JPH0356431A - Diphenyl compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is halogen, (protected amino, hydrazino, aminophenoxy, (protected) OH, etc.; R<2> is halogen, alkylamino, (protected) amino, (protected) hydrazino, etc.; R<3> is H, alkyl, halogen, CN, carboxy, etc.; R<3a> is H or alkyl; R<4> and R<4a> are H, alkyl or halogen; A is CH(OH), CH2, CO, O, S, SO2, C(=NOR<a>) (R<a> is H, alkyl, alkenyl, etc.), SO2N(RC) (RC is H or alkyl), etc.] and salts thereof. EXAMPLE:1,1-Bis(4-aminophenyl)-1-methoxyiminomethane. USE:A remedy for pains, inflammatory diseases, rheumatism, nephritis and thrombocytophenia. PREPARATION:For example, a compound expressed by formula II, its reactive derivative or salt thereof is reacted with a compound expressed by formula III or salt thereof to afford the compound expressed by formula I (A is SO2NH).

Description

[Detailed description of the invention]

[Industrial Field of Application] This invention is directed to the treatment of pain and inflammation represented by the following general formula [1].
Useful in the treatment of sexually transmitted diseases, rheumatism, nephritis, and thrombocytopenia.
It concerns diphenyl compounds and is useful in the pharmaceutical field.
used. [Conventional technology 4.4'-diaminodiphenylsulfone is an epoxy resin
It is used not only as a hardening agent in the processing of
antifungal agents), antiprotozoal agents, and herpetic dermatitis inhibitors.
It is also known for its activity (Merck Index 9th edition,
280g, p. 370, (1976). [Problems to be Solved by the Invention] The present invention is based on the novel diphenyl compounds disclosed in the above publications.
Undescribed new pain, inflammatory diseases, rheumatoid arthritis,
It has been shown to be useful as a therapeutic agent for nephritis and thrombocytopenia.
It is something. [A Thousand Steps to Solve the Problem] The diphenyl compound that is the object of this invention is novel.
, can be represented by the following general formula (I). [In the formula, R1
is a halogen, an amino group, a protected amino group, or a hydrazide.
group, aminobenzenesulfonylamino group, protected
Aminobenzenesulfonylamino group, lower alkanesulf
Honylamino group, aminophenoxy group, hydroxy group or
or protected hydroxy group, R2 is halogen, lower alkylamine 7 group, di(lower alkyl group),
(cansulfonyl) amino group, amino group, protected amino group
group, hydrazino group, protected hydrazino group, lower a
lukanesulfonylamino group or halo(lower)alkane
sulfonylamino group, R3 is hydrogen, lower alkyl group,
rogene, cyano group, carboxy group, protected carboxy group
cy group, lower alkanesulfonylamino group, hydroxy group
or protected hydroxy group, R3a is hydrogen or lower alkyl group, R4 is hydrogen, lower alkyl group or halogen, R4a is
hydrogen, lower alkyl group or halogen, A is monoCl{(
Ol{)- -CH2- -CO- -COCI
{(OR>-coco-, -COC(NORb)- (
In the formula, Rb means hydrogen or a lower alkyl group),
-CONH--o-, -S- -50- -502
- -C(-NOR")? {In the formula, Ra is hydrogen, lower
Alkyl group, lower alkenyl group, carboxy (lower) atom
alkyl group or protected carpoxy (low k!k) alkyl group
sul}, −50■N(Rc) −(
In the formula, Rclt means hydrogen or lower alkyl group)
, 1C}12S- or 1CH2SO■-] The object compound (I) of this invention is produced by the following production method.
can do. Gloss m + (I [ ) l L or its salt combination 1 + H2NOR2 (It) 2 or its salt 1 or its salt spoonful + H2NOR enemy (■3) or its salt or its salt'0L ± (I [ -1) 4 (1 -2) 4 or its reactive conductor or its salt conductor, or its salt or its salt form 3i [mutual or its salt or its salt form] IL mutual or its salt or its salt Type jILヱ or its salt or its salt manufacturing method 8 or its reactive derivative or its salt or its salt production yield 1 or its salt or its salt rack' uL east or its salt or its salt sales 1ji (U or its salt) Salt or its salt manufacturing method 1 (4) or its salt or its salt production method 1 (east or its salt or its salt manufacturing method 14 or its salt or its salt manufacturing method 16 or its salt or its salt manufacturing method 16 or its salt or Salt manufacturing method 17 or its salt or its salt 31! ) 19 or a salt thereof (1-2) 19 or a salt thereof [wherein R1, R2, R3, R3a% R4, R4a and
and A have the same meaning as before, and R? is a lower archi
X1 is an acid residue, R is hydrogen, a lower alkyl group, a lower alkenyl group, or
protected carboxy (lower) alkyl group, Rb is hydrogen or lower alkyl group, 3 R1 is halogen, protected amine group, hydrazino group, protected aminobenzenesulfonylamino group,
Aminobenzenesulfonylamino group, lower alkanesulf
Honylamino group, halo (lower) alkanesulfonylamine
- group, amino group, lower alkylamino group, aminopheno group
oxy group, protected hydroxy group or hydroxy group, R1' is nitro group, halogen, protected amino5 group, hydrazino group, protected aminobenzenesulfonyl group
Ruamino group, aminobenzenesulfonylamino group, low a
Alkanesulfonylamino group, halo (lower) alkanes
sulfonylamino group, amino group, lower alkylamino group,
aminophenoxy group, protected hydroxy group or
droxy group, R2 is di(lower alkanesulfonyl) amino group, 6 lower alkylamino group, protected amino group, protected
hydrazino group, hydrazino group, lower alkanesulfony
lyamino group or amino group, R2' is di(low realcane)
sulfonyl)amino6 group, lower alkylamino group, protected amino group, protected
hydrazi7 group, hydrazino group or lower alkane
Sulfonylamino group, A6-C(=NOR")-C, where R"it water
, t, lower 7-alkyl group, lower alkenyl group, carboxy
(lower) alkyl group, or protected carboxy (lower)
], -CH2-CO-
-COCO- -CONH- -0- -
S--50- -So2-t Taha-So2N (Rc)
-(In l, R0 means hydrogen or lower alkyl group
), 1 R7 is a protected amino group or a protected aminoben
Zenesulfonylamino group, l' R7 is an amino group or aminobenzenesulfonylamino
group, 2 R7 is halogen, di(lower alkanesulfonyl)amino
group, lower alkylamino group, protected amino group, protected
hydrazino group, hydrazino group, lower alkanesulfate
Honylamino group or amino group, R' is halogen, di(lower alkanesulfonyl)amine
group, lower alkylamino group, protected amino group,
Protected hydrazino group, hydrazino group, lower alkanes
sulfonylamino group or amino group, l R8 is halogen, amino group, protected amino group, protected
aminobenzenesulfonylamino group, lower alkali
sulfonylamino group, protected hydroxy group or
hydroxy group, 2 R8 is hydrazino group or amino group, R2' is protected hydrazino group or protected 8-amino group, R1 is halogen, amine 7 group, protected amino 9 group, protected aminobenzenesulfonylamino base, low
alkanesulfonylamino group, protected hydroxy
group or hydroxy group, R2 is an amino group, 9 R2' is a di(lower alkanesulfonyl) amino group, 9 or a lower alkanesulfonylamino group, A,4t -
C(=NOR")- (wherein, R"tt hydrogen, lower a
Alkyl group, lower alkenyl group, carboxy(lower)alkyl group, lower alkenyl group,
Kill group or protected carboxy (lower) alkyl group
}, -CH2- -CO--COCO--
In the COC(=NORb)-C formula, Rb is hydrogen or lower
meaning an alkyl group), -CONH--o--s
- -so- -so2- or -So2N(Rc
) − (In the formula, Re means hydrogen or a lower alkyl group.
taste), Rlo is a halogen, a protected amino group, ;hydrazi?
group, protected aminobenzenesulfonylamino group,
Minobenzenesulfonylamino group, lower alkanesulfonyl group
nylamino group, amino group, aminophenoxy group, protected
Rfo is di(lower alkanesulfonyl)amino group, 2' R1o is alkanesulfonylamino group, 1 R11 is halogen, protected amino group, hydrazino group
, protected aminobenzenesulfonylamino group, amino
Nobenzenesulfonylamino group, lower alkanesulfony group
Ruamino group or amino group, aminophenoxy group, protected
hydroxy group or hydroxy group, A 1■+t −C(=NOR”)− (in the formula, R”
4t water jl, lower 17 alkyl group, lower alkenyl group, cal
Boxy (lower) alkyl group or protected carboxy
(lower) alkyl group}, -CH(OR)-,
CH2- -CO- -COCH(OH)- -
COC(NORb)-(wherein, Rb is hydrogen or lower
Do you mean alkyl group? ), -CONH- -0-
-8- -So2- or -So2N(Rc)-
(In the formula, R0 means hydrogen or a lower alkyl group)
, 3 R1■ is a protected hydroxy group, 1 R13 is a protected hydroxy group, 2 R13 is a di(lower alkanesulfonyl) amino group, lower
Alkylamino group, hydrazino group, lower alkanesulfo group
nylamino group or amino group, 1 R14 is halogen, protected amino group, protected amino group,
Minobenzenesulfonylamino group, lower alkanesulfonyl group
nylamino group or protected hydroxy group, 2 R14 is di(lower alkanesulfonyl) amino group, lower
alkylamino group, protected amino group or protected
hydrazino group, 3 Rl4 is hydrogen, halogen, lower alkanesulfonyl amine
- group or protected hydroxy group, A15 -co group
or -coco -A15 is one CH(OR) one or
-COCR(OH) -1 A16 is a protected carpoxy (lower) alkyl group, A de. is a carboxy (lower) alkyl group, 3' R17 is a protected carboxy group, and X18 is a halogen]. In the above and following descriptions of this specification, this invention
Preferred examples and explanations of various definitions encompassed within the scope of
will be described in detail below. “Lower two means that unless otherwise specified, there is no carbon atom.
This means 6 pieces. Suitable “halogen” and
and “halo (lower) alkanesulfonylamino group”.
"Halogen, moieties include fluorine, chlorine, bromine and
Examples include iodine. Suitable “protected amino” groups and 1-protected amino groups
"Nobenzenesulfonylamino" group and "Protected low
alkylamino, a preferred r-protected amino moiety of the group
For example, the following acyl groups, such as benzyl,
Benzhydryl, trityl mono-(or di-)
is an alkyl group such as tri)phenyl(lower)alkyl group
Protected by commonly used amino protecting groups such as (lower) alkyl groups
Examples include amino groups. Suitable acyl groups include aliphatic acyl groups and aromatic acyl groups.
and aliphatic acyl groups substituted by aromatic groups
Listed below. Examples of aliphatic acyl groups include formyl, acetyl,
Propisaril, petilil, imptyril, valeril, i
Lower alkaline compounds such as nvaleryl, pivaloyl, hexanoyl, etc.
Noyl groups, such as methoxycarbonyl, ethoxycarbonyl
nyl, propoxycarbonyl, butoxycarbonyl,
Lower alkoxycarbonyl such as tertiary poxycarbonyl
groups, such as acryloyl, methacryloyl, crotonoy
Lower alkenoyl groups, such as carbamoyl groups, etc.
Saturated or unsaturated, acyclic or cyclic acyl groups may be mentioned.
It will be done. Examples of aromatic acyl groups include benzoyl, tolyl, and
and aroyl groups such as xyloyl and xyloyl. Examples of the aliphatic acyl group substituted with an aromatic group include
Phenylacetyl, phenylpropylene, phenyl
Like phenyl (lower) alkanoyl groups such as xanoyl
(lower) alkanoyl groups, e.g.
Phenyl such as carbonyl, phenethyl
(lower)alk such as alkoxycarbonyl group
Alfoxycarbonyl groups, such as phenoxyacetyl,
Phenoxy (lower) alkaline compounds such as phenoxybromine
Examples include noyl group. These acyl groups are further
For example, methyl, ethyl, probyl, isopropyl, butyl
Lower alkyl groups, such as pentyl, hexyl, etc., e.g. salts
Halogens such as chlorine, bromine, iodine, fluorine, e.g.
Oxy, ethoxy, propoxy, imbropoxy, butoki
Lower alkoxy, such as chlorine, benzyloxy, hexyloxy, etc.
Substituted with one or more suitable substituents such as
Good too. 1 lower alkanesulfonylamino group, di(lower) a
lukanesulfonyl)amino” group and rhalo(lower)a
Preferred 1-lower alkane of lukanesulfonylamino group
Parts include methane, ethane, propane, butane, etc.
Listed below. Suitable protection of “protected hydrazino” groups
Examples of groups include those exemplified above for amino protecting groups.
Examples include commonly used hydrazino protecting groups. Suitable protected hydroxy groups include, for example,
Lower alkoxy groups such as toxoxy, ethoxy, propoxy, etc.
can be mentioned. Suitable protected carboxy groups include, for example,
Toxicarbonyl, ethoxycarbonyl, proboxyl
Norebonil, Improboxycanoleponil, Butoxy
Lower alphs such as carbonyl, tertiary poxycarbonyl, etc.
xycarponyl group, e.g.
4-Nitrobenzyl carbonyl, phenethyl carbonyl
Cycarbonyl, Penzhydryl, Oxycarbonyl, Tricarbonyl
May have a nitro group such as carbonyl
Mono (or di or tri) phenyl (lower) alkoxy
Esterified carboxy groups such as cycarponyl groups, etc.
Examples include groups. Suitable "lower alkyl" groups and "lower alkylamino"
Preferred lower alkyl moieties of the group include methyl, ethyl,
Examples include groups such as til, probyl, and isoprobyl. Suitable "lower alkenyl" groups include vinyl, allyl, etc.
Examples include the following groups. Suitable r-acid residues include fluorine, chlorine, bromine, and iodine.
Halogens such as benzenesulfonyl,
Arenesulfonyl group such as tosyl group, e.g.
Lower alkaline acids such as mesyl, ethanesulfonyl, etc.
Examples include sulfonyl group and the like. As suitable pharmaceutically acceptable salts of compound (1)
For example, hydrochloride, hydrobromide, hydroiodide, sulfuric acid
Inorganic acid addition salts such as salts, borates; e.g. formates, acetates,
Trifle acetate, maleate, tartrate, methane
sulfonate, benzene sulfonate, p-toluene
Organic carboxylic acid addition salts such as sulfonates or organic sulfonate salts.
acid addition salts; for example, aspartic acid, glutamic acid, etc.
Examples include salts with acidic amino acids. The method for producing the target compound of this invention will be explained in detail below. Compound (I-2) or a salt thereof can be obtained by reacting compound (111l) or a salt thereof with compound <I1>.
It can be manufactured more easily. Suitable salts of compounds (I-1> and (11-2))
1. Examples of compounds such as those exemplified for compound (1)
It will be done. Suitable acid residues for X1 include chlorine, iodine, etc.
．． The reaction is usually carried out using an alkali such as sodium or potassium.
Alkaline earths of metals such as magnesium, calcium, etc.
metals such as sodium hydride, sodium hydroxide,
Hydrogen of those metals such as sodium carbonate, hydrogen carbonate, etc.
In the presence of bases such as compounds, hydroxides or carbonates etc.
It will be done. This reaction is usually carried out using water, e.g. methanol, ethanol,
Alcohols such as probanol, tetrahydrofuran, dihydrofuran, etc.
Oxane, ethyl acetate, N. N-dimethylformamide
, carried out in common solvents such as dimethyl sulfoxide.
However, other solvents may be used as long as they do not adversely affect the reaction.
The reaction can be carried out in any organic solvent. transformation
If the compound (■1) is a liquid, use it as a solvent.
You can also use The reaction temperature is not particularly limited, and may be under cooling or heating or
The reaction can be carried out under heating. Production method 2 Compound (12-2) or its salt is compound (121)
or its salt as a hydroxylamine derivative <I2) or
can be produced by reacting with its salt
．． Suitable salts of compounds (1-1) and (12-2)
2. Examples of compounds such as those exemplified for compound (I)
It will be done. As a suitable salt of hydroxylamine derivative (II2)
Examples include hydrohalides such as hydrochloride.
．． This reaction is usually carried out using water, e.g. methanol, ethanol,
Alcohols such as propanol, tetrahydrofuran, dihydrofuran, etc.
Oxane, ethyl acetate, N. N-dimethylformamide
, carried out in common solvents such as dimethyl sulfoxide.
However, other solvents may be used as long as they do not adversely affect the reaction.
