous sodium bicarbonate solution is added to the resulting residue, extracted with ethyl acetate, the extract is washed with water, and then dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (developing solvent;
Purified with chloroform:methanol-9=1) and purified with furan containing the target compound at 219-221°C (recrystallized from a mixed solvent of chloroform:Mechnol-9=1).Eng.R (Nujol): 3375. 3295. 15
40. 1350°1180, 1140cm -1 HMR (DMSO-d6.δ): 7.98 (d,
J=9Hz), 8.22 (a, J=9Hz) Elemental analysis: (Cr+H4C1!2N204S) Calculated value: C26,58, H1,49, N 10.33 Actual value: C26,45, Hl, 38. N10.67 Example 27 2-chloro-4-fluoro-3 in the same manner as Example 26
-Nitrobenzene sulfonyl chloride IJF (25,0y
) as a slightly brown powder, 2-chloro-4=fluoro-3-
Nitrobenzene sulfonamide (12, 29) is obtained. mp210-212°C (recrystallized from ethanol) IR (Nujol): 3380. 3275. 1
545. 1350°1320, 1180. 115
0cm' NMR (DMSO-d6.δ): 7.8
7 (t, J-9Hz), 7.87 (s), 8
．． 33 (d, d, J=9Hz, 6Hz) elemental analysis + (c6H4cl!F N20.S) calculated value, C
28, 30,! (1,58, N11.00 Actual value: C2
8,96+ Hl, 56. N11.28 practice, Example 28 4-rioosulfonyl-2-10ro-3-nitrobenzenesulfonamide (4,0y) in acetone 20
10(-me) solution,
Add dropwise to a mixed solution of 28% aqueous ammonia (fI4rne) and acetone (50y+e) at 5-7°C using a cooling stirring bar. After the completion of the dropwise addition, the mixture was further stirred at the same temperature for 1 hour, and then the reaction solution was concentrated under reduced pressure to 100 mA. The resulting solution was adjusted to pH 2.0 with 35% hydrochloric acid,
Concentrate to 50 ml' under reduced pressure. The precipitated crystals were collected and air-dried to give colorless needle-like crystals of 2-chloro-3-nitro-4-sulfamoylbenzenesulfonamide (2,1y
). mp304-306℃ (decomposition) (aqueous LJ-
(Recrystallized from) IR (Nujol): 3380
．． 3290. 3080. 1540°1366,
1170. 1160c+++ ”NMR (DMS O
d61 J): 8-07 (2H9s),
8.13 (L Hld, J=8.0Hz), ,8
．． 23 (2H, s), 8.40 (IH, d.

J=8.0Hz) Elemental analysis: (C6H6C7?N306S2) Calculated values: C22,83, Hl, 92. N13.31 actual value: C22,28, Hl, 87. N13.18 Example 29 In the same manner as in Example 26, slightly brown powder crystals of 2- Obtain methyl ((4-sulfamoyl-3-chloro-2-nitro)phenoxy)benzoate (2,41;').mp188-1
909C (↑η crystals from ethanol) IR (Nujol): 3400. 3280. 1
710. 1548°1345, 1182. 117
0cm-1HMR (DMSO-d6.a): 3.
68 (3H, s), 6.89 (LH, d, J, = 9H
z), 7.32-8.08 (4H, m).

7.82 (2H9s), 8.03 (I H9d+
J-9Hz) Elemental analysis: (C,4HBC71'
N207S) Calculated value: C43,48,' H2,8
7, H7, 24 actual measurement value, C43, 50, H2, 91, H
7,16 Example 30 In the same manner as in Example 26, 2-chloro-3-Schiff/-4
--Phenoxybenzene sulfonyl chloride (2,
25y) to white powdery crystals of 2-chloro-3-cyano-
4-Phenoxybenzene sulfona triF (1,15'
). mp 224-226°C (recrystallized from a mixed solvent of tetrahydrofuran and n-hexane) IR (Nujol): 3360. 3240. 2
230. 1330°1185cm' NMR (DMSO-d6.δ): 6.94 (LH, d
, J=9Hz).

7.24-7.60 (5H, m), 7.78 (2H,
s'), 8.15 (IH, d, J=9Hz) Elemental analysis = (C13H9ClN203S) Calculated value: C5
0.57, N2.94. N9.07 Actual value: C50.6
4, N2.91. N9.17 Example 31 2-Chloro-3-nitro 4-7 enoxyhenzenesulfonamide (4,5y) is refluxed with acetic anhydride (45me) for 3 hours. After cooling, evaporation was carried out under reduced pressure, and the residue was recrystallized from a mixed solvent of inpropatol and ethanol to obtain a pale brown powder of N-acetyl-2-chloro-3-nitro-4-phenoxybenzenesulfonamide (0, 65p
). mp212-215°C IR (KBr tablet): 3060. 2870. 169
0. 1545°1455, 1360. 11'85
．． 1175. 1155cm-1HMR (DMSO-
d6. δ): 2.04 (3H, s), 7.07-
7.70 (6H, m), 8.23 (IH, d, J-9H
z), 12.80 (IH, brs) Elemental analysis: (C, 4H,, CI N206B) Calculated value: C45, 35, N2.99. N7.56 actual value:
C45, 44, N3.00. N7.58 Example 32 2-chloro-3-nitro 4-phenoxybenzenesulfonamide (0,5y), potassium carbonate (0,63fl
), acetone (10 mt') is stirred at reflux for 1 hour and then at room temperature for 4 hours.

Isobrobyl isocyane-1-
(0,19y) was added with a stirrer at room temperature, and the mixture was further stirred at the same temperature for 1 hour. The powdery residue obtained by distilling off the solvent under reduced pressure is dissolved in water (20-25 ml!) and acidified with 5% hydrochloric acid to precipitate a powder.

P handling, washing with 5% hydrochloric acid and water, white powder 2-
Chloro-N-(Inglovir-lupamoyl)-3-nitro-4-7 enoxybenzenesulfonamide (0,6y
). mp 79-1O1°C (decomposition) IR (Nujol): 3350. 3080. 1
670. 1540°1368, 1285. 119
5. 1180. 1160cm -1HMR (CDC
13, δ): 1.13 (6H+ d+ J=6.5
Hz).

3.88 (I Hlm), 6.12 (I H9d,
J = 8H2) + 6.90 (IH, d, J = 9Hz)
, 7.0-7.65 (5H, m).

8, 10 (I Hld, J-9Hz), 9-0 (
I H+ br8 ) Example 33 A mixture of 4-throlephaceyl-nitrololo-2-nitrobenzoic acid (4,0y), acetic anhydride (25mf') and dry pyridine (25me) is stirred at 130<0>C for 2 hours.

The reaction mixture is allowed to cool to room temperature and poured into water (200 mf'). Count the number of deliveries that will be precipitated with concentrated hydrochloric acid at pH 2.0.

The crude crystals (3,5y) were mixed with methanol (20 ml') and water (
Recrystallization from a mixed solvent of 80me) gave light brown needle-like crystals of 4. (N-acetylsulfamoyl)-3-chloro-
2-nitrobenzoic acid (2,8y) is obtained.

mp 253-255°C (decomposition) IR (Nujol): 3610. 3550. 3
080. 1725°1680, 1550. 136
0. 1160σ-1HMR (DMSO-d6.δ)
: 2.05 (31,s), 8.28 (IH.

d, J-8,0Hz), 8.43 (IH, d, J=
8.0Hz) Elemental analysis: (C1H, CI!N20.S
-UH20) Calculated value: C32,15, Hl-55+
R8,a j.

H2O4.02 Actual value: C32.28, N2.78. N8.08H
204,03 Example 34 3-amino/-2-chloro-4-phenoxybenzenesulfonamide (2,50y) and acetic anhydride (0,79
me ) in pyridine (25y&) and heated under reflux for 1
Stir for 5 hours. During this time, 8 hours after the start of the reaction, 1
After 2 hours and 14 hours, acetic anhydride (0,4
mfl'). After the reaction was completed, n-hexane (5
After shaking, n-hexane is removed by decanting. This operation is repeated four times to remove excess acetic anhydride, the acetic acid produced, and most of the pyridine solvent. The residue was recrystallized from ethyl acetate to obtain slightly brown lumpy crystals (1,7y), and further recrystallized from ethanol to obtain white plate-like crystals of N-acetyl-3-amino-2-chloro- 4
-Phenoxybenzenesulfonamide (1,409) is obtained. mp 208~21O℃ER (Nujol)+
3450. 3360. 3210. 1760°1
330. 1160. 1140c+n -1HMR(
DMSO-d6, δ): 2.00 (3H, s),
5.64 (2H.

bs), 6.75 (IH, d, J=, 9Hz), 7.0
6-7.57 (6H1m) + 12.16 (IH, b
s) Elemental analysis: (CuH13C1!N204S) Calculated values: C49,34,H3,85,H8,22 real! 11
Value: C49,23,H3,80,H8,12 Example 35 Acetic anhydride (0,51me) and 4-amino-2-chloro-3-nitrobenzenesulfonamide)' (1°40
y) was dissolved in pyridine (10me), stirred at room temperature for 63 hours, and further stirred at 55°C for 8 hours.

Pyridine is distilled off from the reaction solution under reduced pressure, and the resulting residue is
Add dilute hydrochloric acid, extract with ethyl acetate, wash the extract with water, and dry with sulfur and magnesium acid.

The residue obtained by distilling off the solvent under reduced pressure was washed with n-hexane and recrystallized from methanol to give a yellow-orange powder of N.
-Acetyl-4-amino-2-chloro-3-nitrobenzenesulfonamide)' (0,8f?) is obtained. mp
220-2210C Engineering R (Nujol): 3470. 3350. 3
300. 1725°1535, 1345. 117
5. 1150cIn-1HMR (DMSO-d6.δ
): 1.98 (3H, s), 6.99 (I
H.

d, J=9Hz), 7.07 (2H,s,), 7.91
(IH, d.

J=9Hz), 12.33 (IH, bs) Cl elemental analysis = (~HsCI N305S) Calculated value: C
32,72,H2,75,N14.31 Actual value: C3
2,44,H2,72,N14.49 Example 36 A mixture of 2-chloro-4-fluoro-3-nitrobenzenesulfonamide (3,41) and acetic anhydride (50me) is stirred at 150 °C for 8 hours. .

The reaction mixture was concentrated to dryness and the residue (4,0y) was recrystallized from 20% aqueous methanol (120+++e) to give colorless needles of N-acetyl-2-chloro-4-fluoro-3.
-Nitrobenzene sulfona E)' (3°7y)
get. mp 189-194°CIR (Nujol)
: 1700. 1640. 1360. 1180
゜1160σ-1 NMR (DMSO-d6.J): 2.00 (3H
, s), 7.86 (LH.

t, J=8.0Hz), 8.40(LH, q, J=
8.0; 6.0Hz) Elemental analysis = (C8H6ClFN2
05S・-m-H20 calculated value: C31,81,H2,
20,H9,27゜H2O1,79 Actual value: C31,81,H2,47,H9,11゜H
2O1,73 Example 37 ~203°C (recrystallized from aqueous methanol) IR (Nujol): 31so; 1685. 1540. 1
360°1180, 1160cm-1 NMR (DMSO-d6.δ) + 2.00 (3H,
s), 2.40 (3H.

s), 7.71 (IH, d, J=8.0Hz),
8.17 (IH.

d, J=8. QHz) NoI nitrogen analysis: (C9H+CJ N2058) calculated value, C36,93,H3,10,H9,57 actual value, C
36,72,H3,01,H9,69 Example 38 In the same manner as in Example 31, 2-chloro-3-nitro-4
-Phenoxybenzenesulfonamide (1,50y) as slightly yellowish orange lumpy crystals of 2-chloro-N-phlopionyl-3
-nitro 4-phenoxybenzenesulfonamide (1
, 20y) t-obtain. mp189-192℃ (Recrystallized from methanol) Engineering R (Nujol): 3230.
1?40. 1540. 1360°1340cm-
1 NMR (DMSO-d6+δ): 0.93 (3H,
t, J=7Hz).

2.33 (2H, q, J=7Hz), 7.11 (I
H, d, J = 9Hz).

7.25-7.65 (5a, m), 8,18 (
I H1d+ J -9Hz).

12.67 (IH, bs, NH) Elemental analysis: (C,5H,3CIN,06S) calculated value, C46,82,l (3,40,H7,28 actual value:
C46,56,H3,41,H7,07 Example ゛39 2-chloro-3-nitro-4-phenoxybenzenesulfonamide (1,5(N;') in pyridine (10me
) 2-Methylpropionic acid chloride (0,5+++t') is added to the solution at room temperature while stirring, and the mixture is stirred for 2 hours. Dilute with water (200 mO) and collect the precipitated white pasty product. Dissolve this in ethyl acetate, wash with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, then water, dry over magnesium sulfate, The solvent is distilled off under reduced pressure.The resulting crude powder is recrystallized from a mixed solvent of ethanol and n-hexane to give -2-chloro-
N-inbutyryl-3-nitro-4-phenoxybenzenesulfonamide (0,75y) is obtained. mp192~
956C IR (Nujol): 3220. 1728. 1
550. 1358°1348σ-1 NMR (Acetone-d6, δ): 1.1
0 (6H, d, J=7Hz).

2.72 (IH, 5ept, J=7Hz), 7.
12 (IH, d.

J=9Hz), 7.17-7.74 (5H, m),
8.28 (IH, d.