The reaction can be carried out in any organic solvent. transformation
If the compound (■2) is a liquid, use it as a solvent.
You can also use The reaction temperature is not particularly limited, and may be under cooling or heating or
Reactions can be carried out on heated plates. Compound (13-2) or a salt thereof is compound (131)
or its salt is reacted with compound <■3) or its salt.
It can be manufactured by Compound (I-
1) and (I,-2).
It will be done. Suitable salts of the compound (Ti3) include, for example, hydrochloride, etc.
Examples include hydrohalides. This reaction is usually
water, such as methanol, ethanol, probanol, etc.
Alcohol, tetrahydrofuran, dioxane, acetic acid
Chill, N. N-dimethylformamide, dimethylsulfo
Although it is carried out in commonly used solvents such as oxide, it has a negative effect on the reaction.
Any other organic solvent may be used as long as it has no harmful effects.
The reaction can also be carried out in a medium. Compound (II3) is
If it is a liquid, it can also be used as a solvent.
can. The reaction temperature is not particularly limited, and may be under cooling or heating or
The reaction can be carried out under heating. The compound (It, -1) or a salt thereof is the compound (It, -1
) or a reactive derivative thereof, or a salt thereof, as compound (II) or a reactive derivative thereof, or a salt thereof.
4-2) or a salt thereof.
be able to. As suitable salts of compounds (1) and (I4-2)
4 includes those exemplified for compound (1).
It will be done. Suitable compounds (II4-1) and reactive derivatives thereof
Examples of salts include those exemplified for compound (1).
and salts with inorganic bases, such as sodium
Alkali metal salts such as aluminum salts, potassium salts, e.g.
salts such as alkaline earth metal salts such as aluminum, magnesium, etc.
Examples include salts with groups. Suitable reactive derivatives of compound (n4-1) include acid
Examples include halides and acid anhydrides. A good example is
Examples include acid halides such as acid chlorides, acid bromides, etc.
You can get it. The reaction also includes alkali metal bicarbonates, tri(lower) alkaline
Killamines, such as N. Di( such as N-dimethylaniline)
(lower) alkylaniline, pyridine, N-(lower)alk
Kilmorpholine, N. N-di(lower)alkylbenzyl
carried out in the presence of an inorganic or organic base such as an amine, etc.
You can. This reaction is usually carried out using water, e.g. methanol,
Alcohols such as ethanol and probanol, and tetrahydrides
Lofuran, dioxane, ethyl acetate, dichloromethane,
N. N-dimethylformamide, dimethyl sulfoxide
, carried out in common solvents such as diethyl ether.
, other solvents may be used as long as they do not adversely affect the reaction.
The reaction can be carried out in any organic solvent. None of the above
If the organic base or organic base is a liquid, it can be used as a solvent.
It can also be used as The reaction temperature is not particularly limited, but is usually heated or heated.
The reaction takes place under heat. Compound (I) or a salt thereof is compound <I5> or
5 can be produced by reducing the salt. Suitable salts of compound (I) and <15) include:
5 Examples include those exemplified for compound (1)
．． Reduction can be carried out by conventional methods, i.e. chemical or catalytic reduction.
This can be done by Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc, iron and ammonium chloride or e.g.
Combination with bases such as monium, sodium hydroxide, etc.
Metals such as tin, zinc, iron or chromic chloride, chloride
Metal compounds such as stannous, dichromic acetate and e.g. formic acid
, acetic acid, prohyacic acid, triple vinegar M. p = Toluet
organic or inorganic acids such as sulfonic acid, hydrochloric acid, hydrobromic acid, etc.
combination with acids, e.g. lithium borohydride, hydrogenation
Hydrogenates such as sodium boron and potassium borohydride
Uron alkali metals, e.g. sodium cyanoborohydride
Alkali metal cyanoborohydrides such as
Aluminum hydride such as lithium aluminum hydride
Potassium metals, etc. Suitable catalysts used for catalytic reduction are, for example, platinum plates, white
Gold sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
Platinum catalysts, e.g. palladium-carbon, colloidal palladium
palladium-pallium sulfate, palladium-barium carbonate
palladium catalysts such as reduced nickel, nickel oxide, etc.
Nickel catalysts such as Nickel, Raney nickel, etc., e.g. reduction
Cobalt catalysts such as Raney cobalt, e.g.
Iron catalysts such as original iron and Raney iron, such as reduced steel, Raney copper,
These are commonly used materials such as Ullmann steel and other copper catalysts. The reduction in this process is usually carried out using water, e.g. methanol, ethanol, etc.
Alcohols such as alcohol and probanol, acetic acid, dioxic acid
N., tetrahydrofuran, N. N-dimethylformamide
solvents such as dimethyl sulfoxide, or
any other organic solvent that does not have an adverse effect, or
It is carried out in a mixture of them. The above reducing agent is a liquid
In some cases, it can also be used as a solvent. reaction
is carried out under cooling or heating, or under heating. 1' When R5 is a nitro group, the nitro group also becomes an amino group.
It will be returned. For the type Jl interaction, first, take the compound (I6-t> or its salt as an example)
For example, it reacts with alkali metal nitrites such as sodium nitrite.
This can be done by setting This reaction takes place under acidic conditions.
, for example, organic or inorganic acids such as hydrochloric acid, acetic acid, etc.
It is preferable to do this in the presence of This reaction is usually performed using water, e.g.
Alcohols such as methanol, ethanol, and propanol
acetic acid, dioxane, tetrahydrofuran, N. N-
such as dimethylformamide, dimethylsulfoxide
solvent or any other material that does not adversely affect the reaction.
in an organic solvent, or a mixture thereof, under cooling or
It is done under heat. Then, the obtained compound (16-t)
Compound (16-2) is obtained by reducing the diazo compound. child
The reduction reaction is carried out in the same manner as in Production Method 5. In this production method, the raw material compound (I-1) is R2
When 66 has an amino group, this group also becomes a hydrazino group.
Change. Suitable salts of compounds (16-t) and (Is-2)
Examples include those exemplified for compound (I).
It will be done. LL Incarnation (1,-2) or its salt is the compound (I 7
-1> or a salt thereof to an amino-protecting group elimination reaction.
It can be manufactured by As suitable salts of compounds (17-1) and (17-2)
Examples include those exemplified for compound (1) (
f. This reaction is carried out according to conventional methods such as hydrolysis, reduction, etc.
It will be done. Hydrolysis is carried out in the presence of bases or acids, including Lewis acids.
It is preferable. Suitable bases include, for example, sodium, potassium, etc.
Alkali metals, such as sodium hydroxide
hydroxides or carbonates or bicarbonates, such as sodium acetate.
Examples include alkali metal alkanoates such as thorium.
．． Suitable acids include, for example, formic acid, acetic acid, and propynic acid.
, organic acids such as trichloroacetic acid, trichloroacetic acid, and
Examples include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid.
．． For example, trichloroacetic acid, trifluoroacetic acid, etc.
Desorption using a Lewis acid such as acetic acid can be performed, e.g.
Performed in the presence of a cation scavenger such as Sol, phenol, etc.
It is desirable that The reaction is usually carried out using water, an alcohol such as methanol or ethanol.
Lucol, dichloromethane, tetrahydrofuran, it
It is carried out in a solvent such as a mixture of
In any other solvent that does not
Reactions can be carried out. Liquid bases or acids can also be used as solvents.
It can be used as Reaction takes place under cooling or heating
Alternatively, it can be performed under heating. Reduction methods that can be applied to elimination reactions include chemical reduction and
and catalytic reduction. Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc, iron or e.g. chromic chloride, chloric acetate etc.
Metal compounds such as dichromium and e.g. formic acid, acetic acid, propylene
trifluoroacetic acid, p-toluenesulfonic acid, salt
Acids, Hydrogen Bromide # In combination with specialized organic or inorganic acids
be. Manufacture for suitable catalysts used in catalytic reduction
You can refer to the example given in Law 5. Reduction is common
water, methanol, ethanol, probanol, tet
Lahydrofuran, N. Like N-dimethylformamide
Commonly used solvents that do not adversely affect the reaction, or
It is carried out in a mixture of Further used in chemical reduction
When the above acids are liquid, use as their solvent.
can do. Furthermore, it is used for catalytic reduction.
Suitable solvents include the above solvents and diethyl ether.
, dioxane, tetrahydrofuran etc.
Commonly used solvents or mixtures thereof may be mentioned. The reaction temperature is not particularly limited, and may be under cooling or heating or
The reaction can be carried out under heating. In this manufacturing method
, the salt of the starting compound (17-1> or mo) is protected by R2.
Compound (1-2) or a salt thereof has an amino group, which also changes to an amino group.
8-t)8 or its reactivity at amino or hydrazino groups
The derivative or its salt is added to the amino group or hydrazino group.
It can be produced by subjecting it to a protection reaction. Suitable compounds (1-1) and (I 8-2)
Examples of the salt 8 include those exemplified for compound (I).
It will be done. The preferred amino group protecting agent 4 or hydrazino group protecting agent used in this production method has the formula: Rs-OH (
In the formula, R4 means an amino-protecting group or a hydrazino-protecting group) or a reaction thereof.
sexual derivatives or salts thereof. Compound R'-O
Suitable reactive derivatives of R include 8 acid halides, acid anhydrides, activated amides, activated esters, etc.
Examples include Tell et al. Suitable examples include acid chloride,
Acid bromide; acid azide; e.g. dialkyl phosphoric acid, phenate
phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid,
Substituted phosphoric acids such as rogogenated phosphoric acids, dialkyl phosphorous acids
acids such as methanesulfonic acid, ethanesulfonic acid, etc.
Lower alkanesulfonic acid, sulfite, sulfuric acid, sulfuric acid,
Rukyl carbonates, such as pivalic acid, pentanoic acid, impene
Fats such as tannic acid, 2-ethylbutyric acid or trichloroacetic acid
group carboxylic acids or aromatic carboxylic acids such as benzoic acid
Mixed acid anhydrides with acids such as acids; symmetrical acid anhydrides; imida
zole, 4-monosubstituted imidazole, dimeterpyrazole,
Activated amides with triazoles or tetrazoles;
or e.g. cyanomethyl ester, methoxymethyl ester
Teru, dimethyliminomedel (<CH3>2 Aichi CH1
〉Ester, vinyl ester, propargyl ester,
p-nitrophenyl ester, 2,4-sinitrophenyl
ester, tricr1o phenyl ester, pentac
Lolophenyl ester, mesyl phenyl ester, fue
Nylazophenyl ester, phenylthiazophenyl ester, p
-Nitrophenyl ester, p-cresinoester
Stenole, canoleboxymethylthiol ester, biranyl
ester, pyridyl ester, piveridyl ester, 8
-activated esters such as quinolyl esters, or e.g.
For example, N. N-dimethylhydroxylamine, 1-hydro
xy-2-(IH)-pyridone, N-hydroxysucci
N-imide, N-hydroxyphthalimide, 1-hydroxy
N-Hydrogen such as C-6-chloro-IH-benzotriazole
Examples include esters with droxy compounds. these
Reactive derivatives may be used depending on the type of compound R8-OH to be used.
You can arbitrarily choose from. The reaction usually involves water, methanol, ethanol, acetone,
Dixane, acetonitrile, chloroform, dichloro
Methane, ethylene chloride, tetrahydrofuran, ethyl acetate
Le, N. N-dimethylformamide, such as pyridine
Although it is carried out in a commonly used solvent, it does not adversely affect the reaction.
The reaction can be carried out in any other organic solvent as long as it is a solvent.
It can be carried out. These commonly used solvents are mixtures with water
You can also use it as When the compound R'-OH is used in the reaction in the form of the free acid or its salt, N. N'-dicyclohepheasant
lupodiimide; N-cyclohexyl-N' 1 mol
Folinoethyllupodiimide; N-cyclohexyl N
'-(4-diethylaminocyclohexyl)carposiy
Mid; N,N'-diethyl luposiimide. N. N'
-Diimpropylene diimide; N-ethyl-N
'-(3-dimetelaminopropynole)carbodiimide
;N. N-kanolebonylbis(2-methylimidazole)
): Pentamethylene ketene-N-cyclohexylimine
; diphenylketene-N-cyclohexylimine; etho
xyacetylene; 1-alkoxy-1-chloroethylene
;trialkyl phosphite; ethyl boriphosphate; boriline
Isopropyl acid: Phosphorus oxychloride (phosphoryl chloride):
Phosphorus trichloride; Chinyl chloride; Xalyl chloride; Trichloride
Nylphosphine; 2-ethyl-7-hydroxybenzi
xazolium salt; 2-ethyl-5-(m-sulfof
enyl)inoxazolium hydroxide inner salt;
1-(p-')lorobenzenesulfonyl-6-
Chloro IH-penzotriazole: N,N-dimethyl
Formamide and dichlorochloride, phosgene, dichlorochloride
The so-called Pilsmeyer prepared by reaction with
The reaction is carried out in the presence of a commonly used condensing agent such as a reagent.
desirable. The reaction can also be performed with e.g. potassium carbonate, sodium carbonate
Alkali metal carbonates such as lithium, alkali metal hydrogen carbonates
salt, tri(lower)alkylamine, pyridine, N-(lower)
class) alkylmorpholine, N. N-di(lower)alkyl
Presence of inorganic or organic bases such as benzylamine etc.
You may go to your residence. The reaction temperature is not particularly limited, but
The reaction is usually carried out under cooling or at room temperature. Compound (I-2) or a salt thereof is compound (1)
9-1>9 or a salt thereof to a sulfonation reaction of an amino group
It can be manufactured more easily. As a suitable salt of compound (I-1) and -2>
9, the same as those exemplified for compound (1) are listed.
It will be done. Preferred lower alkanesulfonations used in this production method
As an agent, the formula: R:-OH (wherein R5 is a lower alkali
(representing a sulfonyl group) or
Examples include reactive derivatives or salts thereof. 5 Suitable reactive derivatives of compound R9-OR include acid
Examples include halides and acid anhydrides. A good example is
acid chlorides, acid bromides; acid azides; e.g.
Ruphosphoric acid, Phenyl phosphoric acid, Diphenyl phosphoric acid, Diben
Substituted phosphoric acids such as dilyphosphoric acid and halogenated phosphoric acid,
Dialkyl phosphorous acids, e.g. methanesulfonic acid, ethane
Lower alkanesulfonic acids such as sulfonic acids, sulfites, and
Sulfuric acid, sulfuric acid, alkyl carbonates such as pivalic acid, penta
niconic acid, impenconic acid, 2-ethylbutyric acid or trichloric acid
aliphatic carboxylic acids such as oral acetic acid or e.g. benzoic acid;
Mixed acid anhydrides with acids such as aromatic carboxylic acids; symmetrical acids
Examples include anhydrides. These reactive derivatives are
can be arbitrarily selected from among the nine types of compounds R 5-OH.
Ru. The reaction usually involves acetone, dioxyquinane, acetonitrile,
Chloroform, dichloromethane, ethylene chloride, tetra
Hydrofuran, ethyl acetate, N. N-dimethylformua
It is carried out in commonly used solvents such as amide, pyridine, etc.
Any other solvent may be used as long as it does not have an adverse effect on the
The reaction can be carried out even in organic solvents. These constants
The solvent may be used as a mixture with water. The reaction is
Also alkali metal bicarbonates, e.g. trimethylamine
, tri(lower)alkylamines such as triethylamine,
Pyridine, N-(lower)alkylmorpholine, N. N-
Inorganic bases such as di(lower)alkylbenzylamine, etc.
Alternatively, it may be carried out in the presence of an organic base. The reaction temperature is not particularly limited, but usually under cooling or heating.
The reaction takes place at room temperature.艷潅迭昶 Compound (t 1o-2> or its salt is compound "1")
01> or a salt thereof to hydrolysis using a base.
It can be manufactured by Suitability of compounds (1-1) and (I 1o-2)
10 Then, the examples given for compound (1) are listed.
It will be done. Suitable bases include sodium, potassium, etc.
water of alkali metals, such as sodium hydroxide
oxides or carbonates or bicarbonates, e.g. sodium acetate
Examples include alkali metal alkanoates such as lithium. The reaction is usually carried out using water, an alcohol such as methanol or ethanol.
alcohol, dichloromethane, tetrahydrofuran, it
It is carried out in a solvent such as a mixture of
In any other solvent that does not
can also perform a reaction. Liquid bases can also be used as solvents.
It can be used. The reaction can be carried out under cooling or heating.