J=9Hz) Elemental analysis: (C16H+, Cl2N206S) Calculated value: "C48,19, H3,79, H7,02 Actual value:
C48,08, H3,84, H6,96 Example 40 In the same manner as in Example 39, 2-chloro-3-nitro 4
- 2-chloro-N-piparoyl-3-nitro 4 from phenoxybenzenesulfonamide (1,50y) and piparic acid chloride (0,59me) in pale yellow needles
-Phenoxybenzenesulfonamide (1,00p) is obtained. m9194-197°C (recrystallized from ethanol) Engineering R (Nujol): 3280. 1728. 1
535. 1363°1345cm -1 NMR (DMSO-d6.δ): 1.13 (9H,
s), 7.11 (IH.

d, J=9Hz), 7.137.67 (5H1m
), 8.18 (I H, d, J-9HZ) + 12.
00 (L H2bs, NH) Elemental analysis: (Cl7
HI7CI N206S) Calculated value: C49,46,
H4, 15, H6, 79 actual measurement value: C49, 38, H3
,99,N 6.68 Example 41 In the same manner as in Example 39, 2-chloro-3-nitro 4
-phenoxybenzenesulfonamide (1,50y),
2-chloro-N-cyclopentylcarbonyl-3-nitro-4-phenoxybenzenesulfonamide (1,30y) is obtained as a white powder crystal from cyclopentanecarboxylic acid chloride (0,64y). mp 201-2038
C (recrystallized from ethanol) IR (Nujol): 3240. 1?28. 1
555. 1360°1350cm-1 mMR (DMSO-d6.δ): 1.33-2.00
(9H, m), 7.09 (IH2d, 9H2),
7.12-7.63 (5H1m).

8.16 (IH, d, J-9Hz), 12.75 (
IH, bs, NH) Elemental analysis = (C18H17C7?H
2O6S) Calculated value: C50,89,H4,03,H6
,59 actual measurement value: C50,81,H3,91,H6,4
4 Example 42 In the same manner as in Example 39, 2-4 row 3-nitro 4
- Phenoxybenzenesulfonamide (1,50p) and 2-furoyl chloride (0,47me) in pale yellow needles, 2-chloro-N-(2-furoyl)-3-
Nitro 4-phenoxybenzenesulfonamide (0,
80y). mp263-265°C (recrystallized from a mixed solvent of tetrahydrofuran-n-hexane) IR (Nujol): 3240. 1708. 1
542. 1350σ-1NMR (DMSO-d6.δ
): 6.65 (IH, d, d, J=3Hz,
2Hz).

7.13 (I Hld, J -9Hz) + 7.
137.50 (5H1m).

7.58 (I H1+iy J-3Hz), 7.9
4 (I Hls )+8.25 (IH, d, J=9
Hz) Elemental analysis: (CuHoC1!N207S) Calculated value:
C48, 29, H2, 62, H6, 63 actual measurement value: C4
8,14,H2,70,H6,50 Example 43 2-tri-4-3-ditro-4-phenoxybenzenesulfodiamide (1,1;'), 37% formalin aqueous solution (
0,91me) and n-butanol (10me)
The mixture was heated and stirred at 100°C for 4 hours, and then
Stir and reflux for 3 hours. The n-butanol was distilled off under reduced pressure, and the residue was pulverized with n-hexane.

The obtained powder (1,0y) was mixed with n-hexane and n-
Recrystallized from a mixed solvent of butanol, a pale yellow powder of N
-(n-butoxymethyl)-2-chloro-3-nitro-4-phenoxybenzenesulfonamide (0,85y)
get. mp84-88℃ IR (Nujol): 3
400. 3070. 1545. 1360°134
0.1280+ 1190,1175cInNMR(
CDCf3. δ): 0.65-1.5 (7H, m
), 3.28 (2H.

t, , r=6Hz), 4.59(2H,d, J
= 7Hz), 6.12 (IH, t, J = 7Hz),
6=83 (IH, d, J=9Hz).

6.95-7.60 (5H, m), 8.03 (IH
, d, J=9Hz) Elemental analysis: (C1yH+9Cj
'N206S) Calculated value: C49, 22, H4, 62
, H6, 75 actual measurement value: C48, 96, H4, 55, H6
, 72 Example 44 4-sulfamoyl-3-chloro-2-nitrobenzoic acid (5,6y), methyl iodine (8,5 g), powdered potassium hydroxide (3,4y-) and dry dimethyl sulfoxide (25 mff ) is stirred at 20°C for 2 hours and then at 50°C for 2 hours.To this mixture is added methyl iocide (8,5y
) and powdered potassium hydroxide (3,4y) to make 50
Stir for 1 hour at °C.

Water (25me) and methanol (25me) were added to the reaction mixture.
) and potassium hydroxide (5,0y) at 80℃.
Stir for an hour.

The resulting reaction mixture was poured into ice water (300=e), the pH was adjusted to 2.0 with concentrated hydrochloric acid, and then 1 each of ethyl acetate was added.
Extract 3 times with 00 me each. The organic layer is saturated with saline,
Wash sequentially with 10% aqueous sodium sulfite solution and saturated saline, and strain with magnesium sulfate. The pale yellow oil obtained by distilling off the solvent under reduced pressure crystallizes when water (100mf') is added, and after air-drying PJllX, air-drying - methanol e)
Recrystallization from a mixed solvent of and water (100 mf') gives colorless needle-like crystals of 3-chloro-4-(N,N-dibutylsulfamoyl)-2-nitrobenzoic acid (4,6y). m
p208-211'C IR (Nujol): 3080. 2650. 2
500. 1715°1550, 1360. 116
5σ-1NMR (DMSO-d6.δ): 2.91 (
6H,s), 7.26(2H.

8) Elemental analysis: (C9H7CI!N206S/DingH20) Calculated values: C34,79,H2,99,H9,02H20
0,64 Actual value: C34,841H3,40, N8.81°H
200,67 Example 45 4-sul7amoy-3-chloro-2-nitrobenzoic acid (20,0y) was dissolved in dry N,N-dimethylformamide (
Thionyl chloride (42,4y) is added dropwise to the solution over 1 hour while cooling to 0° C. and stirring, and the mixture is further stirred at room temperature for 4 hours.

The reaction mixture is poured into ice water (400=e), P is removed from the precipitated crystals, and the crystals are washed until the washing liquid becomes neutral.

The crude crystals (23,0y) were dissolved in 33% aqueous acetone (300=
Recrystallization from e.g. gave pale yellow needle-like crystals of 3-chloro-4-(
N,N-dimethylaminomethylene (sulfamoyl)-
2-nitrobenzoic acid (19,sy) is obtained. mp
255-257°C IR (Nujol): 1730. 1630. 1
550. 1370°1160crn NMR (DMSO-d6.δ): 3.00 (3H,
s), 3.20 (3H, s).

5.33 (IH, wide S), 8.00-8.40
(3H, m) Elemental analysis: (C2°H, oCf N306
S T H, O) Calculated value: C35,14, H3,15,
N 12.30H201,75 Actual value: C34,73, H3,09, N 12.24
H201,81 Example 46 Ethanol (10me) and metallic sodium (0,16y
) to prepare a sodium ethoxide-ethanol solution, add 0-chlorophenol (0,91'), and stir at room temperature for 10 minutes. 2,4-dichloro-3-nitrobenzenesulfonamide (1,90y) and dimethylsulfoxide (10y) were added to the residue obtained by distilling off ethanol under reduced pressure.
me) and stirred at 100°C for 6 hours. After cooling the reaction solution to room temperature, water (250=e) was added, extracted with ethyl acetate, and diluted with 5% aqueous caustic soda solution (100
+++t, then washed with water and dried over magnesium sulfate.

An orange paste-like substance (1,80y) obtained by distilling off ethyl acetate under reduced pressure is powdered with a mixed solvent of n-hexane and diisopropyl ether to obtain a crude powder of 1.252. Silica gel column chromatography (developing solvent;
From the fraction containing the target product, a crude powder (1,00y) of the target product was obtained, which was recrystallized from a mixed solvent of ethyl acetate and n-hexane.
2-10 rho 4-(2-chlorophenoxy)-3-nitrobenzenesulfonamide)'(0,6
5y) is obtained. mp 168”170°C elemental analysis:
(C+2HsC12N205S) Calculated value, C39
, 69, N2.22. N7.71 actual value, C39,
54, N2.21. N7.75 Example 47 In the same manner as in Example 46, m-chlorophenol (0,
95y) and 2,4-dichloro-3-nitrobenzenesulfonamide (2,00y), 2-chloro-4-(3-chlorophenoxy)-3-, slightly brown powder crystals.
Nitrobenzenesulfonamide (0,65y) is obtained. m9187-189°C (recrystallized from ethanol) IR (Nujol): 3450. 3330.15
35. 1320°1185, 1160cm-1 NMR (DMSO-d6.δ): 7.28 (IH, d
, J-9Hz).

7.1'3-7.70 (4H, m), 7.91 (2
H, bs).

8.17 (IH, d, J=9Hz) Elemental analysis: (C1□H8Cl2N205S) Calculated value:
C39,69,N2.22. N7.71 actual value: C40
,07,N2.17. 'N7.95 Example 48 In the same manner as in Example 46, a slightly brown plate was prepared from 2,3-dimethylphenol (1,36y) and 2,4-dichloro-3-nitrobenzenesulfonamide (3,00y). crystalline 2-chloro-4-(2,3-dimethylphenoxy)
-3-nitrobenzenesulfonamide (0,9Jl;'
). mp '185~187°C (ethanol-
Recrystallization from a mixed solvent of n-hexane) IW (Nujol): 3390. 3275. 1
540.1325° 1180, 1155 cm NMR (DMSO-d6.δ): 2.01 (3H, s
), 2.28 (3H,s').

6.84 (LH, d, J-9Hz), -6,92-7,
21 (3H, m).

7.78 (2H, s), 8.03 (LH, d, J-9H
z) Elemental analysis: (C,4H,,CeN20.S)
Calculated value, C47,13, N3.67, N7.85 Actual value: C47,55+N3.62. N8.03 Example 4
9 In the same manner as in Example 46, 3-chlorophenol (1,
01y) and 2-chloro-4-fluorololophenoxy)-3-nitrobenzenesulfonamide (1,20y
). mp187-189'c (recrystallized from ethanol) Example 50 In the same manner as in Example 46, 3-methylphenol (0,
919) and 2-chloro-4-fluoro-)IJ-ruoxy)-3-nitrobenzenesulfonamide (1,o
oy). m9157~158°C (ethanol-
(Recrystallized from a mixed solvent of n-hexane) IR (Nujol): 3380. 3280. 1
535. 1365°1320, 1185.1155c
m-1HMR (DMSO-d6.δ): 2.35 (3H
,s), 6.97-7.43(5H,m), 7.8
8 (2H, bs), 8.15 (LH, d.

J=9Hz) Elemental analysis: (Cl5H1□C1! N20., S)
Calculated value: C45.55, N3.23. N8.17
Actual value: C44,75,l (3,22,N8.26 Example 51 In the same manner as in Example 46, 3-trifluoromethylphenol (1,40y) and 2-taloloro-3-nitro-4-(3 -Trifluoromethylphenoxy)benzenesulfonamide (1,00y) is obtained.mp180~
182°C (recrystallized from a mixed solvent of ethyl acetate and n-hexane) IR (Nujol): 3390. 3
280. 1535. 1365°1320, 118
0. 1155. 1120cIn'NMR (DMSO
-d6. δ): 7.29 (IHld, J =
9Hz)+7.50-7.74(4H,m), 7
．． '90 (2H, bs), 8.15 (IH, d, J
=9Hz) Elemental analysis: (C,3H8CI F3N205S) Calculated value: C39,36+N2.03. N7.06 actual value: C39,10, Hl, 91. N7.08 Example 52 In the same manner as in Example 46, 2,3-dichlorophenol (1,28y) and 2-chloro-4-fur3-dichlorophenoxy)-3-nitrobenzenesulfonamide (1 , 60y). mp204-206℃ (recrystallized from ethanol) IR (Nujol): 3360
．． 3280. 1535. 1365°1335,
1180. 1160. 1150cIn-”NMR (
DMSO-d6. δ): 7.17 (IH, d, J=
9Hz).

7.50-7.83 (3H, m), 7.95 (2H
,s), 8.16(H(,d, J=9Hz) Elemental analysis: (Cl2H7C1!3N2f)5S) Calculated value: C36,25,Hl,77, N7.05°C
126,75 Actual value: C36,31, Hl, 67, N7.11°C
126,40 Example 53 In the same manner as in Example 46, 3.4.5-trimethoxyphenol (1,52y) and 2-chloro-4-3-
4-(3,4,5-)rimethoxyphenoxy)
Benzenesulfonamide (1,20y) is obtained. mp2
33-235°C (recrystallized from tetrahydrofuran) IR (Nuji-i-#): 3330, 3230. 154
0.1365°1350, 1180. 1155.
1130c+++'NMR (DMSO-d6.δ):
3.68 (3H, B), 3.78 (6H.

s), 6.62 (IH, s), 7.19 (IH
, a, J=9Hz).

7.83 (2H, bs), 8.09 (LH, d, J
=9Hz) Elemental analysis: (C15Hy, C12N20@
S) Calculated value: C43.02, N3.61. N6
．． 69 actual measurement value: C43.13, N3.37. N6.5
8 Example 54 Methanol (30me) and metallic sodium (0°27
From y), sodium methoxide-methanol! F[f
2-chloro-4-fluoro-3-nitrobenzenesulfonate El' (3,0 Oy) was added, and the mixture was stirred under reflux for 13 hours. The residue obtained by distilling methanol off under reduced pressure is neutralized and made acidic by adding water-cooled hydrochloric acid, then extracted with ethyl acetate, washed with water, and the extract is dried over magnesium sulfate.

The solvent was distilled off under reduced pressure to obtain a 2.75 y crude powder. It was purified by silica gel column chromatography (developing solvent: ethyl acetate), and the fractions containing 2. A pale yellow powder of lOy is obtained. Among these, 1.
50y is recrystallized from ethanol to obtain pale yellow columnar crystals of 2-chloro-4-methoxy-3-nitrobenzenesulfonamide)'(1,20/)&. m-cho) 213-2
15°C TR (Nushor): 3380. :t2so,
1535. 1345°1330, 1175.
1160cIn-1HMR (DMSO-d6.δ):
4.03 (3H+s), 7.53 (IH, d, J=9
Hz), 7.82 (2H, bs).

8.20 (IH, d, J=9Hz) Elemental analysis: (C, H, CI N, 058) Calculated value:
C31,53, N2.65. N10.51 actual value:
C31,59, N2.76, N10.64 Example 55 2-chloro-4-fluoro-3-nitrobenzenesulfonamide (2,0y) and powdered hydroxide liquid (2,0y)
A solution of 0y) in dry dimethyl sulfoxide (25me) is stirred at room temperature for 2 hours.

The reaction mixture is poured into wood plants (200 mt') and extracted with acetic acid ethyl ester. Wash the extract with saturated saline,
Dry with anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure, and the residual oil (10me) was subjected to alumina column chromatography (basic). Elution with ethyl Nisder acetate was followed by acetic acid-methanol (20:80), and a yellow crystalline residue (
2, (1) was obtained and recrystallized from 20% aqueous methanol (50 m
) You can get it.

mp261-268°C (decomposition) IR (Nujol): 3400. 3380. 30
60. 1600°1550, 1370. 1175
, 1155σ-1HMR (DMSO-da *δ):
7.23 (LH, d, J=9.0Hz).

7.68 (2H, s), 8.02 (IH, d, J
=9.0Hz) Elemental analysis: (c6H5ce N205
B-Ha2o) Calculated value: C28,30,N2.07
．． N11.00°N20 0.79 Actual value: C28,19,N2.09. N11.00
°N200.85 Example 56 N-acetyl-2-chloro-4-fluoro-3-nitrobenzene was added to a mixture of potassium hydroxide (3,8y), acetone (40ml) and water (40me) under water cooling and stirring. sulfonamide)' (4,0y) and stir this mixture at room temperature for 6 hours.

The reaction mixture was made acidic (pH 3,0) with 7% hydrochloric acid under water cooling, and then evaporated to a liquid volume of 40 me.

The precipitated powder was collected and treated with acetone (50me) and n-
When recrystallized from a mixed solvent of hexane (100+++e), N-acetyl-2-chloro-4-
Hydroxy-3-nitrobenzene sulfonamide (2
, 9y) are obtained. mp254-255℃ (decomposition) IR (Nujol): 3300. 1700. 1
535. 1345°1180c+++-1 NMR (DMSC) l-d6. δ): 2.02 (3H
, s), 7.32 (, IH.

d, J=8.0Hz), 8.16(IH, d, J=
8.0Hz) Elemental analysis: (C8H7C1!N206S)
Example 57 Two-hydroxy-3-methyl-2,3-dihydrobenzofuran-2-one (1,6y), powdered potassium carbonate (1,35y) and dry N,N-dimethylformamide (50me) Add the mixture to 80°C and stir for 2
-Chloro-4-fluoro-3-nitrobenzene l sulfonamide)' (2,5y) in dry 9N,N-dimethylformamide (20 ml) was added dropwise over 60 minutes, and after the addition was completed, an additional 6 ml of solution was added at the same temperature. Stir for an hour.

Insoluble inorganic substances are separated from each other, and the p-liquid is diluted with 3.5% hydrochloric acid (100%
me) and extracted with ethyl acetate.

The extract is washed with saturated brine and then dried over anhydrous magnesium sulfate.

The residue (40y) obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography and eluted with ethyl acetate-toluene (2:8). The fractions containing the target product were combined and the solvent was distilled off under reduced pressure to obtain a pale yellow powder (il, ll).
was obtained and recrystallized from 20% aqueous methanol to give colorless needle-like crystals of 7-(4-sulfamoyl-3-chloro-2-nitrolphenoxy)-3-methyldihydrobenzofuran 2,3-dihydrobenzofuran. -2-one (0,6y) is obtained. m
p121-126”C 1R (Nujol): 3600.3400.3
280. 1790°1540, 1355. 117
5cm' NMR (DMSO-d6.δ): 1.5
0 (3H, d, J, = 8.0Hz).

3.87-4.17 (IH, m) + 6.86-8.
13 (5H, m).

7.79 (2H, B) Elemental analysis: (Cl5HIICj? N207S-5N
20) Calculated value: C44,76+N2.86.
N6.96°N20 0.90 Actual value: C44.75, N2.90. N6.96°N2
0 1.00 Example 58 Allyl alcohol (30me) and metallic sodium (0
, 23y) to prepare a sodium allyl oxide solution.

Add 2-chloro-4-fluoro-3-nitrobenzenesulfonamide F (2,5y) to this solution and reflux the mixture for 6 hours with stirring.

After cooling, the reaction mixture was poured into 1% aqueous hydrochloric acid (100me) and extracted with ethyl acetate. The extract is sequentially washed with saturated brine, aqueous sodium bicarbonate solution, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a pale brown oil (3,3y), which was subjected to silica gel column chromatography and eluted with ethyl acetate-toluene (8:2). The fractions containing the target product are combined and the solvent is distilled off under reduced pressure.

The residue was crystallized with n-hexane to give 2 colorless fine needles.
-Chloro-3-nitro 4-71J oxybenzenesulfonamide F (0,7y) tf'4. mp171
~177°C Engineering R (Nujo #): 3360. 3280. 31
00. 1535°1335, 1180. 1160
cm −1 HMR (DMSO-d6.δ): 4.83
(2H, d, J=6.0Hz).

5.17-6.00 (3H, m), 7.50 (LH,
d, J=9.0Hz).

7.78 (2H2s), 8-10 (I H+ d
, J = 9.0 Hz) Elemental analysis: (C9H9Cf
N205S' 17-N2o) Calculated value: C36,
80,' N3.13. N9.54°H,,OO,36 Actual value: C36,23,H3,08,N9.69°N2
00.36 Example 59 Thiophenol (3,46 gt
) and 2,4-dichloro-3-nitro Ibenzene sulfonamide (8,50y).
J Rolow 3-nitro-4-7enylthiobenzenesulfonamide <1.3oy>. mp182~184°
C (recrystallized from methanol) IR (nuji a-#):
3375. 3260. 1530. 1355°13
40, 1150 硼-1 NMR (DMso-a6.δ): 7.37 (IH, d
, J=9Hz).

7.52 (5H, s), 7.95 (2H, bs),
8.10 (LH.

d, J=9Hz) Elemental analysis: (C,2HgCf N20.S2) Calculated value: C41,85, N2.63. N8.13 actual value: C41.65, N2.44. N7.98 Example 6
0 A solution of 2-chloro-4-fluoro-3-nitrobenzenesulfonamide (2,00y) in methanol (3°me) was mixed with 20% methylmercaptan sodium salt (2,75y) in methanol (5me) while stirring at room temperature. Drop the solution. After stirring for an additional hour at room temperature, methanol was distilled off under reduced pressure. Water is added to the residue, acidified with dilute hydrochloric acid, extracted with ethyl acetate, and the extract is washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give light yellow columnar crystals of 2-chloro-
4-Methylthio-3-nitrobenzene sulfonamide (1,35y) is obtained. mp 224~226°CIR
(Nujol): 3370, 3280. 1525
．． 1355°1335.1150cm-1 NMR (DMSO-d6.J): 2.67 (3H,
s), 7.77 (IH.

d, J=9Hz), 7.92 (2H1bs, 5o2N
H2).

8.12 (LH, d, J=9Hz) Elemental analysis' (C7H7C1!N204S2) Total threat value: C29,74, N2.50. N9.91゜CJ12
．． 54 Actual value: C29.63, N2.41. N9.93゜CI
! 12.64 Example 61 A mixture of benzyl mercaptan (2,43P), powdered potassium carbonate (2,71y) and dry N,N-dimethylformamide (75me) was cooled to 3-7°C and stirred for 2 hours.
A solution of -chloro-4-fluoro-3-nitrobenzenesulfonamide (5,0y) in dry N,N-dimethylformamide (25 mt) is added dropwise over 10 minutes. Chima agitates.

The reaction mixture is poured into water (200me) and extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate.

The yellow semisolid (7,02) obtained by distilling off the solvent under reduced pressure was recrystallized from 25% aqueous methanol to give pale yellow plate-like crystals of 2-chloro-3-nitro-4-(benzylthio)benzenesulfonamide. (obtain s, 6y>.mp165~1
66°C Engineering R (Nujoru door 3370. 3270. 152
0. '1350°1160cm-1 7,96 e), Darkness (IH, d, J=8.0Hz), 8
．． 00 (2H, s).

8.20 (IH, d, J = 8.0) (z) Elemental analysis: (C+3HoCj? N204S2) Calculated value:
C43,52,N3.09. N7.81 actual value: C
43,72,H3,10,N7.71 Example 62 2-chloro-4-fluoro-3-nitrobenzenesulfonamide (5,6y) was dissolved in tetrahydrofuran (60ml).
The mixture is stirred at room temperature for 3 hours while introducing ammonia gas. While continuing to introduce ammonia scum, the mixture was heated to 45°C and stirred for an additional 6 hours. Water was added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was extracted with ethyl acetate.

The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from ethanol to give a yellow mass of 4-amino-2-chloro-3-nitrobenzenesulfonamide (3, 35y) Obtain t”.

mp217-2188C IR (Nujol): 3460. 3350. 32
60. 1520°1325, 1170. 1160
．． 1150c+++-1NMR (DMSO-d6.δ
): 6.75 (2H, bs, NH2).

6.93 (fH, d, J=9Hz), 7.48 (
2H, bs).

7.75 (LH, d, J-9Hz) jL elementary analysis: (C6H6CZ' N304S) Measured value: C28,64, H2,40, N16.70 Actual value: C28,43,'H2,35, N16 .90 Example 63 Iron powder (1,34y) and Asimonicum chloride (0°16
y) was added to a mixture of ethanol (20d) and water (3me), and 2-chloro-3-nitro-4-
Slowly add 7-enoxybenzenesulfonamide (1,80y). After continuing stirring and refluxing for an additional hour, the reaction solution is filtered while hot. After evaporating the solvent under reduced pressure and stirring, the mixture was extracted with diethyl ether. The extract is washed with saturated hydrogen carbonate, IJ cum solution and brine, respectively, and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was recrystallized from a mixed solvent of ethyl acetate and benzene to obtain 3-amino-2-chloro-4-phenoxybenzenesulfonamide (1,00 gI) as a white powder crystal. get o'
mp 127-129°CIR (Nujol):
3450. 3330. 3230. 3075°1
335, 1230. 1200cm-1NMR (DM
SO-d6. δ): 5.53 (2H,s),
6.70-7.58 (9H, m) Elemental analysis: (C1□H31ClN203S) Calculation Tsukuda:
C48, 24, H3, 71, H9, 38°S10.73
．． C111,87 Actual reconnaissance: C48,52, H3,80, H9, 35°S1
0.86. CfLl, 70 7 Example 64 In the same manner as in Example 63, 2-chloro-N-(2-chlorobenzyl)-3-nitro-4-phenoxybenzenesulfonamide (2,00y) was obtained. Silica gel column chromatography (ff (1 m solution i)
; Purify with ethyl acetate: toluene-1=4) to obtain white powdery crystals of 3-amino-2-chloro-N-(2
-chlorobenzyl)-4-phenoxybenzenesulfonamide (0,50y) is obtained. mp96.5~99℃(
Ethyl acetate (recrystallized from 〇-hexane) IR (Nujol): 3495. 3375. 3
295. 1325°1150c1n' NMR (DMSO-d6.δ): 4.20 (2H+
bs), 5.52 (2 Hlbs), 6.66 (
IH, d, J=9Hz), 6.72-7.55(
IOH, m), 8.22 (IH, bs) elemental analysis:
(C+q, H+aC7?2N, 20°S) Calculated value:
C, 53, 91, H3, 81, H6, 62 Actual value: C5
3,92,H3,66,H6,61 Example 65 In the same manner as in Example 63, 2-chloro-N-methyl-3
-Nitro-4-phenoxybenzenesulfonamide (1
, 60y) to 3-amino-2-chloro-N-methyl-
4-phenoxybenzenesulfonamide (0,60y)
get. mp 119-1210C (recrystallized from ethyl acetate-n-hexane) IR (Nujol): 3460. 3360. 33
30. 3295°1315, 1150cm' NMR (CDCl3+δ): 2.63 (3H, d, J=
6Hz), 4.60 (2H, bs, NH2),
4.72 (IH, q, S 02NHJ=6Hz)
.

6.69 (IH, d, J=9Hz), 6.97-7
．． 60 (5H, m).

7.41 (IH, d, J=9Hz) Elemental analysis = (C13H13ClH203S) Calculated value:
C50,00,)I4.19. N8.96 actual value: C
49,85,H4,15,N8.87Example 66 In the same manner as in Example 63, 3-aninoyl dimethyl-3-nitro-4-phenoxybenzene sulfonamide (1,40y) was prepared. 2-chloro-4-phenoxy-N,N-'; methyl I benzenesulfonamide (0,951) is obtained. mp104-107°C (recrystallized from ethyl acetate-n-hexane) IR (Nujol): 3460. 3370. 13
25. 115561n-'NMR (CDC/3.J
): 2.88 (6H, s), 4.58 (2H, b
a).

6.66 (IH, d, J = 9Hz), 6.13
-7.57 (5H, m).

7.34 (LH, d, J = 9Hz) Elemental analysis:
('C+4H+s(J' N203S) measurement value:
C51,45, H4,63, N8.57 Actual value: C5
1,53,H4,57,N8.66 Example 67 In the same manner as in Example 63, 2-chloro-N-(isopropylcarbamoyl)-3-nitro 4-ra pale 'M-colored powder, 3- Amino-2-chloro-4-7 enoxy N-(
Isopropylcarbamoyl)benzenesulfonamide (
o, ssy > get it.

mp171-173°C IR, (Nujol): 3450. 3350. 3
280. 1665°1567, 1555. 147
9. 1340. 1234°1200, 1157σ
-1 NMR (DMSO-tun, δ1', 03 (6H, d,
J=7Hz).