Wear. Gloss 1st L■ Compound (I tt-2) or its salt is compound (I tt-2)
1, Reduction of 1) or its salt in the presence of acetone
It can be manufactured by subjecting it to. Compound (1
-1) and (1 1, -2) are suitable salts such as those exemplified for compound (1).
It will be done. Reduction methods that can be applied to this production method include chemical reduction.
and catalytic reduction. used in chemical reduction
Suitable reducing agents include metals such as tin, zinc, iron or
For example, metal compounds such as chromic chloride, chromic acetate, etc.
and for example, formic acid, acetic acid, chloroacetic acid, triple chloroacetic acid
, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.
It is a combination with an acid or an inorganic acid. used for catalytic reduction
Examples of suitable catalysts include those exemplified in Production Method 5.
You can refer to . Reduction is typically performed using water, methanol, or
Tanol, alcohol, tetrahydrofuran, N
．． N-dimethylformamide, or mixtures thereof
Like? Contains AceC and N, which have no adverse effect on the reaction.
It is carried out in a commonly used solvent. Furthermore, used for chemical reduction
If the above acids to be used are liquids, they can also be used as solvents.
It can be used as The reaction temperature is not particularly limited, but usually under cooling or heating.
The reaction takes place at room temperature. Compound (11.-2) or its salt is the compound (I1
1) or a salt thereof is subjected to a hydroxy protecting group elimination reaction
It can be manufactured by Compound (I12-1
) and (■12-2>) include the compound (
Examples of 1) are as shown above. Preferred reagents used in this method include hydrochloric acid, odor
Hydrohydric acid, boron trichloride, boron tribromide, aluminum chloride
pyridine hydrochloride, trimethylsilyl iodide, etc.
You can get it. Hydrolysis is typically performed using water, methanol, ethanol, or
Nor, tertiary butyl alcohol, tetrahydrofuran
, N. N-dimeterformamide, N. N-dimethyl
Acetamide, dioxane, dichloromethane or
Commonly used solvents that do not adversely affect the reaction, such as mixtures of
It is carried out in a medium, but if the above acid is also liquid, it can be used as a solvent.
It can be used as The reaction temperature for this hydrolysis is not particularly limited, but usually
The reaction takes place under cooling or heating. Compound 331 (I 13-2) or its salt is a compound (!
131 l> or a salt thereof to remove the hydroxy protecting group of R13.
It can be manufactured by applying the following steps. Compound (1
Suitable salts of 13-1) and (113-2> include:
Examples include those exemplified for compound (I).
．． This production method is carried out in the same manner as described in Production Method 12. Compound (1 14-2) or a salt thereof is manufactured by compound (l)
141) or its salt by oxidizing it.
can be done. Suitability of compounds (1-1> and (1 14-2))
14 Then, the examples given for compound (1) are listed.
It will be done. The preferred oxidizing agent used in this process is chromium dioxide
combinations with acids such as sulfuric acid, acetic acid, and dichromic acid.
combination of lithium and sulfuric acid, tertiary butyl chromate, di
These include manganese oxide and selenium dioxide. This reaction is usually carried out using water, e.g. methanol, ethanol,
Alcohol such as propanol, acetic acid, diethyl ether
, dioxane, tetrahydrofuran, dichloromethane,
Chloroform, N. N-4; Methylformamide, di
Solvents such as methyl sulfoxide or adversely affect the reaction
or any other organic solvent that does not
It is carried out in a mixture of If the above acid is a liquid,
It can also be used as a solvent. The reaction can be carried out under cooling or heating.
Wear. Compound (I-2) or a salt thereof is compound (I1.
15 1) or can be produced by reducing its salt
can. Suitable salts of compounds (1-1) and (11.-2)
15 For example, compounds such as those exemplified for compound (1) are listed.
It will be done. Suitable reducing agents used 11 such as lithium borohydride
sodium borohydride, potassium borohydride, etc.
Alkali metal borohydride, e.g. cyanoborohydride
Alkali metal cyanoborohydrides such as sodium chloride, e.g.
For example, sodium hydrosanolephite, potassium high
Alkali metal hydrosulfites such as dorosulfite
or hydrogenation of e.g. lithium aluminum hydride.
Aluminum, alkali metals, etc. This manufacturing method is preferably carried out in the presence of a base. Suitable bases include sodium, potassium, etc.
water of alkali metals, such as sodium hydroxide
oxides or carbonates or bicarbonates, e.g. sodium acetate
Examples include alkali metal alkanoates such as lithium. The reduction in this process is usually carried out using water, e.g. methanol, ethanol, etc.
Alcohols such as alcohol and propanol, acetic acid, diethyl
Ether, dixane, tetrahydrofuran, N. N-
such as dimethylformamide, dimethyl sulfoxide
solvent or any other material that does not adversely affect the reaction.
The process is carried out in an organic solvent, or a mixture thereof. The reaction can be carried out under cooling or heating.
Wear. The compound (116-2) or its salt is the compound (116-2) manufactured by LuL.
1) or a salt thereof to remove the carboxy protecting group of R16
It can be made into a mold by applying the appropriate conditions. Compound (I
Suitable salts of -1) and (I16-2) include those exemplified for the target compound (1).
The same thing can be mentioned. Suitable methods for this elimination reaction include hydrolysis, reduction, etc.
Examples of common methods include: (1) Hydrolysis Hydrolysis is preferably carried out in the presence of an acid. with a suitable acid
For example, hydrochloric acid, hydrobromic acid, sulfuric acid, etc. acids, e.g.
For example, formic acid, acetic acid, trifluoroacetic acid, propionic acid,
Tansulfonic acid, benzenesulfonic acid, p-toluene
Organic acids such as sulfonic acid, acidic ion exchange resins, etc.
Ru. Triflic acetic acid and p-toluenesulfonic acid
When using organic acids such as
The reaction is carried out in the presence of a cation scavenger such as Nisole.
preferable. Furthermore, instead of the above acid, boron trifluoride, boron trifluoride
element/ether addition compound, antimony pentachloride, second chloride
Such as iron, stannic chloride, titanium tetrachloride, zinc chloride etc.
Lewis acids can also be used in this reaction, and Lewis acids can be
When used, cations such as anisole
Preferably, the reaction is carried out in the presence of a scavenger. Hydrolysis is typically performed using water, methanol, ethanol, or propane.
Nor, tertiary butyl alcohol, tetrahydrofuran
,N. N-dimedelformamide, N. N-dimethyla
Reactions like cetamide, dixane, dichloromethane
Commonly used solvents or mixtures thereof that do not adversely affect
In addition, if the above acids are liquid, they are removed as a solvent.
It can also be used as The reaction temperature for hydrolysis is not particularly limited, but is usually cooled.
The reaction takes place at a lower or slightly higher temperature.
．． (i) Reduction Reduction is carried out by conventional methods including chemical reduction and catalytic reduction.
．． Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc, iron, or dichromium chloride, dichromium acetate, etc.
Metal compounds such as dichromium and e.g. formic acid, acetic acid, bromine, etc.
trifluoroacetic acid, p-toluenesulfonic acid, salt
In combination with organic or inorganic acids such as pentahydrobromic acid
be. Suitable catalysts used for catalytic reduction are e.g. platinum plates.
, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire
Platinum catalysts such as palladium sponge, palladium black, etc.
Palladium oxide, palladium-R element, colloidal palladium
palladium-barium sulfate, palladium-barium carbonate
palladium catalysts such as reduced nickel, nickel oxide, etc.
Nickel catalysts such as Nickel, Raney nickel, etc., e.g. reduction
Cobalt catalysts such as Raney cobalt, e.g.
Iron catalysts such as original iron and Raney iron, such as reduced steel, Raney copper,
These are commonly used materials such as Ullmann steel and other copper catalysts. Reduction is typically performed using water, methanol, ethanol, or probanol.
Le, N. Negative effect on reactions such as N-dimethylformamide
in non-toxic conventional solvents, or mixtures thereof.
It will be done. Additionally, if the acid used in the chemical reduction is a liquid,
In some cases, they can also be used as solvents. Ma
Furthermore, suitable solvents for use in catalytic reduction include the above-mentioned solvents.
Solvents and diethyl ether, dioxane, tetrahedron
Other common solvents such as Dorofuran etc. or
Examples include mixtures of these. The reaction temperature for this reaction is not particularly limited, but it is usually cooled.
The reaction takes place under low temperature or heating. Compound (117-2) or its salt is compound (!17
3′ l) or a salt thereof to remove the carboxy protecting group of R17.
It can be manufactured by applying the following steps. Compound (1
17-1> and (r 17-2) as a suitable salt
Examples include those exemplified for compound (1).
It will be done. This manufacturing method can be carried out in the same manner as building method 16.
．． Compound (118) is compound (118-t) or a salt thereof
with compound (II 18-2) or a salt thereof, e.g.
In the presence of a Lewis acid catalyst such as aluminum chloride, the so-called
In order to react according to the Friedel-Crafts reaction,
It can be manufactured more easily. Suitable solvents used in this process include nitrobenzene, etc.
It is. Compound (I 1,-2) or a salt thereof is
Manufactured by subjecting 19l) or its salt to an oxidation reaction
can do. Suitable salts of compounds (11,-1> and (119-2>)
As exemplified for compound (I),
Listed below. The oxidation of this production method can oxidize one -S group to one -SO2 group.
It is carried out in a conventional manner using a commonly used oxidizing agent. such oxidation
Suitable examples of agents include periodic acid, peroxysulfuric acid, etc.
are inorganic acids such as their sodium or potassium salts.
or a salt thereof, such as perbenzoic acid, 3-chloroperbenzoic acid
Acid, performic acid, peracetic acid, chloroperacetic acid, trifluoroperacetic acid
acids, etc. or their sodium or potassium salts, etc.
Organic peracid or its salt, ozone, hydrogen peroxide, urea filtrate
Hydrogen oxide, etc. This reaction occurs with metals from the Vb group or Vtb group in the periodic table.
compounds such as tungstic acid, molypdic acid,
vanadine # etc. or sodium, potassium etc.
alkali metals, such as calcium, magnesium, etc.
Potash earth metals or their salts with ammonium etc.
It is preferable to conduct this in the presence of vanadium pentoxide or vanadium pentoxide. This oxidation is typically performed in water, acetic acid, ethyl acetate, or chloroform.
, dichloromethane, tetrahydrofuran, dioxane,
N. carried out in a solvent such as N-dimethylformamide
However, any solvent that does not adversely affect this reaction can be used.
The reaction can be carried out in any other solvent. There are no particular restrictions on the reaction temperature, but it is usually room temperature or cold.
This reaction occurs upon rejection. Some of the raw material compounds used in the above manufacturing method are new.
Yes, such new raw material compounds can be produced by the following manufacturing method.
It can be manufactured. (Left below) JjL hill or its salt or its salt IL tan (mB-t) (I [ -2) B or its salt (If -3) B or its salt ILL tan (n -1) C ( (I, -2) or a salt thereof (I[ -2) D or a salt thereof (IF -1) E or a reactive derivative thereof or a salt thereof + (It, -2) or its salt L or its salt manufacturing method F (IIF-1) or its reactive derivative or its salt (If, -2) or its reactive derivative or its salt (IIF-3) or its salt iG-t) or its salt (n, -2) or its salt CM-1) H or its salt (n -2) H or its salt nsx (II-1) ■ or its salt ( If -2) ■ or its salt manufacturing method J (ff -1) J (1 -2) J or its salt (II-3) J or its salt form JJL animals (nK-1) (![K-2) or a salt thereof or a salt thereof (IIK-3) or a method for producing a salt thereof L (M,-1) or a reactive derivative thereof or a salt thereof (n,-2) or a reactive derivative thereof or a salt thereof (I[L- 3) or a salt thereof m (If, -1) or a reactive derivative thereof or a salt thereof (II-2) H or a salt thereof manufacturing method N (IfN-1) or a salt thereof (IIN-2) or a salt thereof 1 (I[o-1) or its salt (Ifo-2) or its salt salmon alliance (n, -t) or its salt (n, -2) or its salt made'1 (9 (I [-1) Q or a salt thereof or a method for producing a salt thereof R (nR-1) (IIR-2) or a salt thereof or a salt thereof (IR-3) or a salt thereof [wherein R1, R2, R3, R3a, R4, R4aX1
8 and A each have the same meaning as before, R1 is halo
Gen, amino group, protected amino A group, hydrazino group, aminobenzenesulfonylamino group
, protected aminobenzenesulfonylamino group, lower
Alkanesulfonylamino group, aminophenoxy group, hydrogen
Droxy group or protected hydroxy group, R2 is di(lower alkanesulfonyl) amino group, A lower alkylamino group, amino group, protected amino group
, hydrazino group, protected hydrazino group or lower a
lukanesulfonylamino group, R3tt hydrogen, halogen,
Lower alkanesulfonyl A Amino group, hydroxy group or protected hydroxy group
, 1 RB is a halogen, nitro group, amino group, protected amino group
group, hydrazino group, protected aminobenzene sulfonate group
nylamino group, aminobenzenesulfonylamino group, low
alkanesulfonylamino group, aminophenoxy group,
Hydroxy group or protected hydroxy group, xB is halogen, Aa is hydroxy group or mercapto group, AB is 101
or -S- R1 is a di(lower alkanesulfonyl)amino group, CR1' is an alkanesulfonylamino group, and CAD is -CH2- -CO- -0- -S-
-So-502- -502N(CH3)-
-So2NH- or -C(=NOR")- (wherein,
R" represents hydrogen, lower alkyl group or lower alkenyl group
), R3 is hydrogen, halogen, lower alkanesulfate
Honyl D amino group or protected hydroxy group, R1' is protected
ER1 is a protected aminobenzenesulfonylamino group, RC is hydrogen or a lower alkyl group, FR1 is a protected amino group, FAF is -so2N(cR;> - <wherein, R" is hydrogen
or a lower alkyl group), 1 RG is a halogen, nitro group, amino group, or protected amino group.
group, hydrazino group, protected amine benzene sulfonate group
nylamino group, aminobenzenesulfonylamino group, low
alkanesulfonylamino group, aminophenoxy group,
Hydroxy group or protected hydroxy group, l RH is halogen, amino group, protected amino group, hydroxyl group,
lacino group, aminobenzenesulfonylamino group, protected
aminobenzenesulfonylamino group, lower alkane
Sulfonylamino group, aminophenoxy group, hydroxy
group or protected hydroxy group, 1 R1 is halogen, amino group, protected amine group, hydroxide
Radino group, aminobenzenesulfonylamino group, protected
aminobenzenesulfonylamine group, lower alkane
Sulfonylamino group, aminophenoxy group, hydroxy
group or protected hydroxy group, R1 is halogen, amino group, protected amino J group, hydrazino group, aminobenzenesulfonylamino group
, protected amine benzene sulfonyl amino group, low
alkanesulfonylamino group, aminophenoxy group,
Hydroxy group or protected hydroxy group, M is alkali metal, XJ is halogen, RL is halogen, nitro group, amino group, protected L amino group, hydrazino group, protected aminobenzene
Sulfonylamino group, aminobenzenesulfonylamino
group, lower alkanesulfonylamino group, aminophenol group
hydroxy group, hydroxy group or protected hydroxy group, R2' is a protected amino group, H R2 is a halo (lower) alkanesulfonylamino N group, R1 is an amino group, a protected amino group, a hydrazio group, Aminobenzenesulfonylamino group, protected
Aminobenzenesulfonylamino group or lower alkane
sulfonylamino group, R1 is a protected amino group or protected lower P alkylamino group, R1' is an amine group or lower alkylamino group, PR1 is an acyl group, Q R1' is a lower alkyl group]. Q The method for producing the raw material compound will be explained in detail below. Compound (If-2) or a salt thereof is a compound (ff
A-1) Reacting A or its salt with copper sulfur in pyridine
It can be manufactured more easily. Preferred compounds of compounds (I-11 and (II A-2)
Examples of the salt A include those exemplified for compound (1).
It will be done. The reaction temperature is not particularly limited, but is usually heated or heated.
The reaction takes place under heat. Compound (II-3) or its salt is the compound (U,
-1>B or a salt thereof to react with compound (If, -2)
It can be manufactured by Suitable salts of compounds (II-1) and (IIB-3)
Examples of B include those exemplified for compound (I).
It will be done. Suitable examples of XB include chlorine and bromine. This reaction is usually carried out using alkaline substances such as sodium, potassium, etc.
Potassium metals, such as magnesium, calcium, etc.