3.63 (LH, octet, J=7Hz)+5.
63 (2H, brs).

6.22(it(,d,J=7Hz), 6.74(
IH, d, J = 9Hz).

7.00-7.64 (6H, m), 10.34 (I
H, brs) Elemental analysis: (C16H18CI N30
4S) Calculated values: C50,06,H4,73,N10
．． 95 actual value, C49.76, H4.56, N10.1
3 Example 68 In the same manner as in Example 63, 3-amino-2-chloro-N
-(2-Furfuryl)-4-phe/xybenzene sulfona triF(o,6sy) is obtained. mp68-72℃ (
Acetic acid ethyl ester (recrystallized from n-hexane) IR (Nujol): 3550. 3450. 33
95. 1325°1150cm-1 NMR (DMSO-d6.δ): 4.08 (2H,
d, J=5Hz).

5.48 (2H, s), 6.10 (IH, d, 'J=
3.5Hz).

6.28 (IH, q, J-3,5Hz), 6.6
9 (IH, d, J=, 9Hz6.937.57 (
6H9m) + 7.38 (IH, d, J = 9Hz).

8.12 (IH, t, J=3.5Hz) elemental analysis:
(C,,H,,C/N204S) Calculated value: C53
,90,N3.99. N7.40 Actual value: C53,
59, N3.87. N7.32 Example 69 In the same manner as in Example 63, 1-(3-nitro-2-chloro-4-phenoxybenzenesulfonyl)-4-(2
-Hydroxyethyl)hyherazine (2°507) was subjected to silica gel column chromatography.
After purification using 1), it is dissolved in 40 thihydrochloric acid mechnol solution and stirred at room temperature. The solvent was distilled off under reduced pressure, and the residue was diluted with ether.
By adding ethanol mixed solvent and powdering, 1-
(3-Amino-2-chloro-4-phenoxybenzenesulfonyl)-4-(2-hydroxyethyl)hyperazine I monohydrochloride (0,90y) is obtained. mp221-2
23°C (recrystallized from methanol), IR (Nujol): 3450.
3360. 3250. 1350゜1160cIn-
1 NMR (DMSO-d6.δ): 3.03-4.03
(12H, m) 5.00 (3H, be), 6.76
(LH, d, J=9)iz).

7.23 (LH, d, J-9Hz), 7.03-
7.67 (5H, m).

11.23 (IH,be) Elemental analysis: (C,8H22C1! N304S-HC
Calculated value: C48, 22, N5. l? , N9.37
゜Q? 15.82 Actual value: C48.23, H'5.12. N9.35
°C115,40 Example 70 In the same manner as in Example 63, 1-(2-chloro-3-nitro-4-7enoxybenzenesulfonyl)-4-(2-
70yl) piperazine (3,15y) to 1-(3-
Amino-2-chloro-4-phenoxybenzenesulfonyl)-4-(2-furoyl)piperazine (1,701 is obtained. mp 131-133°C (recrystallized from ffl ethyl ester: toluene = 1; l) IR (Nujol) ): 3425. 3330. 1
630. 1615°1600, 1340. 114
5cm −1HMR (DMSO-d6.δ): 3.1
7-3.35 (4H, m), 3.67-3.83 (
4H, m), 5.67 (2H, s), '6.62
(IH, d, d.

J=3.5Hz), 6.73(LH9d, J=9t
(z), 7.00-7.58 (7H, m), 7.8
0-7.85 (IH, m) Elemental analysis: (C2, H2o
CI N305S) Total q value, C54,60,H4,3
6, N9.10 Actual value: C54, 56, H4, 29, H
8,84 Example 71 A suspension of 3-chloro-2-nitro-4-sulfamoylbenzamide (3,07) in ethanol (30me) was
Iron pile (3,051') Asimonicum chloride (0,3y),
The mixture was added dropwise to a mixture of water (15mC) and ethanol (45mC) under stirring and refluxing for 30 minutes, and after the completion of the dropwise addition, the mixture was stirred and refluxed for 90 minutes.

The reaction mixture was adjusted to pH 10 with a 1N aqueous potassium hydroxide solution.
Set to 0. Insoluble materials were removed, and the P solution was adjusted to pH 2 with 35% hydrochloric acid.
, set to 0. Collect the precipitated crystals and leave under reduced pressure for 40 minutes.
After drying at ℃ for 6 hours, 2-amino-3-chloro-4-sulfamoylbenzamide (2,
4y) is obtained. mp250-253°C IR (Nujol): 3460. 3355. 3
300. 3230°1660, 1635. 133
5. 1155c+++ -1HMR (DMSO-d6
．． δ): 6.60 (2H,brd,s).

7.20-8.33 (7H, m) Elemental analysis: (c7H8ceN3o, s H, H20)
Calculated values: C33, 37, H3, 25, N16.68°H
2O0,88 Example 72 A solution of 3-chloro-2-nitro-4-sulfamoylbenzoic acid (5,6P) in water (60me) was stirred under reflux, and a solution of sodium bisulfite (10,4y) in water (50me) was stirred. The mixture was added dropwise after 1 hour, and the mixture was further stirred at the same temperature for 2 hours. The reaction mixture was allowed to cool to room temperature, additional sodium hydrogen sulfite (10,4y) was added, and the mixture was refluxed for 15 hours with stirring.

The resulting reaction mixture was adjusted to pH 2.0 with 35% hydrochloric acid, and then refluxed for an additional 30 minutes in a stirring knife.

Cool the reaction solution and count the precipitated crystals.

The crude crystals were mixed with ethanol (40+++e) and water (60mf
') was recrystallized from a mixed solvent of 2-
Amino-3-chloro-4-sulfamoylbenzoic acid (2
, 3y). mp 260-262℃ IR (Nujol) + 3500. 3360. 3230. 3
060°1680, 1610. 1335. 116
0σ-1HMR(, DMSO-d6.δ) near, 16(
IH, d, J = 8.0 Hz).

7.56 (2H, s), 7.84 (18', d,
, T = 8.0Hz) Elemental analysis: (C7H7CrN2
04S), 11 calculation value: C33,54,H2,82,1
18 actual measurements (rl: C33, 41, H2, 68,
N10.96 Example 73 In the same manner as in Example 63, 2-chloro-4-methyl-3
3-Amino-2-chloro-4-methylbenzenesulfonamide (120y) is obtained as light brown powder crystals from -nitrobenzenesulfonamide F (1,85y). mp
1.68-169°C (recrystallized from ethanol) Engineering R (Nujol): 3480. 3280. 3
205. 3200°1320, 116 (1,113
0trn'NMR (DMSO-d6.δ): 2.20
(3H, s), 5.40 (2H.

bs), 7.03 (d, J-9Hz), 7.2
0(d,,T=9Hz).

7.30 (sf Elemental analysis: (C7H9CeN20□S) Calculated value: C38
, lO, H4,11, N12.69 Actual value: C38,3
2,H3,98,N12.87Example 74 In the same manner as in Example 71, 3-chloro-4-(N,N-
dimethylsulfamoyl)-2-nitrobenzoic acid (2,
5y) to obtain 2-amino-3-chloro-4-(N,N-dimethylsulfamoyl)benzoic acid <1.8y).

mp186~188°CIR(nujo-)I,): 3
500. 3450. 3360. 2700°260
0, 2550. 1675. 1350. 1160
cm 'Total value: C38, 79, H3, 98, N10.
05-1. Actual value: C38,76+ H3,87,N
10.04 [Example 75] In the same manner as in Example 71, 4-(N-acetylsulfamoyl')-3-10 rho-2-nitrobenzoic acid (1,
7gI), 4-(N-acetylsulfamoyl)-
2-Amino-3-chlorobenzoic acid (1,3,7) is obtained. mp216-219℃ IR (Nujol): 345
0. 3330. 1740. 1710°1370,
1180. 1130σ-1HMR (DMSOd6
+δ): 2.00 (3H, s), 7.26 (IH
.

d,, T=9.0Hz), 7.84(IH, d, J
=9.0Hz') rQ elemental analysis: (C!l H9Ce
N205S-±H,,O) Calculated value: C35,30,H
3,46,H9,15H204,41 3,67 Actual value: C35,25,H# disorder, H9,22H20
4,30 Example 76 In the same manner as in Example 71, 3-chloro-2-nitro-4
-Sulfamoylbenzenesulfonamide (1,3y)
to obtain 2-amino-3-chloro-4-sulfamoylbenzenesulfonami)' (1,0y). mp2
42-245°C (recrystallized from aqueous ethanol) IR (Nujol): 3340. 3270. 1
615. 1330°1155cm' NMR(]]rMSO-d6.δ: 6.26(2H,
s), 7.33 (IH.

d, J=8.0Hz), 7.66(4H,s),
7.73 (IH.

d, J=8.0Hz) Elemental analysis: (C6H, CI N30482) Calculated value: C25,22, H2,82, N14.71 Actual value: C
25,56, H3,00, N14.62 Example 77 28 Thiammonia water (50me) and acetone (50m
e) The mixed solution of 3-chloro-2-nitro-4-sulfamoylbenzoylchloroIJ)'(6,0y) was mixed with acetone (6,0y) by stirring for 15 minutes while cooling to 5-7°C. 50
mC) solution was added dropwise, and the mixture was further stirred at the same temperature for 45 minutes.

The reaction mixture was concentrated to 100 me under reduced pressure, adjusted to pH 2.0 with 35% hydrochloric acid, and further concentrated to 50 me under reduced pressure.

The precipitated crystals were collected and recrystallized from a mixed solvent of methanol (60 ml') and water (100 me) to obtain colorless needle-like 3-chloro-2-nitro-4-sulfamoylbenzamide (4,2y). ) is obtained. mp246~249°C
(Decomposition) IR (Nujol'): 3600. 3370.
3260. 3060°1680, 1535. 13
60. 1335. 1180°1160cm' NIVIR (1) MSO-d6. a): 3.43
(2H, s), 7.97 (IH.

d, J = 8.0Hz) + 8.00 (2H, s),
8.23 (IH.

(J, , T = 8.0 Hz) Elemental analysis = (C7H6C4N305S) Calculated value: C3
0,06,H2,1・6. N15.03 Actual value: C
30,24,H2,04,N14.91 Example 78 1-Amino-2,6-dimethylpiperidine (0,83y
) and triethylamine (0.93me) in tetrahydrofuran (50me) were cooled to 10-15'C and were stirred for 20 minutes to form 3-chloro-2-nitro-4.
-Sulfamoylbenzoylchlor IJ)' (2゜0
y) and further stirred at room temperature for 84 hours.

The reaction mixture was poured into 50ml of water, extracted with ethyl acetate, washed with saturated brine (50ml), and dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure to give a light brown oil (3, 8y) and diethyl ether (
6ome) to give a pale yellow powder.

The powder (1,35') obtained by further purification by silica gel column chromatography (eluted with a mixed solvent of methanol and chloroform (1:10)) was added to a 1/20 N aqueous potassium hydroxide solution (20 m(')). After dissolving in P solution and treating with activated carbon (100μ), the P solution was adjusted to 3.51 (pH 6 with acid).
The precipitated crystals were collected and dried under reduced pressure at 50°C at 8 o'clock to obtain a pale yellow powder of 3-chloro-2-nitro-4-sulfamoyl-N-(2 ,6-
simethylpiperidino)benzamide (1,1y) is obtained. mp241-244°C (decomposition) IR (Nujol): 3540. 3320. 3
220. 3060°1670, 1600. 157
0. 1540. 1350°1330, 1160.
1145c+++-1NMR (nMso-C6, δ)
: 1.04 (6H, d, J=6.0Hz).

1.12(,80(6H,m), 2.50(2t2
m) + 7.84 (IH, d, J-8', 0Hz),
8.00 (2H, s), 8.22 (LH, d,
Jτ8.0Hz), 9.50(LH,s).

3 Elemental analysis: (C1C14t(I/N40, S'
10 N20 calculation value: C40.59, N5.26. N
13.52゜N205.65 Flood 1st white: (“ 41.08. N5
．． 00. N13.68゜8206, 10 Fruit stone example 79 i -(#=methylaminomethyl)-2-methyltetrahydrofuran (l, 3gI>, charcoal e potassium (2,87
) and dry acetone (70 mP),
Cooled to °C, under stirring, a solution of 3-chloro-2-nitro-4-sulfamoyl large schizoyl chloride (2,5y) in dry acetone (30+++) was added dropwise over 0 min.
Stir for 100 minutes at room temperature.

Insoluble inorganic materials were removed and the p solution was concentrated under reduced pressure at 10 mei. The residue was subjected to silica gel column chromatography and eluted with methanol and chloroform (1:10). The solution containing the target product was combined and the solvent was distilled off under reduced pressure to obtain a pale yellow oil (2,6y), which was diluted with n-hexane (6y).
Add the powder and IJ-seize at 0+++e) to obtain a colorless powder. This powder was mixed with ethyl acetate and n-hexane (
Recrystallized from a mixed solvent of 1:2) to form colorless fine needle-shaped crystals.
-Chloro-2-nitro-4-sulfamoyl-N-methyl-N-benzamide (1,l') is obtained. mp174
~768C IR (Nujol): 3360. 3170. 30
30. 1650°1535, 1350. 1340
．． 1180. 1160cm'NMR (DMSO-d
6. δ): 1.15 (3H, s), 1.50-
2.10 (4H, m), 3.00 (3H, s), 3.2
6 (2H, s).

3.40-3.89 (2H, m), 7.79 (IH, d
,'J=8.0Hz).

8.00 (2H,s, D20 disappearance), 8.20 (
IH, d, J = 8.01 (z:: elemental analysis = (C1,
H18CeN, 06S) Calculated value: C42,92+H
4,63,N10.72 Actual value: C42,92,H4,
64,Nl0856 Example 80 A mixed solution of 50% dimethylamine aqueous solution (20+++e) and acetone (20mf) was cooled to 18-19°C and stirred. , 5y) in dry acetone (
20u+r) Add the solution dropwise and add another 1.5n in the same width.
: Stir for 1 hour.

The mixture was concentrated under reduced pressure at 30 mei, then adjusted to pH 2.0 with concentrated hydrochloric acid, and extracted with ethyl acetate.
＼7 After sequentially washing with the solution and saturated saline, dry and manipulate with anhydrous magnesium sulfate. , - The yellow residue obtained by distilling off the solvent under reduced pressure was made into a pale yellow powder with n-hexane (40+++e) and recrystallized from a mixed solvent of methanol and water (2:1) to give pale yellow needle crystals of 3- Chloro-2-nitro-4
-Sulfamoyl-N,N-dimethyl 1 benzamide (1,6y) is obtained. mp18'3~185°C IR (Nujol): 3300. 3150. 1
635. 1535°1350, 1340. 118
0. , 1160cm' NMR (DMSOd6.Iy
) + 2.90 (3H, s ), 2.98 (3H.

s), 7.80 (IH, d, J=8.0Hz),
8.00 (2H.

9.24 s, D20 disappeared) + anniversary (I H, d, J = 8
．． 0 Hz) Elemental analysis: (C9H, oCI!N30
．． , S) Calculated value: C35.13, N3.28. N13
．． 66 actual value: C35.02, N3.31. N13.8
7 Ethylamine (1, oy) in dry acetone (30 ml)
'') The solution was cooled to O'C. While stirring, a dry acetone (30 me) solution of 3-chloro-2-nitro-4-sulfamoylbenzoyl chloride (IJ) was added dropwise, and the mixture was further heated at the same temperature for 2 hours. Stir for an hour.

The precipitated triethylamine hydrochloride was removed, and the solvent of the P solution was distilled off under reduced pressure. The resulting brown oil (6°3y) was subjected to silica gel column chromatography (50y).
Elute with a mixed solvent of methanol and chloroform (1:4). The fractions containing the target product were combined and the solvent was distilled off under reduced pressure to give a yellow residue (2,8y), which was diluted with ether (5
A pale yellow powder (2,2y) was obtained using a mixed solvent of 0me) and n-hexane (50me), and then subjected to basic alumina column chromatography and eluted with a mixed solvent of methanol and chloroform (1:4). The solvent is distilled off under reduced pressure from the fraction containing the target product to obtain a pale yellow powder.

This powder (1,0y) was dissolved in methanol (30me), insoluble materials were removed, the furnace solution was made acidic with 5.7N hydrogen chloride methanol solution, diethyl ether (room(')) was added, and the mixture was allowed to stand. Take the delivery and destroy it:, Part 5
After drying at 0°C for 3 hours, N-(3-
chloro-2-nitro-4-sulfamoylbenzoyl)
-N'-(2-hydroxyethyl)/-piperazine hydrochloride (1,05i') is obtained. mp 250-255℃
(Decomposition) IR (Nujol): 3350. 328
0. 2-680. 2580°2480, 1650
．． 1540. 1360. 1340°1160σ-
1 NMR (DMSO-d6.δ): 3.00-4.17
(12H,”)+4.50(IH,brd,s),
7.97 (IH, d, J=8, OHz).

8.10 (2H, s), 8.33 (IH, d, J
=・8.0Hz).

11.50 (IH,brd,s) Elemental analysis: (c,,H,,cz2N,o6s) Calculated value: C36,37,H4,23,N 13.05 Actual value: C36,26,H4,26, N13.22 Example 8
2 Dissolve 1-benzhydrylpiperazine (1,7P) and triethylamine (0,7mf') in dry tetrahydrofuran (30me), cool to 0°C and stir to form 3-chloro-2-nitro-4-sulfamoylbenzoyl chloride. (
2,0y) in dry tetrahydrofuran solution (15m('
) was added dropwise and further stirred at the same temperature for 1 hour.

Removes precipitated triethylamine hydrochloride and reduces tear fluid)
4: Dissolve the pale yellow oil obtained by concentration in ethyl acetate (150me), and dissolve with this enethicum acetate)
explode.

The pale yellow oil obtained by distilling off the solvent under reduced pressure was mixed with acetone (
30me) After dissolving K and removing insoluble matter, add a 7N hydrogen chloride ethanol solution (1,5+++1') to the p solution.

The precipitated crystals were collected and mixed with ethanol (100 ml
) to give colorless fine needle-like crystals of N-(:3-chloro-2-nitro-4-sulfamoylbenzoyl).
N/-benzhydrylpiperazine hydrochloride (3,0y)
get. mp 213-217 (I R: 3350. 2500.
2400. 1640°1540, 1355. os
o, i55cm-1) IMR (DMSO-d6
, J'): 2.83-4.17 (8H,
m), 5.50 (IH, s), 7.17-8
．． 33(14)i,m) Elemental analysis: (c24H,ce
N40. S -Hce -mH20) Calculated value: C51,
76+ H4,45,N10.06°H,,00,9
7 Actual measurement value: C51, 61, H4, 3'8. 'N
9.99゜H2O0,92 Example 83 4-(4-chlorophenyl)-4-hydroxypiperidine (1,1y) and triethylamine (0゜5+++t
') was dissolved in dry tetrahydrofuran (30rne), cooled to 01°C, and stirred. The reaction mixture is stirred for a further 6 hours at room temperature.

The precipitated triethylamine hydrochloride was removed, and the solution was concentrated under reduced pressure. The pale yellow oil obtained was dissolved in ethyl acetate (100 me'), and this solution was dissolved in saturated brine,
Wash sequentially with 7-hydrochloric acid, saturated brine, 5% aqueous sodium bicarbonate solution, and saturated brine, and dry with anhydrous sulfur and magnesium acid.

The light brown solid obtained by distilling off the solvent under reduced pressure was mixed with diethyl ether (80+++e) and n-x xane (80m/,)
A pale yellow powder (2,0y) is obtained with a mixed solvent of 5() and recrystallized from extrahydrous methanol (100me). Furthermore, this crystal (1,5y) was mixed with ethyl acetate (20 mC), diethyl ether (50 mC), and n-hexane (50 mC
) was recrystallized from a mixed solvent of L(
4-sulfamoyl-3-chloro-2-nitrobensoyl)-4-(4-chlorophenyl)-4-hydroxyhyhelycine (1°2y) is obtained. mp 184-190
°CIR (Nujol): 3420. 3380.
3250. 3050°1630, 1610. 1
540. 1370. 1175σ-1HMR (DMS
O-d6. δ): 1.67-2.00 (4H, m)
, 3.17-3, '67 (4H, m), 5.36 (
IH,s), 7.50 (4H).

7.86 (IH, d, J = 8.0Hz), 8.0
0(2H,s).

8.23 (IH, d, J=8.0 Hz) Elemental analysis = (C18H2, Ce2N, 06S--!-H20 calculated value, C44,73, N3.75.N8.94H201,
86 Actual value: (N44.99.l(3,53,N8.6
9°H2O2,18 Example 84 3-chloro-2-nitro-4-
Sulfamoylbenzoylchlor IJ)' (1°59
> to obtain 3-chloro-N-methyl-2-nitro-4-sulfamoylbenzamide (0,8y). mp27
0-273°C (recrystallized from 50% aqueous methanol) IR (Nujol:): 3400. 3280. 1
655. 1535° f365. 1355. 117
5. 1150crn-1HMR (DMSO-46, δ
): 2.79 (3H, d, J-4,0Hz).

7.91 (IH, d, J=8.0Hz), 8°0
0(2H,s).

8.23 (LH, d, J-8,0Hz), 9.0 (
LH) Elemental analysis: (C3H80IN305S) Calculated value: C32,72, N2.75. N14.31 actual value: C32.60, N2.95. N14.38 Example 85 3-chloro, rho-2-nitro-4-sulfamoylbenzoic acid (1,5y), 5-chloro-2-phenoquinaniline (1,2') and phosphorus trichloride (6, A suspension of 36y) in dry chlorobenzene (50 mt) is stirred under reflux for 2 hours.

After removing the brown residue as a by-product by decanting, add n to the reaction solution.
- Add hexane (100me) and leave to cool. The precipitated pale yellow solid was collected and air-dried.

This crystal was mixed with benzene (50me') and n-hexane (
Recrystallization from a mixed solvent of 3-chloro-2-nitro-4-sulfamoyl-N-(
5-chloro-2-phenoxyphenyl)benzamide (
1,8y) is obtained. mp109~115°C (softening) 1
50-160°C (decomposition) IR (nujol): 340
0. 3250. 1685. 1600°1540,
1355. 1160cbNMR (DMSO-d6.
δ): 6.83-7.53 (7H, m), 7.7
4 (IH, d, J=8.0Hz), 7.83 (I
H, d, J=2.0Hz).

8, UO (2H, s), 8.18 (IH, d, J
=8.0Hz).

10.69 (IH, s) Elemental analysis' (C++*H+, (V2N, m06S )+
tlyannr+:C47,32,N2.72. N8.
71 actual measurement: C47,74, N2.65. N8.
41 Example 86 3-chloro-2-nitro-4-
Sulfamoylbenzoic acid (2,8?) Cara, 4-sulfamoyl-3-10 rho 2-nitro N-(2,6
-dimethylphenyl)benzamide (1,3y) is obtained. mp 313-315°C (recrystallized from aqueous Meknol) IR (Nujol): 3350.3250. 165
5.1540゜＼ 1355, 1335. 1155c+++-1HMR
(DMSO-d6.δ): 2.20(6H,8)+
7.13 (3H.

s), 8.08 (2H, s), 8.13 (IH,
d, J=8.0Hz).

8.35 (IH, d, J=8°0Hz), 10.
4(1(LH,8) element/element analysis: (C+5HuCI
L+OsS) Calculated value: C46.94, N3.68.
N10.95 actual value: C46,69,I(3,78
, N 10.79 Example 87 A mixture of 3-10 rho-2-nitro-4-sulfamoylbenzoic acid (5,0y), concentrated silicic acid (1,0ml') and n-propanol (80me) was heated under reflux. After stirring for 16 hours, the mixture was allowed to cool to room temperature.

Water (100 +++ l') is added to the resulting reaction mixture, and the precipitated crystals are filtered off. The crystals are washed with water (50 mt') to obtain colorless needle-like crystals of propyl 3-chloro-2-nitro-4-sulfamoylbenzoate (5,3y). m
p190-192°C IR (nujol)': 3370. 3260.
1725. 1545°1365, 1355. 11
70cm'NMR (DMSO-d6.δ): 1.00
(3H, t, J=8.0Hz).

1.33-2.00 (2H, m), 4.30 (2H
, t, J=8.0Hz).

8.10 (2'H, s), 8.20 (2H, s) Elemental analysis: (CIQHIICI N206s) 37.
22. 3.44 8. Ggal ticket value: C##tsu,
Hfl ke, N=mi 37.13 3.38 8.
8G Actual measurements: C ki - 喀, H ki ≠ also N ≠ Hata Example 88 3-10 rho 2-nitro 4-sulfamoylbenzoyl chloride (1,5y) was mixed with dry ethanol (35 me
), stirred at room temperature for 1 hour, and then heated to dissolve the precipitated crystals. 1 Reaction z Insoluble materials were removed from Y&, and the lacrimal fluid was washed with water (50 ml of water and allowed to cool. The precipitated crystals were washed with water to form colorless needle-like crystals of 3-chloro-2- Ethyl nitros-4-s!lefuamoylbenzoate (1,4y) is obtained.

mp215-216°C IR (Nujol): 3380. 3270. 17
ao, 1540°1370, 1350. 117
0. 1160cm'NMR (DMSO-d6.δ)
: 1.33 (3H, t, J, = 7.0Hz).

4.40 (2H, q+ J=7.0Hz) + 8.1
3 (2H, s).

8.30 (2H,s) Elemental analysis: (C1H9Cf N206S) Calculated value:
C35,02, H2,94, H9,08 Actual value: C3
4,84,H3,1O,H9,08Example 89
e) Heat the solution to reflux with stirring for 2 hours.

The reaction solution was concentrated to 20 me, and acetic acid ethyl ester (8
Add 0m('). This acetic acid ethyl ester solution
% sodium bicarbonate aqueous solution and saturated saline, and rinsed with anhydrous magnesium sulfate. .

The solvent was removed under mixed pressure to obtain a colorless powder (1,5y).

This crude product was recrystallized from a mixed solvent of ethyl acetate and n-hexane (3N) to obtain methyl 3-chloro-2-nitro-4-sulfamoylbenzoate (1, 0y).mp195 ~ 200℃ Ding R (Sujoor): 3390. 3280. 1
725. 1,540°1350, 1180. 11
60cm-1HMR (DMSOd6'+a):
'3.87 (3H,s), 8.08 (2H.

s), 8.27 (2H, s) Elemental analysis = (C8H7CeN206S) Calculation appetizer 1i:c
32.61. H2,39,H9,51￥IIJI
I (!N: C32,68, H2,57, H9,51 Example 90 Same village as Example 89, 3-chloro-2-nitro-4
-sulfamoylbenzoylchloroIJF (2,0y) to hexyl 3-chloro-2-nitro-4-sulfamoylbenzoate (1,5!') wof4yl.

11 hits 13;) ~ 134'C (water/ratio methanol-1
Shikara 4 Poems) IR (Nujol): 338,0.
3250. 1730. 155 (1°1360,
1155㎪-1 NMR (DMSO-d6.δ): 0.83 (3H,
t, J=6.0Hz)+1.00-1.83(8H,m
), 4.26 (2H, t, J=6.0I+z).