Lithium metals, such as potassium hydride, sodium hydride
hydrides of those metals such as potassium carbonate, carbon
hydroxides or carbonates of those metals, such as sodium chloride
, e.g. sodium methoxide, sodium ethoxide
, alkali metal alkoxides such as potassium tertiary ptoxide
acids, such as trimethylamine, triethylamine, etc.
In the presence of bases like trialkylamines, pifrin, etc.
It will be held on. This reaction is usually carried out using water, e.g. methanol, ethanol,
Alcohols such as propanol, tetrahydrofuran, dihydrofuran, etc.
xane, ethyl acetate, dichloromethane, N,N-dimethane
Terformamide, dimedel sulfoxide, diethyl ethyl ether
The reaction is carried out in a commonly used solvent such as
Any other organic solvent that does not
Among them, reactions can be performed. The above lower alkylating agent
If is a liquid, use it as a solvent
You can also. The reaction temperature is not particularly limited, and may be under cooling or heating or
The reaction can be carried out under heating. Compound (If-2) reacts with compound (not) with a base.
It can be manufactured by reacting C. This manufacturing method
This can be done in the same manner as Manufacturing Method 10. Compound (II o-2) or its salt is prepared by
Reacting compound (n, -t) with alkali metal nitrite
, then the diazo compound of the compound (n, -t) obtained is
It can be produced by reduction. Compound (1
Suitable salts of -1) and (If, -2) include those exemplified for compound (I).
It will be done. This manufacturing method can be performed in the same manner as Manufacturing Method 6. The compound (If-3) or its salt is the compound (IE-3)
1) E or its reactive derivative or its salt as a compound (u
Manufactured by reaction with E-2) or its salt
can do. Preferences for compounds (II-2) and (II E-3)
Examples of salts E include those exemplified for compound (1).
It will be done. As a suitable salt of compound (IE-t), the salt of production method 4 is used.
Examples of compounds such as those exemplified for compound (I4-1) include
It will be done. This manufacturing method can be performed in the same manner as Manufacturing Method 4. Atsushi jI (tan compound (II-3) t'tahaso (7) salt ha, compound (
I[F-1)F or a reactive derivative thereof or a salt thereof is converted into a compound (n
Manufactured by reacting with F-2> or its salt
can do. Suitable salts of compounds (If-2> and (I[F-3))
Examples of F include those exemplified for compound (I).
It will be done. As a suitable salt of the compound (I [F-l>), the salt of production method 4 is
Those exemplified for compound (If4-1) are listed.
You can get it. This manufacturing method can be performed in the same manner as Manufacturing Method 4. Salmonmeiyuki tautocompound (If-2) or its salt is a compound (ff, -
1) Produced by subjecting G or its salt to an oxidation reaction
Can be done. Preferred compounds (I-1) and (II,-2)
Examples of the salt G include those exemplified for compound (1).
It will be done. The oxidation of this production method can oxidize one -S group to -S〇1 group.
It is carried out in a conventional manner using a commonly used oxidizing agent. such oxidizing agents
Preferred examples include periodic acid, Bell's xosulfuric acid, etc.
Inorganic peracids such as their sodium or potassium salts
or its salts, such as perbenzoic acid, 3-chlorobenzoic acid
, formic acid, peracetic acid, chloroperacetic acid, triflic acid peracetic acid
etc. or their sodium or potassium salts, etc.
Peroxyacid or its salts, ozone, hydrogen peroxide, urea monoperacid
Hydrogen chloride, etc. This reaction occurs with metals from group Vb or group ■b in the periodic table.
compounds such as tungstic acid, molybdic acid,
Nadic acid etc. or alkaline acids such as sodium, potassium etc.
Potassium metals, such as calcium, magnesium, etc.
salts thereof with lithium metals or ammonium etc., or
It is preferable to perform this in the presence of vanadium pentoxide. This oxidation is typically performed in water, acetic acid, ethyl acetate, or chloroform.
, dichloromethane, tetrahydrofuran, dixane,
N. N-dimethylformamide? carried out in a solvent such as
However, any solvent that does not adversely affect this reaction can be used.
The reaction can be carried out in any other solvent. There are no special restrictions on the reaction temperature, but it is usually room temperature or cooled.
This reaction is shown below. Salmon production 1 Compound (1'2) or its salt is compound (I['
t) or its salt by subjecting it to an oxidation reaction
I can do this. Preferences for compounds (H'1) and (It'2)
Examples of salts include compounds (!) such as those exemplified.
The following can be mentioned. The oxidation of this production method can oxidize one -S group to one -So2 group.
It is carried out in a conventional manner using a commonly used oxidizing agent. such oxidation
Suitable examples of the agent are the same as those described in Manufacturing Method G.
Ru. The compound (1■-2) or its salt is a compound (I [A
1) or produced by subjecting its salt to reduction
Can be done. ? Suitable salts of compounds (IfA-1) and (!II-2>
As exemplified for compound (I),
Listed below. This manufacturing method can be performed in the same manner as Manufacturing Method 5. Production method J Compound (It, -3) or its salt is prepared from compound (It, -3) or its salt.
J-1> or its salt is reacted with compound <ffJ-2)
It can be manufactured by A suitable alkali metal for M in the compound (■■1l) is
Examples include potassium and sodium. Compound < II
,-1) and (II,-2) as suitable salts of
Examples include those exemplified for compound (1).
It will be done. This production method consists of a compound (IFJ-t> and a compound (I, -2).
> by heating in a solvent. [Solvents include ethylene glycol, 2-(2-meth)
(kishetoxy) ethanol, etc. Compound (II K-3) or a salt thereof is a compound (II K-3) or a salt thereof.
II K-1) or its salt with compound (Ifr2) or
is its salt and a Lewis acid catalyst such as aluminum chloride.
According to the so-called Friedel-Crafts reaction,
It can be produced by reacting with Suitable solvents used in this process include nitrobenzene, etc.
It is. Production method L Compound (If, -3) and its salt are produced by compound (I[L
-1) or its reactive derivative at the carboxy group
or its salt to the compound (IfL-2> or amino group)
reacting with its reactive derivative or its salt in
It can be manufactured by Suitable reaction at the carboxy group of the compound (mL-t>
Chemical derivatives include acid halides, acid anhydrides, and activated
Examples include amides and activated esters. reactive derivative
Suitable examples include acid chlorides; acid azides; for example, dia
Rukyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, di-
Substituted phosphorus such as benzyl phosphoric acid and halogenated phosphoric acid
Acids, dialkyl phosphorous acids, sulfites, deosulfates, sulfuric acids, e.g.
Sulfonic acids such as methanesulfonic acid, e.g. acetic acid, butyl
aPyric acid, butyric acid, inbutyric acid, pivalic acid, bentanoic acid
, inventanoic acid, 2-edelbutyric acid, tonochloroacetic acid, etc.
aliphatic carboxylic acids or aromatic carboxylic acids such as benzoic acid.
Mixed acid anhydrides with acids such as luponic acid: symmetrical acid anhydrides;
Imidazole, 4-monosubstituted imidazole, dimethylpyrazo
ole, triazole, tetrazole or! - Hidoaki
Activated amide with C-IH-penzotriazole: also
For example, cyanomethyl ester, methoxymethyl ester
dimethyliminomethyl [(CH3)2-C}i-
] ester, vinyl ester, probargyl ester,
p-nitrophenyl ester, 21-dinitrophenyl
ester, trichlorophenyl ester, pentachloro
Phenyl ester, mesyl phenyl ester, phenyl
Azophenyl ester, phenyl ester, p-ni
Trophenyl thioester, p-cresyl thioester
, carboxymethyl thiol ester, viranyl ester,
Pyridyl ester, biperidyl ester, 8-quinolyl
Activated esters such as deoxyesters, or e.g.
-dimethylhydroxylamine, 1-hydroxy-2-
(IH)-pyridine, N-hydroxysuccinimide,
N-hydroxyphthalimide, 1-hydroxy-IH-
S with N-hydroxy compounds such as penzotriazole
Examples include Tell et al. These reactive derivatives should not be used.
Among them according to the type of compound (IL-1)
You can arbitrarily choose from. Suitable salts of compound (I[11) and its reactive derivatives
For the target compound《! )
Just refer to it. Suitable reactivity in the amino group of the compound (I[L-2>
As a derivative, the compound (I[L-2> and alde
By reaction with carbonyl compounds such as hydrides, ketones, etc.
The base type imino or its energy of Shi / Fu
compound (I[,-2) and bis(trimethane)
delsilyl)acetamide, mono(trimethylsilyl)
Such as acetamide, bis(trimethylsilyl)R, etc.
Silyl derivatives produced by reaction with silyl compounds
; reaction between compound (IL-2) and phosphorus trichloride or phosgene;
Examples include derivatives produced by reaction. Suitable compounds (ItL-2) and reactive derivatives thereof
Regarding salts, those exemplified for target compound (1)
Please refer to . The reaction is usually carried out using water, an alcohol such as methanol or ethanol.
alcohol, acetone, dixane, acetonitrile,
Chloroform, methylene chloride, ethylene chloride, tetrahedron
Dorofuran, ethyl acetate, N. N-dimethylformamide
Although the reaction is carried out in common solvents such as
Any other solvent that does not adversely affect the
Yes#! The reaction can be carried out even in a solvent. These constants
The solvent may be used as a mixture with water. This anti
In the reaction, compound (IIL-1) is used in the free acid form or its free acid form.
When used in the salt form of N. N-dicyclohexy
Lupodiimide; 1 mol of N-cyclohexynole N'
Holinoethynolecanolebodiimide; N-cyclohexyl
-N'-(4-diethylaminocyclohexynole)cal
Bodiimide. N,N'-dietenolopodiimide. N
．． N'-Diisobukuchibinorehoshiimi FANichie
Tinole N'-(3-dimethylaminopropyl)carbo
Simide; N. N'-Carponylbis-N-(2-
Methylimidazole): Pentamethylene ketene-N-cy
Chlohexylimine; diphenylketene-N-cyclohe
xylimine; ethoxyacetylene; 1-alkoxy
1-chloroethylene; trialkyl phosphite; boriline
Ethyl acid; Isopropyl bolyphosphate; Phosphorus oxychloride (
Phosphoryl chloride); Phosphorus trichloride; Phosphoryl chloride; Phosphoryl chloride
Xalyl; e.g. chloroformate ether, chloroformate isobutyl
Low i alkyl haloformate such as lobil: triphenylphosph
2-ethyl-7-hydroxybenzoin;
2-ethyl-5-(m-sulfophenyl)yl salt;
oxazolium hydroxide inner salt;
lorobenzenesulfonyl (oxy)-6-chloro1H-
Penzotriazole iN. N-dimethylformamide and
Dimethyl chloride, phosgene, trichloromethyl chloroformate
, for reactions with phosphorus xychloride, methanesulfonyl chloride, etc.
Therefore, such as the so-called Vilsmeier reagent prepared
It is preferable to carry out the reaction in the presence of a commonly used condensing agent. The reaction also includes alkali metal carbonates, alkali metal bicarbonates
salt, tri(lower)alkylamine, pyridine, N-(lower)
class) alkylmorpholine, N. N-di (lower) alkyl
carried out in the presence of an inorganic or organic base such as an amine, etc.
You can. The reaction temperature is not particularly limited, but is usually
The reaction takes place under cooling or heating. (Left below) Type m compound <If-2) or a salt thereof is a compound (ItM-
1) H or its reactive derivative or salt at the amino group
can be produced by subjecting the amino group to a protection reaction.
can be done. Suitable salts of compound (I-1) and ]'2> include those exemplified for compound (1).
It will be done. This manufacturing method can be performed in the same manner as Manufacturing Method 8. Hair is gone! The compound (If-2> or a salt thereof is the compound (If-2)
N-t) By subjecting N or its salt to sulfonation of the amino group
It can be manufactured. Suitable salts of compounds (If-1) and (II,-2)
As N, the same compounds as those exemplified for compound (I) can be mentioned.
It will be done. This manufacturing method uses a halo (lower) alkanesulfonating agent.
However, it can be carried out in the same manner as Production Method 9. Production method 0 The compound (II.-2> or a salt thereof is the compound (r
i o-t> or its salt as N-chlorosuccinimide
It can be constructed by reacting with. Compound
Preferences for (I[o-t) and (If o-2)
Examples of salts include those exemplified for compound (1).
The following can be mentioned. The compound (II, -2> or a salt thereof is the compound (II, -2)
, -t)1 or a salt thereof with an amino protecting group of R, or a lower alkyl
It can be produced by removing the Ruamino protecting group.
can. Compounds (II, -1) and (I[, -2)
Examples of suitable salts include those exemplified for compound (1).
There are many things that can be mentioned. This manufacturing method is similar to manufacturing method 7.
This can be done by The JJL decay compound (I[o-2) or its salt is the compound
(IQ-1) or a salt thereof to be subjected to an alkylation reaction
It can be manufactured by Preferences for compounds (IfQ-1) and (I[Q-2)
Suitable salts include those exemplified for compound (1).
There are things that can be mentioned. The alkylating agent used in this alkylation reaction is
, for example, di(lower) sulfates such as dimethyl sulfate and diethyl sulfate.
) alkyl, such as diazomethane, diazoethane, etc.
Azo (lower) alkanes, such as methyl iodide, ethyl iodide
lower alkyl halokenides such as 9-toluene
Examples include lower alkyl sulfonates such as methyl sulfonate.
It will be done. Di(lower)alkyl sulfate, lower alkyl halide or
or lower alkyl sulfonate, water, alkyl sulfonate, etc.
Setone, ethanol, ether, dimethylformamide
It is carried out in a solvent such as, but it does not adversely affect the reaction.
The reaction can be carried out in any other solvent as long as it is a clean solvent.
I can. This reaction is carried out using the inorganic base or organic base described in Production Method 1.
It is preferable to perform this in the presence of a base such as The reaction temperature is not particularly limited, usually under cooling or boiling of the solvent.
The reaction takes place under heating to near the point. diazoalkane
Reactions using ether, tetrahydrofuran, and
It is carried out in a solvent such as The reaction temperature is not particularly limited, but usually under cooling or under normal conditions.
The reaction takes place at high temperatures. Production Benefit 1 Compound (II-3) or a salt thereof is a compound (n,-
t) Reaction of R or its salt with compound (IIR-2> or its salt)
It can be manufactured by adapting it. Compound (I
As a suitable salt of I-1) to (If,-3)
Examples of R include those exemplified for compound (1).
It will be done. This manufacturing method can be carried out in the same manner as manufacturing method B. The target compound and its pharmaceutically acceptable salts are novel.
It exerts pharmacological effects, such as osteoarthritis and lower back pain.
symptoms, glenohumeral joint periarthritis, menstrual pain, afebrile otitis media, protrusion
Pain caused by glandular pain, erythema nodosum, herpes, pseudogout, gout-like attack, etc.
pain or inflammatory diseases, autoimmune diseases, e.g. rheumatic
Rheumatism such as arthritis, nephritis, idiopathic thrombocytopenia
Thrombocytopenia such as purpura, secondary thrombocytopenic purpura, etc.
It is used for the treatment and prevention of. In order to demonstrate the usefulness of the target compound (I), the target compound (
1) Analgesic effect, anti-inflammatory effect, anti-rheumatic effect, anti-nephritis
The effects and platelet count increasing effects are explained below. L-breathing 1 Samekanyu Method of acetic acid writhing in mice Ten male DDY mice were used per group. 0.6
Mice were induced to writhe by intraperitoneal injection of % acetic acid.
I met it. Animals were observed from 3 to 13 minutes after the acetic acid injection;
The total number of Isings was recorded. drug 1 hour before acetic acid injection
It was administered orally. The number of writhing times in treated animals was compared with that of control animals.
We compared. Result 1 32
30.45 32
74.56 3
2 36. 48
32 39.311
32 69
．． 112 32
52. 613
32 60.757
32 54. 75
9 32
70. 2 Sho” 1 Kuchumi Ii KM2 For carrageenan-induced hopping edema in rats
Effect method: Ten male Sprague-Dawley rats were used per group.
I used it. After 24 hours of fasting, under the plantar surface of the right hind paw of a rat.