8.05 (2H), 8.23 (2H) Elemental analysis: (C13H,, CI N206S) Calculation ID: C42, 80, H4, 70, H7, 68 characters,
Measured value: C42, 5'2. H4,90,H7,69 Example 91 In the same manner as in Example 89, 3-chloro-2-nitro 4
-Recrystallized from sulfamoylbenzoyl chloride (1,4y) from a mixed solvent of 3-chloro-2-nitro-4-sulbenzene and n-hexane) IR (Nujol):
3350. 3420. 3090. 1725°15
50, 1360cn+' NMR (DMSO-d6.δ): 0.89 (6H, t
, J=7.0Hz).

1.67-2.69 (8H, m), 3.50 (4H
,t, J=6. OH7,).

3.61 (4H, d, J=6.0Hz), 5.3
3 (12H, s).

5.30 (111,q, J=5.0 Hz), 8
．． 07 (LH, d, J=9..0)1. z).

8.25 (], H, d, J = 9.0'Hz)
Elemental analysis, (C, JI2. C1N2O, S. H20
) Calculated value: C45.85, N5.88. N5.94゜u
2o O, 96 actual value, C45, 40, N5.62. N6.26)+2
0 0.92 Example 92: 3-chloro 2-nitro 4-sulfamoylbenzoyl chloride (1,8y) and 2,2-dimethyl-1,
3-dioxolan-4-ylmethanol (6,4me)
The mixture was stirred at 150°C for 1 hour.

Ethyl acetate (80me) was added to the reaction mixture, washed with saturated brine (20ml) and a 5% aqueous sodium bicarbonate solution, and then dried over anhydrous magnesium sulfate.

The brown oil (6,4y) obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography, and then treated with a mixture of dichloromethane and acetone (9:1), and then
Elute with a mixed solvent of dichloromethane and acetone (1:1). The fractions containing the target product were combined and the solvent was distilled off under reduced pressure to obtain a colorless oil, 3-chloro-2-nitro-4-sulfamoylbenzoic acid/2,2-dimethyl-1,3-dioquinran-4-yl- Methyl (2,3p) is obtained. Cono compound in 7N hydrogen chloride ethanol solution (25me)
and stir at room temperature for 30 minutes.

The reaction solution was concentrated under reduced pressure to obtain a brown residue (1,2 r), which was mixed with inglovil alcohol and diethyl ether (2:8).
) Recrystallized from a mixed solvent of 3-1t: +
rho 2-nitro 4-sulfamoylbenzoic acid/2.
3-dihydroxy-1-butavir (0,7y) is obtained.

mp189-194℃ IR (Nujol): 350
0. 3300. 3180. 1720°1650,
1360. 1160cm'NMR (DMSO-d
6. δ): 3.33-3.50 (2H, m), 3
．． 54-3.91 (IH, m), 4.17-4.3
3 (2H, nn), 4.63 (IH9t, J-6-
OHz), 4.96 (I H1d+ J-6, O
Hz) 18.07 (2H, s), 8.25 (2H
, s) H elemental analysis: (CH, Hl, CI N2Os) calculation (
+n: C33,86,N3.13. N7.90
m people [61 lii 1 white, C33,75, N3.17.
N7.76 Example 93 Dry ethanol (0
, 5me) and dry carbon tetrachloride (0.05me) and stirred at 50°C for 10 minutes. After adding dry diethyl ether (15+r+e) to this mixture at room temperature,
Diethyl malonate (2,9y), @: dry ethanol (2
, Ome) and dry diethyl ether (2°5+++7
') was added dropwise while controlling the reaction solution to vigorously reflux, and at 8.5 o'clock, the mixture was further stirred under reflux.

While refluxing this solution, 3-chloro-2-nitro-4
-Sulfamoylbenzoyl chloride (5,69')
, a solution of 30
Add the mixture dropwise and stir at high speed for another 2.5 hours.
After cooling at room temperature, ethyl acetate (1
00+++C) and lO% sulfuric acid water solubility meter (100ml')
Add, shake, and separate the organic layer. These 11 layers were concentrated under M pressure, and the resulting residue (ltoy) was mixed with wood acetic acid (
6,0mr), water C5,0mr) and concentrated sulfuric acid (1,0mr)
mfl') and stirred for 2 hours under heating and reflux.

After cooling the reaction mixture, acetic acid ethyl ester (200 me
) The resulting solution is extracted with saturated saline and saturated hydrogen carbonate.) The IJ cum aqueous solution is further washed with saturated saline and dried over anhydrous magnesium sulfate. The pale yellow solid (6,0y) obtained by distilling off the solvent under reduced pressure was mixed with methanol and water (1:2
), 3'-chloro-2'-nitro-4'-sulfamoylacetophenone (4,4F) is obtained as colorless needle-like crystals. mp201-202℃ Engineering R (Nujol): 3400. 3370. 32
80. 3100°1700, 1540. 1360
．． 1160 cm-'NMR (DMSOd6, δ):
2.73 (3H, s), 8.13 (2H.

8), 8.36 (2H, El) Elemental analysis: (C8H, C/N20., S) Calculated value: C34,48, N2.53. N10.05 actual value: C34,74, N2.66, N10.18 Example 94 3-amino-2-chloro-4-phenoxybenzenesulfonamide (4,0Oy) was dissolved in n-methanol (40mf
f), add concentrated sulfuric acid (0.4me), and heat under reflux for 22 hours. After cooling, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (developing solvent = ethyl acetate:
Toluene = 1:9) to produce two types of products A (
1°50y) and B(2,65y) are obtained.

Product A was recrystallized from a mixed solvent of acetic acid ethyl ester and n-hexane to form white powdery crystals of 3-(n-butylamino)-2-chloro-4-phenoxybenzenesulfonamide (0,75y )fNru. mp82-84℃
On the other hand, product B was recrystallized from petroleum ether to give a white powder of 2-[70-3-(N,N-dibutylamino)-4-phenoxybenzenesulfonamide (2,
15y) was obtained, AOmp 50-52°C Umbrella 3-(n-butylaminophenoxybenzenesulfonamide IR (Nujol): 3395. 3280.
1335, 1155! -1HMR (CDC71
! 3, δ): 0.73-1.67 (7H, m),
3.39 (2H, t, J-6Hz), 4.27 (I
H, bs), 5.20 (2H, s), 6.74
(IH, d, J=9Hz), 6.88 -7, 27
(5H, m), 7.48 (IH, cutting Hz) Elemental analysis: (C,6H,9CI N20,S) Calculated value:
C54.15, H5.40, ~7, 89 actual value: C
54.12, H5'. 30, ~7.84 umbrella 2-
Chloro-3-(N,N-dibutylamino)-4-phenoxybenzenesulfonamide ■R (Nujol): 33
95, 32501 1330, l170cm'
NMR (CDCI!3, δ): 0.72-1.6
7 (4H, m), 3.15 (4Hl t, J=
8Hz), 5.20(2I(1s, SO2NH
2) +6, 70 (IH, d, J=9Hz), 6
．． 91-7.53 (5H, m).

7, 78 (IH, d, J29Hz).

Elemental analysis = (C2oH27cI!N2o3s) Calculated value:
C58.45, H6.62, ~6.82 Actual value: C
58.27, H6.61, ~6.95 Actual, Example 95 Ammonium thiocyanate (1.53y) was dissolved in acetone (
Dissolve the solution at 70 + K, add benzoyl chloride (1.63 me) while heating under reflux, and stir under reflux for an additional 15 minutes. Add 3-amino-2-chloro-4-phenoxybenzenesulfonamide (4.00y) to this solution in acetone (
30 mf of the solution was added dropwise at the same temperature, and the mixture was further stirred under reflux for 3 hours. After cooling, acetone is distilled off under reduced pressure. Water is added to the resulting residue, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give white powdery crystals of N-benzoyl-N'-[(2-chloro-6-phenokyle-3-sulfamoyl)phenyl]thioclea (2,
ooy). mp 1 24 ~ 1 266CI
R (nujol) = 3425, 3320, 325o,
313o.

1655, 1345, 1170. 1155
G-1HMR (1) Mso-C6, 2 units 6.83-8
．． 10 (14H, m).

11,90(IH,s), 12.13(,IT(,
s) Element X Analysis: '(C2oH 16C/'N
304 & 0.19 x C2H50 C2H5) Calculated value. C52.38, H3.79, ~8.83
Actual value: C52.42. H3.96, ~8.58 Example 96 N-benzoyl-N'-[(2-chloro-6-phenoxy-3-sulfamoyl)phenyl]thioclea (4.
45y) and sodium hydroxide (0, 39y
) in methanol (50'mf?) for 10 minutes.
Stir and reflux. Water and concentrated hydrochloric acid (approximately 2 mt') were added to the residue obtained by distilling methanol off from the reaction solution under reduced pressure, followed by extraction with ethyl acetate and dilution with sodium bicarbonate.
After washing with cum aqueous solution and saline, drying with magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was washed with diethyl ether, then with ethyl acetate,
N-(2-chloro-6-7 enoxy 3-
sulfamoylphenyl)thiofrea (2.25p) is obtained.

This I crystal (1.oo y) was recrystallized from a mixed solvent of methanol and water to give slightly brown needle-like crystals (0.8'O
y) is obtained. mp 197-200°C Ding R (Sujoor): 3410. 3375. 3
275. 3150°1615. 1335. 116
0. 1140cm'NMR (DMSO-d6.δ)
: 6.83 (IH, d, J=9Hz).

7.10-7.67 (m), 7.23 (s),
7.53(s).

7.93 (LH, d, J = 9Hz), 9.20 (I
H, bs, NH) Elemental analysis: (Cl5H12CI!
N30382) Calculated value: C43,63,H3,38
, N 11.74 Actual value: C43,69, N3.41.
N11.62 Example 97 Methyl iocide (0,26mf') and N-(2-chloro-6-fe/xy-3-sulfamoylphenyl)thiourea (1,25y) were added to methanol (30me), Stir and reflux for 1 hour. Methanol is distilled off from the reaction solution under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution is added to the residue, followed by extraction with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from a mixed solvent of ethanol/chloroform to obtain white (1. powdery N-(2-chloro) -6-phenokidi-3-sulfamoylphenyl)-8-methylisothiophrea (0°90y) is obtained.mp19-5~
198°C IR (Nujol): 3425. 3400. 3
340. 3260°1625, 1315. 1.1
60cm-1NMR (DMSO-d6.δ): 2.2
2(3H,s)+6.67(2H.

s), 6.88 (IH, d, J=9Hz), 7
．． 05-7.42 (5N1m), 7.38 (2H1s)
, 7.59 (LHld.

J=9Hz) Elemental analysis: (C,4H,4CIN303S2) Calculated value: C45,22, H3,79, Nl 1.30 Actual value: C45,41+ N3.78. N11.33 Example 98 tert-butyl nitrite (1,97mf) and cupric chloride anhydrous salt (1,77y) were dissolved in ayatonitrile (50me)
3-Amino-2-chloro-4-
Phenoxybenzenesulfonamide (3,30ff)
A solution of ayatonitrile (20+++e) is added dropwise. After stirring for an additional 20 minutes at the same temperature, the mixture is further stirred at room temperature for 1 hour. After removing ayatonitrile from the reaction solution under reduced pressure, dilute hydrochloric acid was added to the residue to make acid f1, and the mixture was extracted with ethyl acetate. The extract was added to a saturated aqueous solution of sodium bicarbonate,
and brine, and dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (developing solvent: ethyl acetate:benzene - 1:9), and the crude powder obtained from the fraction containing the target product was purified by methanol. - 2,3-dichloro-4-phenoxybenzenesulfonamide (0,7
5y) is obtained. mp168-171°C IR (Nujol) + 3425. 3330. 1
335. 1165cm-1N M R (D M S
O-d 6 + δ): 7.02 (IH, d, J=9H
z).

7.03-7.60 (5H, m), 7.68 (2H
,s).

7.94 (IH, d, J = 9Hz) Elemental analysis: (
C421 (, Cf2N OlS・0.18 N20)
Total 1>(l white: C44,85, N2.91.
N4.36゜C/22.07 Mi 1 Misaki II (1 White: (Si 45.10. N
2.69. N4.30°C7' 21.69 Example 99 Add 4-amino-2-chloro-3-nitrobenzenesulfonamide (2,'ooy) to acetic acid (30me) and add 10
Heat and melt at 0°C. Add mechunsulfonyl chloride (0,77me'?'f) to this solution.
ff1-acid sodium (0,
2057). Furthermore, every 10 minutes thereafter, the acetic acid solution was
IJum was added three times in 0.15 y portions, and the reaction mixture was further stirred under reflux for about 34 hours, during which time 24 hours and
After 31 hours, notanesulfonyl chloride (0,3
5me) and blood, acid sodium (0,3!7), respectively. After cooling the reaction solution, reduce the solvent to LI0S.
Saturated sodium bicarbonate and an aqueous solution are added to the residue obtained by removing the mixture with attenuator, and the mixture is extracted with ethyl acetate.

After washing the organic layer with water, it is dried with magnesium sulfate.

The residue obtained by distilling off the solvent under reduced pressure was recrystallized from methanol to obtain 4-anadamide-2-chloro-3-nitrobenzenesulfonamide (0,8F) in the form of pale brown flakes.
get. mp 249-251℃ Engineering R (Nujol)
: 3360. 3320. 3150. 3080°1690.1575. 1535. 1345. ．． 11
75°1155c+++-1 NMR (, DMSO-d6.δ): 2.07 (3H
,s), 7.80 (2H.

s, SO2NH2), 7.85 (IH, d, J=9
Hz), 8.14 (LH, d, J=9Hz),
10.28 (IH, bs, -CONH-) elemental analysis:
(C3H8CIN,,05S) Calculated value: C32,
72, N2.75. N14.31 actual value: C32,
28, N2.58. N14.49 Example 100 4-Mef-2-10-3-nitrobenzene sulfonamide (92y) and sodium hydroxide (14,7y
) in water (600me) and heated at 60°C with stirring.
Potassium permanganate (116y) in water (500me
) The suspension was added over a period of 3 hours, heated with nitrogen, and stirred for 5 minutes.