1% 7-carrageenan 0.1- was injected subcutaneously. to animals
The test drug was orally administered 1 hour before carrageenin injection. medicine
Right hind paw volume immediately before carrageenin injection and 3 hours after carrageenin injection
The difference was used as an index of edema. Result 50 27.1 50.0 40.5 59.1 72.7 57.1 52.2 48.0 28.6 42, 0 37, 5 27.1 25.0 62.7 57.1 57.1 39.2 Effect on collagen-induced arthritis in mice: Eight DBA/1 strain male mice were used per group. ■
Type bovine flagen was dissolved in 0.1M acetic acid and Freund's
emulsified in complete adjuvant (CFA). 2 to mouse
Intradermal injection of type I collagen in CFA of 004 at the base of the tail.
The animals were given a primary antigen stimulation. The same effect was applied to mice after 21 days.
It was induced using the same method. Administer the drug once a day from the 10th day of induction.
, administered orally for 4 weeks, and mice were observed weekly for signs of arthritis.
I inspected it. Arthritis index to evaluate the effect of drugs
It was used. The arthritis index is a severity score of 0-3 for each limb.
It is accompanied by joint swelling and erythema (stage 1), which is visible to the eye.
joint damage (stage 2) and detectable joint ankylosis
(3rd stage), but by summing the scores of the limbs
I got it from Result 6 100
21.37 100
40.08
10G 92.69
100
33.812 100
56.913
100 46.219
10G
27.920 100
27. l21
10G 61.822
100 1
6.937 100
19. 151
100 29.0 (2) Method 10 DBA/1 strain male mice were used per group.
■Dissolve type bovine flagen in 0.1M acetic acid,
emulsified in complete adjuvant (CFA). of mouse
Ironically injected type I collagen 125κ in CFA at the base of the tail.
The animals were given a primary antigen stimulation. 21 days later in the same way
Induced. 1! From the day of onset, take the drug orally once a day for 4 weeks.
and mice were observed and examined weekly for signs of arthritis.
．． Arthritis index was used to evaluate the effect of the drug
．． The arthritis index assigns a severity score of 0-3 to each limb, and
is joint swelling and erythema II (stage 1), visible joints
disability (stage 2) and detectable joint ankylosis (stage 3).
floor), which was obtained by summing the scores of the four limbs.
．． Results 32 44 100 93 100 32 32 19 100 37 100 60 100 31 100 30 100 38 100 17 100 47 100 21 100 59 100 46 Chlorine GVH disease (nephritis) ) Effect method for 6 weeks after birth (57BL/6XDBA/2)
F1 and DBA/2 male mice were used. versus
Host-mediated graft disease (GVH) (57BL/6
XDBA/2) DBA/2 tiles on F 17us
Cells were induced by two injections 5 days apart.
Each injection contained 5 x 107 cells. second time
The drug was orally administered once a day for 8 weeks starting 3 days after cell injection.
Ta. 8 weeks after last cell injection to assess renal disease
Proteinuria was measured in the eyes. Urine serum albumin concentration in rabbits
Simple radioimmunization was performed using anti-mouse serum albumin antiserum.
It was quantified by the diffusion method. 10 mice were used per group.
did. The anti-nephritis effect of the compound is expressed by suppression of proteinuria.
Ta. (Left below) Results Naosa 141L Nijiki B ILi: The number of platelets decreased due to mitomycin C.
Method for increasing the effect of test compounds on 6- or 7-week-old DDY male mice
was orally administered once a day for 5 days. 10 animals per group
I used it. 3. Mitomycin C. 2mg/k
Day 08, 2 days after the first administration of the test compound, at a dose of
It was administered intravenously to mice on the second and fourth day. platelet count
Blood was collected from the orbital plexus of the mice 5 days after the final administration of the test compound.
The collected blood was counted. Platelets are collected using an automatic blood analyzer.
and counted. The number of platelets in each group was determined from the blood counts obtained from the group not administered the test compound.
Calculated based on the number of boards. (Left below) Result 50 32
18660 32
16897 32
17498 3
2 139100
32 151101
32 1441
02 32
181103 32
159 For therapeutic administration, the compound of interest
(1) and its pharmaceutically acceptable salts are powders.
, fine granules, granules, tablets, dragees, microcapsules,
Capsules, suppositories, solutions, suspensions, emulsions, syrups
It is used in the form of commonly used pharmaceutical preparations such as
If desired, diluent or e.g. sucrose, lactose
, starch, crystalline cellulose, low 11! converted hydroxy
Disintegration of cellulose, synthetic aluminum silicate, etc.
agents, such as cellulose, methylcellulose, hydroxy
Hydroxypylcellulose, Hydroxypylmethylcellulose
base, voribrovir pyrrolidone, polyvinylpyrrolidone
, gelatin, gum arabic, polyethylene glycol, etc.
binders, colorants and sweeteners, such as magnetic stearate.
A lubricant such as sium may be included in the composition.
．． The dosage of said composition according to this invention is determined by the age and weight of the patient.
Although it varies depending on the conditions etc., it is generally administered orally.
Target compound! 〉or its salts in a daily dosage of 10
0mg to 10g1 preferably 1g to 1g on the same basis
5g is administered at intervals of 5 to 3 times per day. teenager
Typical unit doses are 50mg, 100mg, 200mg
mg, 500 mg, 1 g, etc., but these
are just examples and are not limited to these. This invention will be described in further detail according to the following production examples and examples.
Explain. 1 4-methoxyphenol (5.2g) of N,N-dimethane
Sodium hydride was added to the dichloroformamide (100+nR) solution.
Divide thorium (1.09g) into small portions at 5°C with stirring.
and add. After stirring the mixture at room temperature for 1 hour, 4-chloro
Add nitrobenzene (6 g). Stir the reaction mixture
Heated to 100°C for 1 hour and placed the reaction mixture in ice water with stirring.
pour. The precipitate was collected by filtration, washed with water, and dried in vacuum to give 4-methoxy
-4' ditrophenyl ester (9.65 g, yield 1
03. 3%). Melting point: 106-107"C IR (striped) 1610. 1590.
1505. 1380.1345 am-1 NMR (DMSO-d6.90MHz.ppm) 3
．． 76 (3H.s). 6.70-7.20 (6H
．． m), 8.15 (2H.d.J=9Hz) Mas
s: 246 (M+1). 245(M). m/e
230 4-amino-4'-hydroxydiphenyl ether (4
．． 7g), 4-chloronitrobenzene (3.3g) and
and potassium carbonate (3.5 g). N-dimedelform
The mixture in amide (3511111) was stirred for 140 min.
Heat to °C for 2.5 hours. Stir the reaction mixture under water-cooled sewage water.
Pour into a bowl and stir for 1 hour while cooling with water. Filter the precipitate and wash with water
, vacuum dried, 4-(4-aminophenoxy)-4'
Nitrodiphenyl ether (6.8g, yield 101
．． 5%). Melting point: 134"C IR (striped) 3450. 3320.
161 (1. 1590. 1510.150
5. 1380. 1355 am-1NMR (DM
SO-d6.90MHz. ppa+) 3.57 (2
H. bs), 6.60 (2H.d.J=9Hz).
6.83 (2H.d.J=9Hz>, 6.80(2
H. d. J; 9Hz>. 6.87 (2H.d.J=
9Hz>. 6.90 (2}1, d.J=9}1z).
8.1j) (2H.d.J=9}1z)Mass
: 323(M+1). 322(M). m/e 2
92, 276.201. 108' I41 4-nitro-4'-dimethanesulfonylaminodipheni
ether (8.3 g) in tetrahydrofuran (24
0111) and water (80111).
Under stirring IN* pH 9. with sodium oxide aqueous solution. key to 5
Arrange. Stir the mixture at 40°C for 8 hours. Further IN
The pH of the reaction mixture was adjusted to 9 by adding aqueous sodium hydroxide solution.
Maintain at -9.5. The reaction mixture was concentrated in vacuo and the residue
to pH 2. with 10% hydrochloric acid under water-cooling and stirring. To 0! ll1!1
do. The precipitate is collected by filtration, washed with water, and dried in vacuum to obtain a solid. solid
f bottles with silica gel (silica gel 6G, 70-230
Column using mesh (manufactured by Merck) (250g)
Chromatography with chloroform and acetone
Elute with a mixture of (25:1°). Images containing the target compound
The components were combined and concentrated under reduced pressure to produce 4-nitro-4'-methane.
Sulfonylaminodiphenyl ether (5.8g, yield
78.4%). Melting point = 162°C IR (streak crush) 3250. 1610.
1590. 1510. 1380.1330
cm-1 NMR (DMSO-d6.90MHz.ppm)
3.00 (3H.s). 7.05 (2H.d
, J=9Hz). 7.10 (2H.d.J=9
Hz>. 7.25 (2H.d.J=9Hz),
8.15 (2H.d.J=9Hz). 9.67 (
IH. bs) Mass: 309 (M+1). 308(M).
m/e 229. Manufactured by 185'l Random 1 i-4-nitro-4'-dimethanesulfonylaminodiph
Tetrahydrofuran (750mQ)
) and water (200 mm) in a mixed solvent.
Adjust the pH to 9-10 with 40% sodium hydroxide while stirring.
Ru. Furthermore, pH was adjusted using 1N sodium hydroxide aqueous solution.
The mixture was heated at 40 °C for 11 h while keeping the temperature at 9-10 J%.
! Stir. The reaction mixture was concentrated under reduced pressure, and the residue was stirred with water cooling.
pH 2. with dilute hydrochloric acid. iiy to 0. Filter the precipitate and wash with water
, vacuum dried to give 4-nitro-4'-methane sulfide sulfide.
Nylaminodiphenyl (45.0g, yield 93.8%
) is obtained. Melting point: 160-162°C IR (streak*-4) 3250. 1600,
1580. 1520. 1345, 1160
．． 1145 am-' NMR (DMSO-d6, 60MHz, ppm>3
．． 10 (3H, s). 7.27 (2H, d, J=9
Hz). 7.33 (2H, d, J: 9Hz), 7
．． 60 (2H.d.J=9Hz>, 8.13 (2H
．． d, J: 9Hz>. 9.17 (LH.s) Mass: 325 (M+1). 324(M),
m/e 245 jLl mutual 4-amino-4' ditrodiphenyl ether (3g
) and concentrated hydrochloric acid (1211111) acetic acid (251
1111) and water (50ml+) in a mixed solvent.
To the mixture, add sodium nitrite (1.08 g) in water (511
111) Add the solution dropwise at 5°C while stirring. Mixture at 5℃
After stirring for 1 hour, stannous chloride (8.8 g) was added to the reaction mixture.
Add a solution of concentrated hydrochloric acid (451Q) dropwise at 0°C with stirring.
The mixture is stirred at 0°C for 2 hours and left at room temperature overnight. Shen
The precipitate was collected by filtration, washed with water, and dried under vacuum to obtain 4-hydrazino-4'.
Nitrodiphenyl ether hydrochloride (3.tsg,
yield of 86.5%). Melting point: 181"c IR (Stripe assembly) 265G-2400.
1610. 1590. 1515.1505.
1380. 1350 cwr-'NMR (DMSO
-d6.90MHz. ppm) 7.00 (2H.d
．． J:9Hz). 7.03 (2H.d.J=9Hz)
．． 7.09 (2H.d.J=9Hz). 8.15
(2H.d.J=9Hz). 10.25 (2H,b
s) Mass: 246 (Ma1). 245(M)
．． ale 229. 214 4-nitro-4'-aminodiphenyl (13g)
N. Mixture in N-dimethylaniline (2amn)
4-acetamidobenzenesulfonyl chloride (llg
) is added little by little at 80°C while stirring. a compound
Heat to 90°C for 2 hours while stirring. Stir the reaction mixture in water.
Pour into dilute hydrochloric acid while stirring. Collect the precipitate by filtration, wash with water, and vacuum dry.
, 4-acetamido N-(4-(4-nitrophenyl
deo)phenyl]benzenesulfonamide (19.5g
, yield 93.0%). Melting point: 218-220°C IR (Stripe l-4) 3400. 3200.
1695. 1600. 1595.1535
．． 1345 am' NMR (DMSO-d6.90MHz, ppm) 2
．． 07 (3H.s). 7.17 (2H.d.J:9
Hz). 7.25 (2H.d, J=9Hz). 7
．． 48 (2H.d.J: 9Hz). 7.77 (4H
．． s). 8.17 (2H.d.J=9HZ). 1
0.27 (IH.!l), 10.47 (IH.S
) Mass: 444 (M+1). 443(M).
rrr/e 413. 23g, 245. 199 JLtヱ4-acetamidobenzenesulfinate sodium (8
g) with ethylene glycol (3.0m) and 2-(2-mer).
mixture with ethanol (5 Inll)
Dissolve by heating in an oil bath. Then add 4-ditrito to this solution.
rho-2-methanesulfonylaminochlorobenzene (8.
0g). Continuously stir the mixture to 140-145℃
Heat with stirring for 7 hours, then allow to cool overnight. Water (20a
After adding ll'), the paste-like mass is crushed and filtered.
Wash with water, vacuum dry, 41acetamide 4'12toro
-2'-1methanesulfonylaminodiphenylsulfone (
8.50 g, yield 68.6%). Melting point: 255°C (decomposition) IR (streak 1-l) 3270. 1680.
1615. 1595. 1530.1350
．． 1330 csa-' NMR (CF3COOH.60MHz.ppm) 2
．． 43 (3H.s). 3.36 (3H.s). 7
．． 73 (2H.d.J=8Hz). 7.90 (2
1. d. J=8Hz). 8.10 (2H.d,
J=8Hz). 8.25 (1B.d.J=8H
z). 8.90 (IH.bs). 9.20 (l
H. bs) Ei' I 4-acetamidobenzenesulfinate sodium chloride
Ethylene glycol 75- and 2-(
Mixture with 120 mQ of 2-methoxyethoxy) ethanol
Dissolve compound 100- by heating in an oil bath. Then 3.4
-Add dichlorobenzene (8.2 g) to the solution.
Ru. The mixture was heated to 140°C for 6.5 hours under continuous stirring.
, then let it cool overnight. After adding 200mQ of water, mix
The material was extracted with ethyl acetate, washed with water and extracted with magnesium sulfate.
dry. The organic layer is removed under reduced pressure to obtain a solid. Shape a solid
Ricagel (Wako Gel C-200, 100-200
Column using mesh (manufactured by Wako Pure Chemical Industries) (400g)
Chromatography with ethyl acetate and n-hexane
(1: 1 v/v - 5: 1 v/v
). Combine the fractions containing the target compound and concentrate under reduced pressure.
Reduced to 4-acetamido2'-chloro4'12
Trodiphenylsulfone (6.75g, yield 48.9%
) is obtained. Melting point + 190-192°C IR (streak) 3370. 1705
．． 1595. 1535. 1405.135
5. 1325. 1155 cm-'NMR (DM
SO-d6.90MHz. ppm) 2.11 (3H
．． s). 7.66-7.96 (4H.m), 8
．． 26-8.51 (3H.m). 10.36(
LH. bs) Mass: 355 (Ma1). 354(M)
．． m/e 314. 312. Made in 156'' U
Sodium 4-acetamidobenzenesulfinate
Ethelene glycol 75- and 2-
Mixing with (2-methoxyethoxy)ethanol 1201
Dissolve in 3 ml of the solution by heating in an oil bath. Then 5-chloro
-Add 2-nitroanisole (1.9 g) to the solution.
The mixture was heated to 140-145°C for 4 hours with continuous stirring.
, then let it cool overnight. Water 5I1l! After adding the
Crush the star-like mass, filter it with suction, and wash it with hot water. next
Transfer the solid to a 100ml flask and add ethanol (201ml) to the solid.
11) Reflux for 15 minutes. After cooling, filter the precipitate with suction.
washed with ethanol, followed by ether,
4-acetamido-3'-methoxy-4'12trodif
Phenyl sulfone (0.85 g, yield 24.3%) 1%
．． M point: 190-191"C IR (streak a-IL) 3350. 1705
．． 1607. 1590. 1530.138
G. 1310. 1265 crm-'NMR (D
MSO-d6.60MHz. ppm) 2.10 (3
H. s). 4.07 (3H.s). 7.50-8.
13 (7H.m). 10.4 (IH.bs) type 1
4-nitro-N-methylaniline (1.6g) and
BiN. Add salt to a mixture of N-dimethylaniline (5mQ)
4-acetamidobenzenesulfonyl compound (2.3g)
Divide into small portions and add at 90°C while stirring. 90% of the mixture
℃ for 1.5 hours, then diluted with 6N hydrochloric acid while stirring in water.
Adjust the pH to 1.0. Collect the precipitate by filtration, wash with water, and vacuum dry.
and 4-acetamido N-methyl-N-(4-nitro
phenyl)benzenesulfonamide (2.38 g, yield
68.0%). Melting point = 218°C IR (streak color) 3350. 1675.