Separate the manganese dioxide by-produced from the reaction solution and wash the manganese dioxide with hot water. Collect the sediment offshore and recover the unformed raw materials.
9.67) On the other hand, the solution was adjusted to pH 2.0 with 35% hydrochloric acid and precipitated.
pIIX the crystals. This crystal was heated to 40°C.
71j is dried to obtain colorless needle-like crystals of 3-chloro-2-ditro-4-sulfamoylbenzoic acid (56,4y). mp 260-262°C IR (Nujol): 3600. 3440. 3
350. 3270°3105, 3095. 245
0. 1715. 1550°1360, 1335.
1175σ-1HMR (DMSO-C6, δ): 8
．． 05 (2H, s), 8.23 (2H, s) Elemental analysis: (C7H5CI!D■206S@H20) Calculated value:
C28, 15, N2.36. N9.38H206,03 Actual value: C28,44, ~H2,18, N9.44H2
05,86 Example 101 4-Sulfamoyl-3-10 rho-2-nitrobenzoic acid (2,(1y) and sodium borohydride (0,
A solution of 54y) suspended in dry tetrahydrofuran (30m3) was cooled to 0°C and stirred for 2 minutes to add 2 to 7 g of boron trifluoride diethyl ether, and the mixture was further stirred at room temperature. Stir for 1 hour.

Water (50me) is added to the reaction mixture to decompose excess diborane, and ethyl acetate is added for extraction.

Boil the extract. After washing with Japanese saline solution, dry and handle with anhydrous W#1 magnesium oxide.

The colorless oil obtained by distilling off the solvent under reduced pressure (2,27) was recrystallized from 50% aqueous methanol (80 m o m to obtain trobenzenesulfonamide (1,4y)
p 180-183°CIR (Nujol): 3
420, 3330, 3200, 3050.

1535, 1335, 1180. 1160
cm'NMR (DMSO-d6, δ)・4.62(2
H, d. , T=4.0Hz).

6, 80 (IH, t, J = 4.0Hz), 7
．． 84 (LH, d.

, T-8.0Hz), 7.94(2H,s),
8.26 (IH.

d, J=8.0Hz) rcX analysis: (C7H7Ce N'205S) Calculated value: C31.5:3, N2.65. N10
．． 51 fruit ill A 1st: C; bite 1.68.
N2.60, N10.52 Example 102 Strained in the same manner as Example 101 to give 3-chloro-4-(N,
N-(dimethinoriaminomethyleneamitsusulfonyl)-
From 2-nitrobenzoic acid (9.0y) to 3-di
-(N,N-(digmethinoriaminomethyleneaminosulfonyl)-2-nitrobenzyl alcohol (5.0,
1;') is obtained. mp194-198℃ (colorless needle crystals,
Redelivered from methanol) IR (Nujol): 3450, 1630,
1530, 1340.

1175, 1145>-1 NMR (DMSO-d6, δ): 2.89 (3H,
s), 3.13 (3H.

s), 4.50 (2H, d, J-5.0Hz),
5.69 (IH.

t, J=5.0Hz), 7.68(IH, d,
J=8.0Hz).

8, 13 (IH, d, J=8.0Hz), 8,
20 (IH, ε) elemental analysis: (C,.H,2CIN30
, S・-Shun-N20) Calculated value: C36.72. N3.8
8, N12.84.

N20 1.65 Actual value: C36.95, N3.71. , N1
2.90.

N20 1.55 Example 103 2-chloro-4-hydroxymethyl-3-nitrobenzenesulfonamide (1,3y) oamhyridine (5
pivaloyl chloride (0,7m
r) was added under water cooling, and the mixture was stirred for 1 hour at 0°C.

The reaction mixture was poured into water (50 rnf') and extracted with ethyl acetate. The extract is washed with 3.5% hydrochloric acid, saturated saline, 5% hydrogen carbonate, IJum aqueous solution, and saturated saline, and then dried over anhydrous magnesium sulfate.

Pale yellow oil (2°4y) obtained by distilling off the solvent under reduced pressure
was subjected to silica gel column chromatography and eluted with ethyl acetate-n-hexane (2:8). Combine the fractions containing the target product and reduce the solvent to 1-L: H1
Upon removal, a colorless powder (1,4y) is obtained. This powder is subjected to basic alumina column chromatography and eluted with chloroform acetone (1:l). Pour the fraction containing the target product and remove the solvent under reduced pressure to obtain a colorless oil (1
,0'l is obtained. This oil was mixed with n-hexane (50mf
pivaloyloxymethyl)-3-nitrobesinsulfonamide (o6y) is obtained. mp191~
195°C IR (Nujol): 3400. 3290. 1
735. 1535°1340, 1160cm -1 HMR (DMSO-H6, δ): 1.10 (9H, s
), 5.15 (2H.

s), 7.79 (LH, d, J=8.0Hz),
7.91 (2H, s) + 8.18 (LH, d, J
=8.0 Hz) Elemental analysis: (C,2H,5Cff
N206S) Calculated value: C41,09,H4,31,H
7,99 actual measurements: C40, 39, H4, 13, H7,
9i Example 104 3-chloro-2-nitro-4-sulfamoylbenzoic acid (30,0y), thionichloride/shiki30me), anhydrous N
, N-dimethylamide (5 drops) and anhydrous benzene (27
0rne) is stirred and refluxed for 1 hour.

Add n-hexane (120mf) to the late reaction solution and cool with water.
Wash with m(ri).

The extracted powder was diluted with dry acetic acid ethyl ester (500 m
e), remove insoluble materials, and reduce the solvent of the p solution.
+: F was distilled off, and the residue was filtered with n-hexane (500mt'
) to give a colorless powder of 3-chloro-2-nitro-4-sulfamoylbenzoylchlor IJ )' (
28, :3 y) is obtained. mp 173-178°C
(Disassembly) IR (Sujoor): 3360. 325
0. 1750. 1540°1360, 133(1
, 1155c+++-1HMR (DMSO-H6, δ)
: 8.10-8.50 (21(, m).

10.0 (2H,brd,s) Elemental analysis: (C7H4Cff2N205S)6L
W ft white: C28, 11+ Hl, 35.
H9, 37 fruit flood 1 eye 1 white: C28, 78, Hl
, 43. H9,85 fruit! J11 Example 105: ('-chloro2'-nitro47-sulfamoylacetophenone (5,0,1) was dissolved in dry acetic acid ethyl ester (60me), heated to 60°C with stirring, and bromine (
Dry acetic acid ethyl ester (5,0 mr) of 315y)
Add 3 drops of solution. After confirming that the reaction solution is decolorized, it is cooled at room temperature, and the remaining bromine solution is stirred at room temperature.
The solution is added dropwise over a period of 20 minutes at such a rate that the color of bromine disappears steadily. The reaction mixture is stirred for a further 40 minutes at room temperature.

The resulting pale yellow solution was concentrated and dried under reduced pressure to obtain a yellow powder (6,6y), which was redelivered from a mixed solvent of acetic acid ethyl ester and n-hexane (1:l) to give a colorless needle-like product. 2
-Bromo-3'-chloro-2'-nitro-4'-sulfamoylacetophenone (5,32) is obtained. mp
202-207℃ (decomposition) IR (nujol): 3
400. 3280. 1720. 1545°136
5, 1180. 1160σ-1HMR (DMSO-
H6, δ): 5.00 (2H, e), 8.1
3 (2H.

8), 8.36 (2H, s) r Elemental analysis - (CI N20., S to C 苧H6) Calculated value, C26, 87, Hl, 69. H7,83 actual measurement value:
C26,82+ H2,02, H7,63 Example 10
6 In the same manner as in Example 79, 3-chloro-2-nide t:1
-4-sulfamoylbenzenesulfonyl chloride (1
.
0,6y) is obtained. mp145-147°C (14 crystals from diethyl ether and n-hexane mixed solvent) IR (Nujol): 3340. 3180. 3
070. 1550°3.50-3.83 (2H, m)
+ 8.12 (2H, s), 8.17 (IH, d
, J-8,0Hz), s, stone (LH, d, J=8.
0L(z) elemental analysis: (CoH+5CeN307S
2) at i value: C36,49,1(4,24,H9
,82 actual value-C36,25,l(4,(19,H9,
81 fruit 41t (Example 107 2-chloro-3-nitro-4-benzylthiobenzenesulfonamide (7,7y), wood vinegar e (150me)
A suspension of water (-50 me) and water (-50 me) was stirred at room temperature and passed through F1 chlorine slag for 30 minutes.

The acetic acid is distilled off from the resulting pale yellow solution, and the precipitated crystals are collected and then washed with n-hexane.

The obtained crude crystals (7,8y) were mixed with diethyl ether and n
Recrystallization from a mixed solvent of -hexane (1:2) gives colorless plate-like crystals of 3-chloro-2-ditro-4-sulfamoylbenzene sulfonyl chloride (5,2').

mp198-201℃ IR (Nujol): 3460
．． 3270. 1540. 1350°1170,
1150crn-1 HMR (DMSO-d6. δ): 7.97 (IH
, d, J=8.0Hz).

8.20 (IH, d, J ~8.0Hz), 10.
50(2H,s) elemental analysis: (C6H4C/!2N20
6S2) Calculated value: C21.50, Hl, 20. H
8,36 actual measurement value: C21,68,I (1,31,H8
, 45 Example 108 3-10 rho 2-nitro-4-sulfamoylbenzamide (3,51) and boron trifluoride diethyl ether complex (4,7p) were dissolved in dry tetrahydrofuran (100me
) and dissolved in sodium borohydride (0,95
Add y). The mixture was incubated at 40°C for 18 hours at 65°C.
After stirring at C for 2 hours and allowing the mixture to cool at room temperature,
After adding sodium borohydride (0,95y) and boron pentafluoride diethyl ether complex (4,7y), the mixture was stirred at 65°C for 4 hours.

The reaction mixture was poured into methanol (50 ml') and the solvent was distilled off under reduced pressure to obtain a pale brown oil (6,05i').

This oil was dissolved in 3,5-dihydrochloric acid (206me) and washed with ethyl acetate. The aqueous layer was adjusted to pH 8.0 with sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated brine (100 m(')) and dried over anhydrous sulfur and magnesium oxide.

The brown powder obtained by evaporating the solvent under hot water pressure was converted into a pale brown powder (0,8y) with diethyl ether (som('). This powder was converted into ethanol (20mff) iY<a, and maleic acid (0,75') Add ethanol (10me) solution of °υ
11. Diethyl ether (100 ml) was added to this mixture.
) was added, the precipitated crystals were collected, and the maleate of 4-atrimethyl-2-chloro-3-nitrobenzenesulfonamide (0 , 63y) as i! )/-1゜mp 1
92-194°C (decomposition) IR (Nujol):, 3080. 1680. 15
40. 135 (1°1180, 1160 side-1 NMR (DMSO-46, δ): 4.10 (2H, s
), 6.00 (2H.

s), 7.83 (lH, d, J=8.0Hz),
8.13 (IH.

+ a + s, o Hz) Elemental analysis: (C,H8Cf N30.・C4H,04
・,C,,H,OH) Calculated value: C35,80,1(3,
74, N10.38 Actual value: C35,43, H3,57
, N10.44 Example 109 2-[(3-chloro-2-nitro-4-sulfamoyl)phenokiabenzoate methyl (1,30y) was mixed with a solution of potassium hydroxide (0,38y) in water (15+y+r) and 30
Stir for 1 minute. After cooling the reaction solution, acidify it with hydrochloric acid.
Extract with ethyl acetate. The extract was washed with water, dried with magnesium sulfate, and the stylized medium was distilled off under reduced pressure. The resulting residue was recrystallized from a mixed solvent of ethanol and n-hexane to give 2-[(3-chloro- 2-nitro-4-sulfaceinophenoxybenzoic acid (0,90
y) get it. , mp 238-240°C IR (Glycol): 3325. 3250. 1
690. 1545.・1330, 1190. 11
65cm-1HMR (DMSO-d6.δ): 6.9
2 (IH, d, J=9Hz).

7.36-7.98 (4H, m), 7.84 (2H
,s), 8.0'9(1)1. d, J=9Hz
) Elemental analysis: (C13H9Ce N207S) Calculated value・C41,89,H2,43,N 7.52 Actual 2[]Real Direction: C41,80,H2,48,H7,56Example 110 10 Implementation, Example with catfish Similarly, 2-chloro-6-phenoxy-3
- Obtain white lumpy 2-chloro-6-phenoxy-3-sulfamoylbenzaa E)' (1,0057) from sulfamoylbenzonitrile (1,20y). mp2
26-228°C (X Knorr to 1]f crystal) JR (Glycol): 3460. 3340. 3
200. t685°1325, 1175c+++ NMR (DMSO-d6.δ): 6.83 (IH, d
, J=9Hz).

7.07'-8,10('7H,m), 7.55(
2H,s).

7.90 (IH, d, J = 9 Hz) Elemental analysis:
(C, 3H,, CI!N204B) Calculated value: C4
7,78,H3,39,H8,,57 actual measurements:,C47
,56,,H3,39,H8,60 Example 111 2-amino-3-chloro-4-sulfamoylbenzamide (2,3fj), 1,1-jethoxypropane (
1.6 mt, 35% hydrochloric acid (6 drops) and ethanol (2
The 30 m(') mixture is refluxed for 1 hour while stirring.

After concentrating the reaction mixture under reduced pressure to 50 me, water (10
0me)・Add. Take the precipitated crystals and add them to acetone (80m) and ethanol (10m/')
and water (100 me) 4. After removing the insoluble matter from door to door and concentrating the p liquid to 100 me under pressure,
Leave it overnight. The precipitated crystals were reduced to lr” My and the pressure was reduced to F’50.
After drying at ℃ for 8 hours, 8-chloro-2-ethyl-7-sulfamoyl-1,2,3゜4-
Tetrahydroquinazolin-4-one (1,8y) with j(
do. n+p 245-247° CIR (Glycol): 3360. 3160. 3030. 165
5°1605, 1340. 1150cm-1HMR
(DMSO-d6.δ): 0.92 (3H,t,J
=5.0Hz).