1595. 1530, 1375.1355
arm-' NMR (Dl'!50-d6.90MHz.ppa+
>2.06 (3H.s). 3.18 (3H.s)
．． 7.39 (2H.d.J=9Hz). 7.43
<2H. d. J=9Hz). 7.70 (2H.d
．． J=9Hz). 8.10 (2H.d. J=9H
z) 1u4■ 4-nitroaniline (0.14 g) and N. N-dimethyl
4-chloride in a mixture with aniline (0.5111 )
Stir acetamidobenzenesulfonyl (0.23g)
Add in small portions at 90°C. Mixture at 90℃
Stir for 2 hours and adjust to pH 1.0 with 6N hydrochloric acid under water cooling and stirring.
and then stirred for 3.5 hours while cooling. Filter the precipitate and water
Washed and dried in vacuum to obtain 4-acetamido-N-(4-nito
Lophenyl)benzenesulfonamide (0.23g, yield
69.7%). Melting point: 250°C IR (Stripe A-4) 3350. 3150.
1695. 1595. 1525.1380
．． 1345 cm-' NMR (DMSO-d6.9011Hz.ppm)
2.05 (3H.s). - 7.23 (2H.d.J
=9Hz). 7.70 (4H.s), 8.05
(2H.d, J=9Hz). 10.25 (LH.s
). 11.05 (11,s)Mass: 3
36(M+1). 335(M). m/e 30
3. 286 1d 4-a 4-nitro-4'-methanesulfonylaminodiphene
Dichloromethane (6011111) of Nil (6g)
Add 3-chloroperbenzoic acid (5.1 g, purity 80%) to the solution.
) in dichloromethane (501lQ) at 5°C.
Add dropwise while stirring at the same temperature. The mixture at a temperature below 5°C
The reaction mixture was diluted with 10% sodium bicarbonate.
aqueous solution, then washed with water and dried over magnesium sulfate.
do. After filtering off the magnesium sulfate, the filtrate was evaporated under reduced pressure.
Dry to obtain a solid. The solid is silica gel (silica gel 6
0.70-230 mesh, manufactured by Merck & Co.) (200g
) and column chromatography using acetic acid.
Elute with a mixture of chill and benzene (1:3). objectification
The fractions containing the compound were combined and evaporated to dryness under reduced pressure to give 4-
Nitro-4'-methanesulfonylaminodiphenylsulfur
Phoxide (3 g/yield 47.6%) was obtained. Melting point F 1
57-158℃ IR (Streak I-4> 3300. 1660,
1605. 1595. 1525, 1350
．． 1300 cm” NMR (DMSO-da.90MHZ.ppm) 3
．． 06 (3H, s). 7.30 (2H, d.J=9
Hz). 7.70 (2}1.d, J:9Hz).
7.90 (2H, d.J=9}1z), 8.3
0 (2H.d.J=9Hz>. 11.60 (IH
．． s) Mass: 340 (M), tale 32
4. 292. 218 Production Example 13 4-acetamido N-(4-(4-nitrophenylte)
phenyl]benzenesulfonamide}' (8g)
Chloromethane (801Q), Chloroform (8
), ethyl acetate (50111) and N.
Mixture of N-dimedelformamide (301111)
3-chloroperbenzoic acid (3.9 g, purity 80
%) in ethyl acetate (501119) with stirring under water cooling.
Add dropwise at a temperature below 5°C. Heat the mixture to less than 5°C.
Stir at room temperature for 3.5 hours, then collect the precipitate by filtration and add
Washed with chill, vacuum dried, 4-acetamido N-
[4-(4-nitrobenzenesulfonyl)phenyl]ben
(4.2 g, yield 50.7%)
obtain. Melting point: 260-261°C IR (Skul) 3250. 3120,
1680. 1610, 1595, 1535.
1350 cm-' NMR (DMSO-d6.90MHz, ppm) 2
．． 03 (3H.s). 7.20 (2H.d.J=9
Hz). 7.65 (2H, d.J=9Hz).
7.70 (4H, s), 7.90 (2H.d.
J:9Hz>. 8.33 (2H.d, J:9Hz
). 10.27 (LH.a), IQ. 63
(LH.s)Mass: 459(M). +
n/e 443. 413. 245 Production Example 14 4-acetamido-N-[(4-nitrophenyl)
[phenyl]benzenesulfonamide (6 g) in ethyl acetate
Le (12011LQ) and N. N-di, +lJL4ru
Add 3-chloride to the mixture solution with Muamide (50 ml).
Ethyl acetate of loroperbenzoic acid (3.0 g, purity 80%)
(501111!) Add the solution dropwise at 5°C while stirring
．． The mixture is stirred at room temperature for 2.5 hours. Satisfy the reaction mixture.
Pour into an aqueous solution of sodium bicarbonate and add sodium chloride.
saturate. The mixture was extracted with ethyl acetate and washed with water.
Dry with magnesium sulfate. Filter off magnesium sulfate
After that, the filtrate was evaporated to dryness under reduced pressure to obtain 4-acetamide.
N-[4-(4-nitrobenzenesulfonyl)phenyl
] Benzene sulfonamide (6.0 g, yield 93.3%
) is obtained. (Left below) Melting point 265-270℃ (decomposition) IR (sujiaru) 3350, 3150, 1
675. 1610, 1595.1530, 1
380. 1350 cm-'NMR (DMSO-d
6,60MHz,ppm>2.10 (3H,s),
7.37 (2H, d.J=9Hz>. 7.80
(4H.s). 7.93 (2H, d, J=9Hz
). 8.13 (2H.d, J=9Hz), 8
．． 40 (2H, d, J:9}1z). 10.40
(IH.s), 11.20 (IH, bs). M
ass: 476 (Ma1). 475 (
M). m/e 433. 368.341,27
8, 198 Production Example 15 Iron powder (t3.sg, 60m/sh) and ammonium chloride
(1.36g) Tonol-cl'/-le (140mQ) and
4- and water (3511IQ) in a mixed solvent
Methanesulfonylaminonitrobenzene (13.6g)
Add in small portions at 80°C while stirring. mixture
Reflux for 8 hours while stirring. The reaction mixture is filtered with suction and
Concentrate the precepts under reduced pressure. Grind the residue with water. Filter the precipitate,
Wash with water, dry in vacuum, and remove 4-methanesulfonylaminoaniline.
Phosphorus (5.44 g, yield 46.5%) was obtained. Melting point: 85-98°C IR (sujiaru') 3470, 3400
．． 3300, 1630. 1520.138
0. 1315. 1150 cm-'NMR (D
M50-d6.90MHz, ppm>2.76
(3}1.s). 4.95 (2H.bs).
6.46 (2H, d, J=9Hz), 6.86
(2H.d, J=9HZ). 8.80 (IH.s)
Mass: 187 (M+1), 186
(M). m/e 107. 80 made 1u ■ Acetanilide (1.7g), anhydrous aluminum chloride (
10.05g) and nitrobenzene (1rnQ)
Stir the mixture at room temperature for 30 minutes. Mixture at 100℃
and then 3-methyl-4-nitrohenzoi chloride.
(2.75 g). 2. Heat the mixture at 100°C.
Stir for 5 hours and pour into water-cooled stirring water. Filter the precipitate
Wash with water and saturated aqueous sodium bicarbonate solution and vacuum
Dry to give crude 4-acetamido 3'-methyl-4'
1 ditrodiphenyl ketone (4.25 g, yield 113.
3%). Melting point 255°C (decomposition) IR (Stripe i-JL): 3330, 1
6g0. 1650. 1590, 1520,
1350. 1310. 1265. 1150 cm
-'NMR (DMSO-d6.90MHz.ppm>
2.10 (3H.s). 2.56 (3H, s).
7.5! lr8.13 (7H.m), 10.
30 (LH, bs) Mass: 299 (M+
1>. 298(M). m/e 257. 2
56.120 1u4■ In the same manner as in Production Example 27, 4-chloro-2-cyanonite
Starting from benzene and 4-nitrophenol,
3-Cyano 4.4'-dinitrodiphenyl ether (
6.27 g, yield 42.8%) was obtained. Melting point: 120-125°C (decomposition) IR (Skyl): 1610. 159
0, 1520. 1345.1250 am"" NMR (DMSO-d6.90MHz, ppm):
7.30-7.50 (3H, m). 7.63 (I
H. dd. J=3Hz. 6Hz>. 8.00 (I
H, dJ=3Hz>. 8.20-8.40 (4H.
m>Mass: 286 (M+1). 285 (
M), m/e 260. 230 4-amino-3-chlorobenzene (12.73g)
4-A chloride was added to the mixture in vinegar 51 (70 mm) of
Cetamidobenzenesulfonyl (17.32g)
and anhydrous sodium acetate (21 g) at 100°C with stirring.
Add it with . Pour the tear mixture into ice water while stirring. Filter the precipitate,
Wash with water and dry in vacuum to obtain a solid. The solid is hydrated with silica gel (silica gel).
Lycagel 60, 70-230 mesh, manufactured by Merck)
Column chromatography using (450g)
A mixture of dichloromethane and acetone (10:
Elute in step 1). Combine the fractions containing the target compound and reduce the pressure
Concentrate to give 4-acetamido N-(2-kIl-4
-nitrophenyl)henzensulfonamide (2.70
1H, yield 13.8%. Melting point 210-213°C IR (Skul) 3350. 1700.
1595. 1535.1345 cm-' NMR (DMSO-d6, 60MHz.ppm) 2
．． 10 (3H.s). 7.62 (IH, d, J=8
Hz>. 7.80 (4H.bs), 8.20 (
2H. d. J=8Hz), 12.35 (1}
1. s) Mass: 373 (M+3>.3
72 (M+2>.371 (M+1).370 (
M), m/e 327. 262, 206.
198 Production Example 19 4-nitro-2-chloro N-methylaniline (16
．． 0g) and dimethylaniline (aomn).
4-acetamidobenzenesulfonyl chloride (
19.0g) was added in small portions at 90°C with stirring.
I get it. Compound a was heated to 90°C for 3 hours, and heated under water cooling with stirring for 6 hours.
Adjust the pH to 1.0 with N hydrochloric acid. Filter the precipitate, Mizutora, Makoto
Dry in the air to obtain a solid. The solid is silica gel (Wako Gel C)
- 200, 100-200 Menosh, manufactured by Wako Pure Chemical Industries
) (370g) for column chromatography 2 fee.
A mixture of chloroform and methanol (30:1)
> elution 1. Combine the fractions containing the target compound and concentrate under reduced pressure.
4-acetamido-N-(2-chloro-4-ni)
trophenyl)-N-methylbenzenesulfonamide (
2.95g (1 yield 9.5%) was obtained. Melting point 148-150'C IR (Stripe i-J' 3350.171
0, 1685, 1595. 1535135
0. 1315 crth-' NMR (DMSO-d6.60MHz.ppm):
2.12 (3H.s), 3.15 (3H,s).
7.01-7.93 (7H, m). 10.3
7 (IH.bs)Mass: 385 (M+
2). 384 (M+1). 383 (M).
m/a 369, 318, 304 Production Example 20 3.4-dichlorobenzene (5.71) li! acid
N. with potassium (6.0 g). N-dimethylformamide
(4511111'') to the mixture in which 4-nitrothi
Stir phenol (5.0g) and blow in nitrogen gas.
Add a lot. Stir the mixture and blow nitrogen gas into it.9
Heat to 0'C for 2.5 hours. Pour the reaction mixture into ice water.
Then, the solution was adjusted to pH 1 with IN aqueous sodium hydroxide solution under water cooling.
Adjust to 0. Collect the precipitate by filtration, wash with water, vacuum dry, and sulfurize.
2-chloro-4,4'-dinitrodiphenyl (5.5g
) (melting point 144-146°C) is obtained. The above filtrate is
Extract with form, wash with water, and dry with magnesium sulfate.
．． After removing magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure to remove the sulfur
2-chloro-4.4'-dinitrodiphenyl (2.1
g, melting point 143-144°C). IR (Suji A-4) 1600. 1570.
1525, 1510, 1345 cm"" NMR (DMSO-d6.60MHz.ppm),
7.43 (LH.d.C9Hz), 7.73 (2}
1. d, J: 9Hz>, 8.10-8.50 (4
H. m) Mass: 314 (M+3>,
313 (M+2). 312 (Ma1), 311
(M). m/e 280. 217 pear 1 child 4
Fufu sulfide 2-chloro-4.4'-'; Nitrodiphenyl
(5.4g) in dichloromethane (55ml!)
Add 3-chloroperbenzoin # (4.1 g) to dichloromethane.
(70mQ) solution was added dropwise at 5°C under water-cooling and stirring.
．． The mixture was stirred at 5°C for 3 hours under water cooling. reaction mixture
I N*washed with aqueous sodium oxide solution and water, and washed with sulfuric acid
Dry with magnesium. After filtering with magnesium sulfate,
The filtrate was concentrated under reduced pressure to obtain 2-chloro4,4'-dinito.
Rodiphenyl sulfoxide (5.55 g, yield 97, 9
%). Melting point 160-161°C (decomposition) IR (X!;*-4) 1605, 1545
．． 1520. 1370-1345 am-'
NMR (DMSO-d6.60MHz.ppm) 8
．． 07 (3H.d, J=9Hz). 8.20-8.5
0 (4H.a+) Mass: 329 (M+3>. 328
(M+2). 327 (Ma1). 326 (M)
．． vale 310. 280 Production Example 22 4-nitroaniline (5.0 g) in tetrahydrofuran
(50 ml) and water (2SIIQ) mixture
Add 4-nitrobenzoyl chloride (9.0 g) to the solution and cool with water.
The pH was maintained between 8-9 with 10% sodium carbonate under stirring.
It drips slowly. The mixture was stirred under the same conditions for 3 hours and
Concentrate under pressure. Grind the residue with water. Collect the precipitate by filtration and add hydroxide
Wash with aqueous sodium chloride solution, dilute hydrochloric acid and water, and dry under vacuum.
Dry to give 4.4″-dinitropenzanilide (6.6
81 yield 64.2%). Melting point 265-268°C (decomposition) IR (X di@-1): 3375. 16
85. 1615. 1600. 1550.1
340 cm-' NMR (DMSO-d6.60MHz.ppm),
7.92-8.50 (8H.m). 11.00 (L
H. s) Mass: 288 (M+1). 287
(M). m/e 150.120,104 1U η 4-nitrobenzoyl chloride (6.5g), 2-chloro-
4-nitroaniline (6.1 g) and 1.8-diaza
Pisikku [5.4.0 Cor 7-Undecene (6.511
11) (7) Hexamylphosphoramide (65ml1
) Heat the mixture under stirring to 100°C for 6.5 hours.
．． The reaction mixture is poured into ice water under stirring. Collect the precipitate by filtration and
Washing with N aqueous sodium hydroxide solution, 10% hydrochloric acid and water
4.4'-dinitro-2'-chloro
Obtain Lopenzanilide (6.7 g, yield 59.5%)
．． Melting point: 194-198°C IR (Stripe Seal) 3400. 1695
, 1605. 1595, 1515.133
0 am' NMR (DMSO-d6.60MHz.ppm).
8.10-8.50 (7H, m), 10.70 (I
H. s) Mass: 324 (M+2). 323 (
M+1). 322 (M). m/a 286.15
4-nitoCl-4'-aminodiphenyl sulfide <2.5
g〉 in acetonitrile (25d),
Chlorosulfonyl cyanate (1.5g) in acetonitrile
(2111Q) solution was added dropwise at 3°C with water cooling and stirring. Mixed
After stirring the mixture at room temperature for 1.5 hours, the reaction mixture was diluted with water (1.5 hours).
Mixing of 5fflQ) and acetonitrile (1.51Q)
Drip onto things. The mixture was stirred at room temperature for 18 hours and the reaction mixture
Pour the mixture into ice water while stirring. Filter the precipitate, wash with water, and vacuum dry.
After drying, 4-nitro-4'-ureidodiphenyl sulfide (
2-5 g% yield of 86.5% was obtained. Melting point 295
°C (decomposition) IR (Z'; w-ru): 349G. 33
50. 3200. 1675. 1595.1
58G. 1530. 1340 cob-lMass
: 29G (M+1). 289 (M). al
e 272. 246 Salmon Concentrated Plastic M 4-nitro-4'-ureido diphenyl sulfide (2.5g
) dichloromethane (25111), chloroform (
25ffll+) and N. N-dimethylformua
Add 3-chloride to a mixture of Mid (10 ml!) in a mixed solvent.