1.54-2.00 (2H, m), 4.79 (IH
, m), 6.73 (IH, s), 7.31 (IH, d,
J=8.0Hz).

7.6:3 (2H, s), 7.71 (LH, d, J=8
．． 0Hz).

8.40 F LH, s') + elemental analysis tatami (:11nH+2Cj? N303S-〒H
20) Calculation (1t1・C40,82,H4,28,N1
4.281120 1.53 Actual value: C40,63, H3,92, N14.31h
20 1.54' Large MII 5 Examples 112 2-amino-3-chloro-4-sulfamoylbenzamide (1,5y), 2,2-jethoxy-1゜1-dichloroethane (1,24y), benzenesulfone h ( 0
, 19) and diethylene glycol dimethyl-L-thyl (30 ml') was stirred at 9 o'clock under reflux.

The reaction mixture was vacuumed at F5. Concentrate with Ome strainer and add 5 to the residue.
% sodium bicarbonate aqueous solution (30me) (!l diisopropyl ether (30me)), the precipitated crystals were collected and washed with water (10me) and diisopropylether (20me). -r-tal/-tal (30me) and water (50m()pi)
Recrystallization from a mixed solvent yields pale yellow-green needle-shaped crystals of 8-chloro-2-dichloromethyl-1-sulfamoyl-1,2.
,3,4-tetrahydroquinaprin-4-one (1,2
P) is obtained. mp142~150°C (softening) 189~
195'c (degraded) IR (glycol): 3560. 3380. 32
70. 3070°1665, 1610. 1335
．． 1180σ-1HMR (DMSO-d6.δ):
5.41 (LH, m) + 6.26 (IH.

d,, T=4.0Hz), 7.38(LH+d+J
=8.0Hz')+7.36(IH), 7.66(
2H, s), 7.78 (IH, d.

J=8.0Hz), 8.94(IH,d, J=4.
01(z) Elemental analysis: (C9H8'Jl'3N303
8) Calculated values: C31, 36, H2, 34, N11.8
6 Actual measurements: C31.46, H2.74, N11.88'
Similar to Example 112, 2-amino-3-
Chlororr --4--sulfamoylbenzaamyl'(
1,8y) and 2,2-jethoxy-1-chloroethane (2,0y) to give 8-chloro-2-chloromethymp242-245°C (decomposition) (water-7tl). -Ethanol 6゛ra Yu 4 mo 10 In (Nujol): 3380.3150.3
050. 1665°1610, 1345. 116
0crn'tJMR (DMSO-c16.δ): 3.
79 (2H, s), 5.20 (IH, m).

7.07 (IH, q), 7.03 (IH, d, J=
8.0Hz).

7.63 (2H, s), 7.37 (IH, d, J-
8.0Hz).

8.50 (LH, s') 7 [1 elementary analysis: (CpHgCe2N30:+S) weighing f] White: C34,85,+(2,92,N13.
55 yen flood 1st shift ・c35.34. N3.15.
N13.41 M+1m 114 Imidazole (0,90y) was dissolved in dry tetranohydrofurasi (35mf), and 3-k4-2-nitro-4-sulfamoylbenzoyl chloride (1,97y) was dissolved under stirring at room temperature. ) and stir for 4 hours.

By-product insoluble matter is removed from the reaction solution and washed with dry tetrahydrofuran (7me). Add N-(2-imidacillin-
(4-ylidene)-5-chloro-2-phenoxyaniline (1,73y) in dry tetrahydrofuran (20 m
e) Add the solution at room temperature and continue stirring with 3 mouths open.

The resulting reaction mixture is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate. The extract is washed with saturated saline, dried and treated with magnesium sulfate. The solvent is distilled off under reduced pressure to obtain a powder residue R17. This powder is subjected to silica gel chromatography and eluted with a mixed solvent of methylene chloride and ethyl acetate (85:15). The fractions containing the target product were combined and the solvent was distilled off under reduced pressure to obtain a white powder residue (1°7y). 1-1) Delivery L1 white powder, 9-chloro-4-(5-
rl rl -, i-phenoxyphenyl)-5-oxo-], 2.4.5--tetrahydroimigzo[
1,2-a1 ginazoline-7,8-sulfonamide (1
oy). mp264-266°C +1 R (:2G1-R): 3330. 321
0. 1675. 1640°1355, 1210.
1165σ−1HMI'? (Dl, 4SO-d 6
, δ): 3.4 -4.0 (4H, m
), 3.5 -8.0 (12H, m) 1+lqr+Rm/e: 502(M”)+467
, 409 (base).

294° element 'j1': (C22H+gCff2N40.
S・-THF-! -N20) 2 Calculator fI white: C51, s3, N3.
48. N10.75 Hanging measurement ar4: C52,0
7, N3.36. N10.79 Length 11/Example 1
15 Cyclopesitylacetaltehyde (0,42y),! :
5-chloro-3-cyclopentylmethyl-6-sulfamoyl-1,2,4-benzothia 25
3°C (colorless needle-like crystals, recrystallized from aqueous ethanol) Engineering R (Nugi-1-#): 3380+ 3210.
1330. 1160c1n-1HMR (DMSO-
d6, a): 1.00-2.20 (IH, m),
4.56-5.00 (IH, m), 6.59 (IH
, s), 7.33 (LH, d.

J-8-OHz) + 7-66 (2Hls), 7
-67 (L H+ 6+J =8.0Hz), 7.
92 (IH, s) Elemental analysis' (Cl5H18Ce N
304S2) Calculated values: C41,10, H4,78,
N11.06 actual value: C40,99, H4,88,N
10.75 Example 116 4'-sulfamoyl-2-bromo-3'-chloro-2
tophenone ('2.3y) and N-methylthiourea (0,6y) in dry acetone (50me
) The solution was stirred at a warm temperature for 3 hours and then left overnight. The precipitated colorless solid was oiled and washed with dry acetone (20me), and the resulting powder (1,4y) was dissolved in methanol (30me).
me). This methanol solution was mixed with a saturated aqueous sodium hydrogen carbonate solution (20+y+r) to give IJH8.5. The precipitated yellow solid is dried in the air.

The obtained yellow powder (1,0y) was mixed with methanol (20me
) dissolves in To this methanol solution, 7N hydrogen chloride methanol solution (2.0me) and diethyl ether (
Add 100 mf and grind to obtain 4-(4-
Sulfamoyl-3-chloro-2-nitrophenyl)-
2-Methylamino-1,3-thiazole hydrochloride (0,9
2) is obtained. mp210-215°C (decomposition) IR (Nujol): 3400. 3110. 3
030. 2600°1625, 1535. 134
5. 1165. 1155σ-1HMR (DMSO-
d6. δ): 2.86 (3H, s), 7.36 (
LH.

s), 7.56 (2H, s), 7.92 (2H
,brd,s).

8.17 (2H, s) Elemental analysis + (C, oH, oCf2N404S2) d value: C31,1g, H2,62,N14
．． 54 actual measurements: C30,98, H2,65, Ni3.9
9 dog example 117 4'-sulfamoyl-2-fromo3'-10 mouths = 2
'-Nitroacetophenone (2,5P) and 1,3=dimethylthiourea (0,76y) @, dry acetone (30m
e) Stir the solution for 1 hour at room temperature.

Separate the precipitated crystals and wash with acetone (30 mC). The obtained crystals (2,0!/?) were dissolved in acetone (50 m
e) and ground to obtain colorless fine needle-like crystals of 4-lysine.
4-ol hydrobromide (1,6y) is obtained. mp
186-1906C (decomposition) IR (Nujol):
3400. 3200. 3100. 1640°16
10, 1560. 1520. 1355. 118
0゜1155σ-1 NMR (DMSO-d6.J)・2.91(3H,s
), 3.10 (3H.

s), 3.92 (2H), 3.97 (IH, b
rd, s).

7.79 (IH, d, J-9,0Hz), 8.02
(2H, s).

8.18 (IH, d, J-9,0Hz) Elemental analysis Tatami C
11H14Cj' N405S2 ' HBr "T
CH3COCHt) Calculated value: C29,9(1,H3
,55,N 11.64 Actual value: C29,51,H3
,55,N11.40'Example 118 4-Sulfamoyl-3-chloro-2-nitrobenzoic acid (2,0y) was dissolved in a mixed solvent of methanol (20me) and acetone (50me) to remove impurities. IF/Separate. 1N hydroxide solution) IJum aqueous solution (7
, 1me) and the solvent was distilled off under reduced pressure to obtain a colorless gel. When acetone (50me) is added to this residue and crystallized, colorless needle-shaped crystals of 4-sulfamoyl-3-chloro-2-nitrobenzoic acid (1,sy) are obtained.
get. mp 292-297°C (decomposition) IR (Nujol): 3600. 3340. 3
270. 3200°1615, 1540. 137
5. 1360. 1170°1150σ-1 NMR (DMSO-d6.δ) ~ 4.66 (2H, br
d, s), 7.86 (IH, d, J=8.0H
z), , 8.02 (IH, d, , T=8.0H2
)+LJ phase separation'(C7H4C" N2 Na O19
・4 H20 calculation lead: C26,60, Hl, 75. H8
,86°H704,27 Actual temperature 1i(1(+:e26.28. +(1,79,
H8,46゜H204,25 Continuation of page 1 ■Int, C1,3 identification code Internal reference number C0
7D 307152 7043-
4C307/68 7043-4
C307/86 7043-4
C4871041128115-4C //A 61 K 31/18
6408-4C31/34 64
08-4 C31/41 640
8-4 C31/425 6408
-4 C31/495 6675-
4 C311546675-4C 31/63 ABU 6675-4C3
1/635 ACX 6675-4CO
Inventor Kiyoshi Taniguchi 3-2 Nagarahigashi, Oyodo-ku, Osaka (public corporation 3-1006) 0 Inventor Yoshimasa Saito 2-6-3-41 Tenma, Kita-ku, Osaka 0 Inventor Yosuke Katsura 3-2 Ueno Nishi, Toyonaka City 9-19 Procedural amendment (spontaneous) April 79, 1980 Kazuo Wakasugi, Commissioner of the Patent Office1, Indication of the case 1982 Patent Application No. 79202, Name of the invention Benzene Nulfonamide Derivatives3, Amendment Patent Applicant: 4-3 Doshomachi, Higashi-ku, Osaka (524) Fujisawa Pharmaceutical Co., Ltd. Representative: Tomoyoshi Fujisawa Honyo 2 Kashima 2, Yodoyo-ku, Osaka 532, Amended Contents (1) From page 175, line 2 to page 176, line 1) of N-(2-chloro...isothiourea) woN-
(2-Clo-made Rho 6-Fetoxy 6-Sulfamoylphenyl)-2-Methylisothiourea" is corrected.

(2) Page 191, line 12 of the same 1 Example 110" [Similar to Example 109," he corrected.

(6) In the first line from the bottom of page 197, [6-sulfamoyl-1,2,4J is corrected to 16-sulfamoyl-5,4-dihydro-2H-1,2,4J.

that's all

Claims (1)

[Claims] (1) General formula [wherein R1 is a halogen atom, a hydroxy group, a lower argyl group, an amino group, a lower alkoxy group, an aryloxy group, a lower alkenyl group! Reoxy group, amino (lower) alkyl group, hydroxy (lower) fur'etv group, lower alkanoyloxy (lower) alkyl group, lower alkylthio group, arylthio group, aralkylthio group, acyl group, lower alkanoylamino group, carboxy group, N, S-containing S-
Lower purkylisothioureido group, cyano group or carbamoyl group, R6 is a halogen atom, R4 and R5 are the same or different hydrogen atom, lower alkyl group, lower alkoxy (lower) alkyl group, aralkyl group, lower alkanoyl group, lower alkyl group Carbamoyl group, cycloalkane carbonyl group, N-containing 6-membered aromatic heterocyclic-substituted (lower) alkyl group, ○-containing 5-membered heterocyclic-substituted (lower) alkyl group,
0-containing 5-membered heterocyclic substituted (lower) alkanoyl group, aryl group, (imino)azidomethyl group or N-containing 5-membered heterocyclic group, and the aryloxy group of R1 is 1
one or more halogen atoms, lower alkyl groups,
It may be substituted with a carboxy group, a lower alkoxycarbonyl group, a halo(lower) alkyl group, or a lower alkoxy group, and the N-, S-containing 5-membered heterocyclic group of R is a hydroxy group, a lower alkyl group, a lower alkylamino group. group and (
or) may be substituted with a lower alkylimino group, and the O-containing fused heterocyclic oxy group of R1 is an oxo group and (
or) may be substituted with a lower alkyl group, the aryl group and aralgyl group of R and R may be substituted with a halogen atom or a nitro group, and further R4
and R5 may form a 6-membered heterocycle together with the N atom to which they are bonded, and this 6-membered heterocycle is a hydroxy (
(lower) alkyl group or O-containing 5-membered heterocyclic substituted lower alkanoyl group, and R4 and R5
may be taken together to form a lower alkylidene group optionally substituted with lower alkylamino, or R1 and R2 may be bonded to form the formula [wherein Z is a carbonyl group or a sulfonyl group, R6
represents a lower alkyl group, a halo (lower) alkyl group, or a cycloalkyl (lower) alkyl group, R represents a hydrogen atom, R represents a hydrogen atom or an aryl group, and R6 and R7 are combined to form an N-containing 5-membered hetero A cyclic group may be formed, and the aryl group of R is a halogen atom and/or
Optionally substituted with an aryloxy group]
and when R is a halogen atom or an amino group, R shall not be a carbamoyl group.] Benzene sulfonamide derivatives and salts thereof.