Roroperbenzoic acid (2.86 g) in dichloromethane (5
0 mA) solution was added dropwise at 5°C while stirring. water mixture
Stir at 5°C for 4 hours while cooling. Sodium hydroxide reaction mixture
Wash with dilute aqueous solution of lium and water, then with magnesium sulfate.
dry. After filtering off magnesium sulfate, reduce the solvent in the filtrate.
Distilled under pressure to give 4-nitro-4'ureido diphenyl.
Obtain sulfoxide (1.0 g, yield 37.9%). Melting point 113-115℃ IR (Sujo 0 3420, 3200.
1715. 1670, 1590, 1535.
1350 cm' NMR (DMSO-d6.60MHz.ppm>6
．． 07 (2H.d.J:8Hz). 7.60-8.5
0 (8H.m), 7.76 (2H.d.J:7H
z), 8, 00 (2H.m>. 8.27 (2H.m>.
d. J=7Hz). 9.17 (IH.s) Mass: 305 (M). m/e 289,
278. Type 240'' Ii 4-amino-4' 1 ditrodiphenyl ketone (0.2
4g) of acetonitrile (10ffll!) and Tet
In a mixture solution with Rahidofuran (11111),
Add chlorosulfonyl socyanate (0.23 g) II'
Drop at 5°C. The reaction mixture was stirred at room temperature for 1.5 hours.
After stirring, water (1 ml) is added to this solution. reaction mixture
Stir at room temperature for 16 hours. Evaporate the reaction mixture to dryness under reduced pressure.
Solidify to obtain a solid. The solid is silica gel (silica gel 60
, 7Q-230 mesh, manufactured by Merck & Co.) (10g
) and column chromatography using dichloromethane.
Elute with a mixture of lomethane and acetone (5:1). eye
The fractions containing the target compound were combined and evaporated to dryness to give 4-urethane.
Ido-4'-bitrodiphenylketone (0.18g, yield
63.2%). IR (streak*-L')
: 3400. 3300. 3200. 1
710. 1690, 1650, 1530. 13
45 cm-'NMR (DMSO-d6.60MHz
．． ppa+): 6.07 (2H.s). 7.6
7 (4H.m). 7.87 (2H.d.J=8Hz
>. 8.37 (2H.d.J=8Hz>.9.0
4 (IH.s) 104ζ 3.4-dichloronitrobenzene (1.92g), 2-
Chloro-4-ditrophenol (1.73g) and charcoal
of potassium acid (2.6 g). N-dimethylformamide
(30111Q) was refluxed for 20 hours under stirring.
do. Concentrate the reaction mixture under reduced pressure and triturate the residue with water.
The precipitate is collected by filtration, washed with water, and dried in vacuum to obtain a solid. Shape a solid
Likage nore (Silikage Jre 60, 70-230 mesh
(manufactured by Merck & Co.) (100g)
chromatographed with ethyl acetate and n-hexane.
Elute with a mixture of (1:10). Contains the target compound
The fractions were combined and concentrated under reduced pressure to give 44′-dinitro-
2.2'-dichlorodiphenyl ester (3.0 g,
yield of 91.5%). Melting point: 147-148℃ IR (Stripe a-L)' 1605, 15
80. 1525, 1350, 1265 a11 NMR (DMSO-d6, 60MHz, ppm):
7.40 <28. d. C9Hz), 8.27 (
2H, dd. J=3Hz. 9Hz), 8.55(2
H, d, J=3Hz) Mass: 332 (M+4). 331 (
M+3). 330 (M+2>.329 (M+1>
．． 32g (M), m/a 298.236.173 Production Example 28 In the same manner as Production Example 27, 4-chloronitrobenzene and
and 3-methyl-4-ditrophenol,
3-Methyl-4,4'-dinitrodiphenyl ether (
4.3 g, yield 49.4%) was obtained. Melting point: 90-100℃ IR (stripe 1-l): 1610, 15
95, 1575. 1515. 1345.1
245 am' NMR (DMSO-d6,60M}Iz.ppm)
: 2.53 (3H.s). 7.03-7.50 (
4H. a+). 8.01-8.47 (3H.m>M
ass: 275 (IDI). 274 (M).
m/e 257. 211 Production Example 29 In the same manner as Production Example 27, 4-chloronitrobenzene and
and 3,5-dimethyl-4-ditrophenol
and 3,5-dimethyl-4,4'-dinitrodipheni
ether (6.5 g, yield 75.2%) was obtained. Melting point F 174-175°C IR (streak): 1610. 15
g5, 1530, 1350, 1310.1
290 am-1 NMR (DMSO-d6,60M}Iz.ppm)
: 2.27 (6H, s). 7.13 (2H, s)
, 7.25 (2H, d.J=9Hz), 8.30
(2H, d.J=9HZ) Mass: 289 (M+1), 288
(M). m/e 271. 258,226.
196 1st bioinhibitor 4-nitro-4'-aminodiphenyl ether (6.9
g) in acetonitrile (7omQ).
Chlorosulfonyl cyanate (4.5g) in acetonitrile
Add the solution (1 omQ) dropwise at 3°C while cooling with water and stirring. Mixed
The mixture is stirred at room temperature for 2.5 hours. Water (
5 mQ) and acetonitrile (5 mN)
and then stir the mixture at room temperature for 16 hours.
Pour the reaction mixture into ice water, collect the precipitate by filtration, wash with water, and dry in vacuum.
Dry to give 4-nitro-4'-ureido diphenyl ether.
(7.1 g, yield 86.7%). Melting point: 185-188℃ IR (Nuji 9-4): 3500, 33
50, 3270. 1680. 1595,1
545. 1350 am' NMR (DMSO-d6, 60MHz, ppm):
5.75 (2}1.bs), 7.00-7.30
(4H.m), 7.57 (2H.d, J:9}1z
). 8.27 (2H.d.J=9Hz), 8.67
<IH,s)Mass: 274 (M+1),
273 (M), m/e 256. 230.184 Production Example 31 In the same manner as Production Example 27, 4-fluoro-2-methelani
Trobenzene and 3-methyl-4-ditrophenol
Starting from 3,3'-dimethyl-4,4'-di
Nitrodiphenyl ether (10.1g, yield 109
%). Melting point; 95-io1℃ IR (1"i-4): 1575, 15
15, 1460. 1345.1255 am-
'NMR (CDCI3+DMSO-d6.90MHz.
ppm): 2.63 (6H.s). 6.90-
7.10 (4H, m). 8.10 (2H.d.J
:9Hz)Mass; 289 (M+1).
28g (M). m/e 271. 258.
4-aminotheophenol (5g), 3.4 dichlorochloride
of trobenzene (8g) and kanium carbonate (llg)
N. Mixed in N-dimethylformamide (501Q)
Stir the mixture for 2 hours at 80"C in a stream of nitrogen gas. Reaction
Pour the mixture into ice water while stirring. Filter the precipitate, wash with water, and vacuum
Dry to give sulfurized 2-chloro-4-nitro-4'-amino
Nodiphenyl (11.7g1 yield 104.4%)
obtain. Melting point: 132-133°C IR (Xdia-1): 3450. 33
50. 1630. 1595. 1565.1
340 c11 NMR (DMSO-d6, 60MHz.ppm):
5.8G (2H.s). 6.67-6.90 (3
H, m), 7.3 (2H.d.J=9Hz>,8.
00-8.33 (2H.m) Mass: 283 (M+3>. 282 (M+
2). 281 (M+1>.280 (M), m/
e 234. 199? 'll■ 4-Amino-2'-chloro-4' ditrodiphenylsulfide
(11.5g) in acetic acid (100+1111) solution
To the solution, acetic anhydride (4.5 g) was added dropwise at 5°C with water cooling and stirring.
Ru. The mixture is stirred at room temperature for 2 hours. Water-cool the reaction mixture
Pour into stirring water. The precipitate was collected by filtration, washed with water, and vacuum dried.
Sulfurized 4-acetamido-2'-chloro-4'
Phenyl (14.2 g, yield 98.5%) is obtained. Melting point + 143-145℃ IR (stainless steel): 3620, 33
00. 1680. 1610. 1595.1
540. 1350 am-' NMR (DMSO-d6.60MHz.ppm):
2.17 (3H, s), 6.83 (IH.d.J
=9Hz). 7.60 (2H.d.J=9Hz).
7.90 (2H.d, J:9Hz). 8.12 (
IH. d. J=9Hz>. 8.33 (IH.d.J:
3Hz). 10.30 (IH.s)Mass
: 325 (M+3). 324 (M+2>. 3
23 (M+1). 322 (M). Im/e 28
0. 234 product' 0 B
Starting from benzene and 4-aminophenol,
4-amino-3'-cyano-4' nitrodiphenyl ether
ter (5.44 g, yield 78.1%) was obtained. NMR (DMSO-d6, 90MHz.ppm):
5.16 (2H.s). 6.50-6.90 (5
H. m), 7.20 (IH, dd, J=3Hz, 6
Hz). 8.30 (11, d, J=9}1z) Ma
ss: 256 (Ma1). 255 (M).
m/e 209. 108 4-amino-4-diphenyl ether (4.6
g) and triethylamine (2g) in dichloromethane
(50ml!) Add anhydrous trifle to the mixture.
Add sulfonic acid (3.1 g) dropwise at 5°C while stirring on ice.
Ru. The mixture was refluxed for 3 hours under stirring, and the reaction mixture was placed in ice water.
Pour into. The mixture was extracted with chloroform,
After washing with dilute hydrochloric acid and water, remove magnesium sulfate.
Dry in a humidifier. After filtering off magnesium sulfate, reduce the filtrate.
Concentrate under pressure and triturate the residue with n-hexane. Filter the precipitate
Washed with n-hexane, dried under vacuum, and washed with 4-tripline.
lomethanesulfonylamino-4'-bitrodifene
Obtain ether (4.2g. Yield 58.0%)
．． Melting point: 60-62℃ IR (streak) + 3290. 16
15. 1595. 1520. 1415.1
215 cm-' NMR (DMSO-d6.90MHz, ppm>:
7.18 (2H.d.J=12Hz>. 7.27
(2H, d.J=12Hz). 7.43 (28,
d, J=12Hz), 8.32 (2}1, d.J=
12Hz) Mass: 363 (M+1>. 36
2 (M), m/e 332. 4-chloro-2-methoxyni
Starting from trobenzene and 4-aminophenol
and 4-amino-3'-methoxy-4' ditrodiphe
Nyl ether (6.94 g, yield 89.0%) was obtained. Melting point: 140-142°C IR (suji carbonate): 3470. 33
g0. 1620. 1575, 1515.1
350 cm-1 NMR (DMSO-d6, 90MHz.ppm)i
3.86 (3H.s), 5.10 (2H,s),
6.40 (IH, dd, J=3Hz, 6Hz)
, 6.60 (2H.d.J=9Hz). 6.75
-6.90 (3H, m), 7.90 (IH, d, J
=9Hz) Mass: 261 (M+1), 260
(M), m/e 229, 213,184 1 uiv ゜ In the same manner as in Production Example 27, 4-full-sized mouth-3-medel
Nitrobenzene and 2-methyl-4-ditrophenol
Starting from 2.2'-dimethyl-4.4'-
Dinitro diphenyl ether (5.74 g/yield 84.
9%). Melting point: 140-142°C IR (streak hole): 1635. 15
B0. 1510. 1350. 1245.1
190 cm-' NMR (DMSO-d6.60MHz.ppm):
2.38 (6H.s), 7.08 (2H.d.J
=9Hz), 8.03-8.43 (4}1.m>M
ass: 289 (M+1). 288 (}i)
, m/e 258. 1ulI manufactured by 195.152 In the same manner as in Production Example 27, 4-chloro-3-diphenyl
Methoxyluponyl nitrobenzene and 4-nitrobenzene
Starting from phenol, 2-diphenylmethoxy power report
Tolu 4.4'-dinitrodiphenyl ether (18.
96 g, yield 103.9%). Melting point: 133-140°C IR (streak seal): 172G. 16
15. 15110. 1520, 1350.
1280. 1255 cm” NMR (DMSO-d6.60MHz.ppm):
7.08-7.63 (14H, m), 8.20-
8.87 (4}1.s) Mass :'a+/e 4
40. 410, 360, 260. 230 made E1
艷I In the same manner as in Production Example 27, 4-chloro-3-cyanonite
Starting from lobenzene and 4-nitrophenol,
2-Cyano 4.4'-dinitrodiphenyl ether
(29.78 g, yield 82.9%) was obtained. Melting point: 135-142℃ IR: 2250, 16
15. 15g5.1275. 1255.120
0 NMR (DMSO-d6, 60MHz.ppm>'
7.38J=9Hz>, 7.58 (2H.d.
J=9Hz>. (3H section) Mass: 286 (M+1>, 285 (t
l>. 168. 139 m/e 26 (L 1530. 1350, ., -1 (2H. d. 8. 27-8. 53 230, (hereinafter blank)
- Starting from 1 mouthful of 4-nitrobenzoyl, 4-a
Cetamide 2'-chloro-4' nitrodiphenyl keto
(19.71 g, yield 87.3%) was obtained. Melting point: 156-183°C IR: 3240. 31
50. 1675. 1595. 1540.1
410. 1315. 1290. 1270 cm”
NMR (DMSO-d6.60MHz.ppm):
2. L3 (31{.s). 7.73-8.57 (
7H. m). 10.45 (lH.bs)Mass
: 32G (M+2). 319 (M+1). 3
1g (M). m/e 278. 276, 120 type' Snake 4l In the same manner as in Production Example 16, 3-methylacetaninide and
Starting from 4-nitrobenzoyl chloride and 4-acetate
toamide 2-methyl-4' ditrodiphenyl keto
(3.8 g, yield 95.0%) was obtained. Melting point: 158-170°C IR (streak meeting) F 3320. 16
70. 1585. 1520. 1400.1
320. 1260 a1l NMR (DMSO-d6, 60MHz.ppm)'
2.13 (3Ls). 2.40 (3H.s),
7.27-7.77 (3}1.m), 7.92 (
2H. d, J=8Hz>. 8.38 (2}1.
d. J=8Hz). 10.25 (IH.bs) Mass: 299 (M+1), 298 (
M). ale 2g1, 256,209.
180 Manufactured by 40 In the same manner as in Production Example 16, 2-methylacetaninide and
and 3-methyl-4-nitrobenzoyl chloride.
and 4-acetamido-4'-ditro-3,3'-di
Medel diphenyl ketone (9.35g 1 yield 89.3%
) is obtained. IR (2-}): 3250, 16
60. 1610. 1580. 152
5,1450. 1350. 1315. 1270,
1185 cm-' NMR (DMSO-d6.60MHz.ppm):
2.35 (3H.s). 2.60 (3H.s).
7.47-7.97 (6H.m). 9.48 <
IH, bs) Mass: 313 (M+1). 3
12 (M). m/e 295. 250.177,
Made by 149, 134

[u40 4-acetamido-41-nitrodiphenylketone (8
．． 0 g) and N-chlorosuccinimide (15.0
2g) of a mixture in dioxane (160111)
Heat to 80°C for 38 hours. Stir the reaction mixture with sewage water (6
Pour into 001〉. Collect the precipitate by filtration, wash with water, and air dry to remove the solid.
obtain. The solid is silica gel (silica gel 60, 70-2
30 mesh, manufactured by Merck & Co., Ltd.) (250g)
eluted with chloroform chromatography and dissolved with chloroform J-rem.
Put out. Combine the fractions containing the target compound and evaporate under reduced pressure.
Dry to give 4-acetamide 3. 5-dichloro-4゛ ditrodiphenylketone (3.
0 g, yield 30.2%). Melting point: 11g-12
0℃ IR (Stripe a-L>: 33g0.17
05. 1650. 1590. 1515,1
355. 1320. 1270 arm-'NMR
(DMSO-d6.90MHz.ppm): 2.2
1 (3}1.s). 7.60-8.43 (6H.b
s) Mass: 354 (Ma1). 353 (M)
．． m/e 318. 285.276, 154 JJL 4-acetamido-4'-nito c7-3+5-dichloro
Diphenyl ketone (12.3g) in concentrated hydrochloric acid (25mQ
) and ethanol (150ml) in a mixed solvent.
The mixture is refluxed under stirring for 5 hours. The reaction mixture was concentrated under reduced pressure.
, dissolve the residue in water. Sodium hydroxide in the solution under water cooling.
Adjust the pH to G with an aqueous solution of sodium chloride. Filter the precipitate, wash with water,
Air dry to obtain a solid. The solid is silica gel (silica gel 6
0, 230-400 mesh, manufactured by Merck & Co.) (400g
) and dichloromethane.
Elute with a mixture of lomethane and acetone (30:1).
The fractions containing the target compound were combined and evaporated to dryness under reduced pressure.
, 4-amino-3,5-dichloro-4'-nitrodife
Nylketone (L56g, yield 79.0%) was obtained. melting point
: 161-163℃ IR (Stripe A-4): 3400. 16
20, 1580. 1515. 1350.1
290. 1260 am-' NMR (DMSO-d, .60M}lz.ppm)
' 6.58 (2H.bs), 7.92 (IH.d
．． J=9Hz). 7.47-8.03 (3H.m)
．． 8.40 (2H.d.J=9Hz) Mass: m/e 294.250,237,
223,181' 0 Toge 2.6-dimethylacetanilide (1.0g) and arsenic salt
Nitrobenzene (21 g) of aluminum chloride (4.91 g)
1! ) The mixture was stirred at room temperature for 0.5 h and then
4-Nitrobenzoyl (1.25 g) was stirred at 80°C.
Add in small portions. Heat the mixture to 100″C under stirring.
Heat for 1.5 hours. Pour the reaction mixture into ice water and bring to room temperature.
Stir for 1 hour. Filter the precipitate under reduced pressure. chamber for precipitation
Grind with ethanol at warm temperature, filter and wash with ethanol.
and dried under vacuum to obtain 4-acetamido-3,5-dimethylene.
Ru-4' ditrodiphenyl ketone (0.9 g, yield 4
7. Obtain 0%》. Melting point: 177-178"C IR (1!'#-4): 3250.16
70. 1845. 1600. 1525,1
347 c11 NMR (DMSO-d6.90MHz.ppm):
2.13 (6H.s). 2.28 (3H.s).
7.73 (IH.d.J=7Hz). 7.93
(2H.d.J=9Hz>.8.25 (IH,d
, J:7Hz), 8.36 (2H.d.J=9H
Z＞Mass: 313 (M+1), 312
(M), m/e 295. 269,253.
223 Production Example 46 2-methylacetanilide (30g) and aluminum chloride
Mixing of nitrobenzene (161g) in nitrobenzene (201)
The mixture was stirred at room temperature for 0.5 h, then 4-nitrobechloride
Divide Nzoil (41g) into small portions at 80℃ with stirring.
Add. Heat the mixture to 100°C for 2 hours while stirring. reaction mixture
Pour the mixture into ice water and stir at room temperature for 1 hour. Precipitate under reduced pressure
The solid was ground with ethanol under stirring at room temperature.
do. The precipitate was collected by filtration, washed with ethanol, dried, and
-acetamido-3-methyl-4'-bitrodiphenyl
Ketone (26.97 g, yield 45.0%) was obtained. Melting point: 125-145℃ IR (2 碕-L> j 3320. 32
20. 1665, 1600. 1525.1
350. 1285. 1265 am-1NMR (
DMSO-d6.60MHz. ppm)' 2.10
(3H.s). 2.37<3H. s). 7.5
0 (LH, b-s). 7.76 (IH.d.J
:7Hz). 7.83-8.07 (3H.m)M
ass: 299 (M+1). 298 (
M). m/e 281, 268.256 1Ulg 4-acetamido-3-methyl-4'-nitrodife
Nylketone (26.9g) +7) Ethanol (5
40ml) and concentrated salt i! iii[(801119
) in a mixed solvent is refluxed under stirring for 6 hours. Concentrate the reaction mixture under reduced pressure and dissolve the residue in water. solution
Adjust the pH to 10 with 2N aqueous sodium hydroxide solution while stirring in water.
Arrange. The precipitate was collected by filtration, washed with water, and dried in vacuum to obtain 4-amino
-3-methyl-4' ditrodiphenyl ketone (22.
75 g, yield 98.4%). IR (sujip-ru): 3470, 34
00, 1645, 1620. 1590,1
515. 1352. 1318 crm-'NMR
(DMSO-d6.60MHz.ppm) ' 2.2
3 (3H.s). 6.67-7.55 (3}1,
m), 7.97 (2H.d, J=8Hz>.8.
43 (2H.d.J=8Hz> Mass: 257 (M+1), 256
(M), m/e 226, 210,195
, 134 Type 1 Mixture of cod anhydrous vinegar # (3.06 g) and Gi # (1.38 g)
Heat the mixture to 50°C for 1 hour while stirring. After cooling, 4-amino
-3-Methyl-4' 1 ditrodiphenyl ketone (2.
56 g) to this mixture. Mixture at room temperature 2.5
Stir for an hour. Pour the reaction mixture into ice water, collect the precipitate by filtration, wash with water, and dry in vacuum.
After drying, 4-formamido-3-methyl-4'
Rhodiphenyl ketone (2.68 g, yield 94.4%
) is obtained. Melting point: 154-170°C (decomposition) IR (striped) i 3400. 32
50. 1670, 1645. 1625,1
520. 1350 a11 NMR (DMSO-d6.90MHz.ppm) i
2.40 (3H.s). 7.50 (2B, b-s
). 7.60 (LH, d.J=7}1z). 7.
96 (2}1.d.J=8Hz>.8.33 (I
H,s). 8.40 (2H.d, J=8Hz). 9
．． 83 (IH.b-s)Mass: 285
(M+1>. 284 (M), m/e 2
67. 254.237. 226 1 tatami mat made of Italian 4-formamide-3-methyl-4'-nitrodipheni
ketone (1.0g), ethyl iodide (1.0g) and
Potassium carbonate (2.0 g) N. N-dimeter formua
The mixture in Mido (190 mQ) was stirred at room temperature for 24 hours.
do. The reaction mixture was poured into water-cooled sewage, and the mixture was diluted with ethyl acetate.
Extract, wash with water, and dry with magnesium sulfate. After filtration, the filtrate is reduced to EEa to obtain a solid. Please read the book
Likage nore (silica gel 60, 70-230 mesh,
Column chromatog using Merck) (500g)
Raffy and elute with chloroform. Fractions containing the target compound were combined, concentrated under reduced pressure, and 4-N
monoethylformamide-3-methyl-4'-nitrodif
Phenyl ketone (1.13 g, yield 102.9%)
Obtained as a solid product. IR (film): 3500, 335
0,3000. 28B0. 1670160
0. 1525, 1350. 1300 am-IN
MR (DMSO-d6, 60MHz.ppm):
0.9-1.2 (3H, m), 2.20 (3H.b
-s). 3.60-3.90 (2H, m). 7.
50-7.83 (3H.m). 7.90-8.20
(LH.m). 8.00 (2H.d..C8Hz)
．． 8.33 (IH.s). 8.43 (28.d
−, J=8Hz> Mass: 313 (M+1>, 312 (M)
．． m/e 287, 274,269, 223 Production example 50 4-N-ethylformamide-3-methyl-4'12
Rhodiphenyl ketone (11.2g) in methanol (
200 ml) and concentrated hydrochloric acid (10 ml) in a decoupling solvent.
The mixture is refluxed under stirring for 3.5 hours. Vacuum the reaction mixture
Concentrate. Add water to the residue and dilute the solution with 2N sodium hydroxide solution under water cooling.
MJ to pHlo in solution! 4 Adjust. Filter the precipitate under reduced pressure.
Then, wash with water and dry in vacuum to obtain a solid. The solid was immersed in silica gel (silica gel 60, 70-230 mesh).
(manufactured by Merck & Co.) (500g)
The mixture of n-hexane and ethyl acetate was subjected to chromatography.
Elute with a mixed solution (10:1). Fractions containing the target compound
Combine and concentrate under reduced pressure to obtain 4-N-ethylamino-3-methane.
Chil-4' nitrodiphenyl ketone (5.31 g, yield
52.1%). Melting point: 143-146℃ IR (Skul) j 3450, 165
0. 160G. 1520. 1350.12
65 a11 NMR (DMSO-d6.60MHz, ppm):
1.27 (3H.t.J=7Hz). 2.27
(3H,s), 3.00-3.50 (2H.II1
). 5.20 (IH.t.J=6Hz), 6.83
-7.07 (2H.m), 7.27 (IH.d, J
=7Hz>. 7.97 (2H.d.J=8Hz>.
8.43 (2H.d.J=8Hz) Mass: 285 (M+1), 284 (M)
, m/e 269, 254,239. 223 1ul■ 4-acetamidobenzyl chloride (llg), 4-bitro
Phenol (9.5g) and potassium carbonate (13g)
g) N. N-dimethylformamide (xoomu
) Heat the mixture under stirring to 100°C for 3 hours. reaction
Pour the mixture into ice water, then stir the mixture under water cooling for 1 hour.
Stir. The precipitate was collected by filtration, washed with water, and dried in vacuum to obtain 4-a-sulfide.
Cetamidobenzyl = 4'nitrophenyl (15.5g
, yield 85.4%). Melting point: 175-180℃ (decomposition) IR (X9*-IL): 3400, 1
665, 1600. 1545.1340 ca
+-' NMR (DMSO-d6.60M}Iz.ppm)
: 2.03 (3H.s), 4.40 (2H.s)
．． 7.36-7.67 (4H.m). 7.6
0 (2H.d, J=8Hz), 8.17 (21
, d. J:8Hz>. 9.90 (IH,s)Ma
ss: M4″' 303, M 302, III
/e 270, 259, 228.148 In the same manner as in Pear IL seat production example 16, 2,5-dimethylacetani
Starting from lido and 4-nitrobenzoyl chloride, 4
-acetamido 3,6-dimethyl-4'1 ditrodif
Obtain enyl ketone (1.15 g/yield 60.1%). Melting point: 18g-191°C IR: 3360. 170
5. 1675. 1655. 1570.15
25. 1350 cm+-' NMR (DMSO-d6.60MHz.ppm):
2.14 (3H, s). 2.20 (3H.s).
2.30 (3H, s). 7.24 (IH.s)
, 7, 63 (IH.s). 7.90 (28,d,
J: 8Hz>, 8.37 (2H, d.J=8Hz>
．． 9.37 (IH.br s)Mass: M
312. m/e 295. 281, 269. 2
65 cover counterfeit 4.4'-diaminodiphenyl ketone (4g) and
Methoxyamine hydrochloride (15 g) in methanol (12
) The mixture was stirred at room temperature for 48 hours. Pour the reaction mixture
Concentrate under pressure and dissolve the residue in water. Dissolve the carbonate under water cooling and stirring
Adjust the state to 8.0 with sodium hydrogen. Filter the precipitate,
Wash with water, dry in vacuum, 1.1-bis(4-aminophenyl)
)-1-methoxyiminomethane (3.5g, yield
rate of 77.0%). Melting point: 200°C (decomposition) IR: 3475. 33
75, 3200. 1620. 1605.1
515, 1380. 1180 cm-1NMR (
DMSO-d6,60M}Iz,ppm>3.80
(3H.s). 5.40 (4H.bs), 6.53
(2H, d, J=9Hz>. 6.60 (2H, d
, J=9Hz), 7.02 (2H.d.J=9Hz
), 7.13 (2H.d, J=9Hz) Mass: 242 (Ma1), 241 (M)
, LII/e 210 Summer Week 1 1,1-bis(4-acetamidof) produced in Example 3
IN of phenyl)-1-methoxyiminomethane (15 g)
Sodium hydroxide aqueous solution (60ml1) and ethyl acetate
The mixture in Nol (10011111) was stirred for 13 min.
It refluxes for a while. The reaction mixture was concentrated under reduced pressure, and the residue was stirred with water cooling.
Grind with sewage. The precipitate was collected by filtration, washed with water, and dried under vacuum.
．． 1-bis(4-aminophenyl)-1-methoxyimide
Obtain nomethane (3.20 g, yield 86.3%). Melting point: 198-202℃ (decomposition) IR (Stripe a-4>' 3450.33
50. 3200. 1620. 1605.1
515. 1380 cob-1 NMR (DMSO-d6.60MHz.ppm) 3
．． 80 (3H, s). 5.40 (4H, bs).
6.54 (2H.d.J=9Hz). 6.59
(2H.d.J=9Hz). 7.00 (2H.
d, J=9Hz). 7.10 (2H.d, J=9
Hz) Mass: 242 (Ma1). 241
(M). m/e 210 mottling 1 1.1-bis(4-acetamidof) produced in Example 4
phenyl)-1-hydroxyiminomethane (4.5 g),
Methyl iodide (18g) and potassium carbonate (7.5g)
N. N-dimethylformamide (501119'
) The mixture was stirred at room temperature for 4 days. Vacuum the reaction mixture
Concentrate and triturate the residue with water. Filter the precipitate, wash with water, and vacuum
Dry to give 1,1-bis(4-acetamidophenyl)
-1-Methoxyiminomethane (5.0 area, yield 106%
) is obtained. Melting point: 260-270°C (decomposition) IR (striped paper) 3250, 1670.
1600. 1520. 1380.1320
cm” NMR (DMSO-d6, 60MHz.ppm> 2
．． 10 (6H.bs). 3.87 (3H.s).
7.17-7.75 (8H.m). 10.07 (2
H. bs) Mass: 326 (M+1>. 325
(M). m/e 310. 294,283.
252 East'0 艷ト4.4'-Diacetamidodiphenylketone (48g
) and hydroxylamine hydrochloride (2.42)
Tanol (some) and water (1011111)
Sodium hydroxide (3.2 g
) is added little by little at room temperature while stirring. chamber the mixture
Stir at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue.
Grind with water. The precipitate was collected by filtration, washed with water, and dried under vacuum.
．． 1-bis(4-acetamidophenyl)-1-hydro
Obtain ximinomethane (5.0 g, yield 100%)
．． Melting point: 210-215°C (decomposition) IR: 3350-3150
．． 1670. 1600, 1570, 152
0. 1320 am' NMR (DMSO-d6.90MHz.ppm) 2
．． 04 (3H.s). 2.08 (3H.s).
7.16 (2H.d.J=9Hz). 7.25
(2H.d, J=9Hz). 7.50 (21,d
．． J=9Hz) Mass: 312 (M+1>,
311 (M). m/e 295. 269,
254 4.4' -diaminobenzyl (6.0g) meta/-
(150mlf) and water (50ffIQ)
Hydroxylamine hydrochloride (13.
0g). The mixture is stirred at room temperature for 24 hours. Mail
After distilling off the tanol, the syrupy residue is diluted with water.
Extract with ethyl acetate. Combine the ethyl acetate layers and add once with water.
Washed, dried with magnesium sulfate, and distilled off the solvent to obtain the crude product.
Obtain crystals (3.65 g). Is the crude crystals ethanol?
Recrystallized from 4,4'-diaminobenzyl monomer.
Obtain shim (thin type) (2.50 g, yield 39.2%)
．． Melting point: 187-191”c IR (x9m-x): 3420.32
00. 1640. 1580. 1550.1
450. 1340. 1260. 1175. 93
0.910. 840 c11 NMR (DMSO-d6, 90MHz, ppm) 5
．． 43 (2H.s). 6.22 (2H.s).
6.56 (2H.d, J=9Hz). 6.60
(2H.d, J=9Hz>. 7.17 (2H.d
, J=9Hz), 7.53 (2H.d.J:9H
z>, 10.7 (IH.s) or 4-amino-4'-chlorodiphenyl in the same manner as in Example 7.
enyl ether (5.1g, yield 9s.4%)
obtain. Melting point 200℃ IR (Xdi-0 F 3350, 161
0. 1590. 1510. 1490.13
80 cab-1 NMR (DMSO-d6.90MHz.ppm) 6
．． 80-7.10 (4H.m). 7.10-7.50
(4H.m). 9.00 (2H.bs)Mass
: 221 (M+1). 220 (M)
．． m/e 219, 185.10g
5g) nomethanol (15ol!1l1) totetrahydride
Mixture solution with Lofuran (150 mQ) was added to 10% buffer.
1 hour at room temperature and atmospheric pressure in the presence of radium-carbon (4 g)
Add hydrogen for a while. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure.
and 4-amino-4'-methoxydiphenyl ether
(7.21 g, yield 86.3%) was obtained. Melting point: 76-77”C IR: 34G0.32
50-3100. 1640. 1590.150
0 cm-' NMR (DMSO-d6.90MHz.ppm) 3
．． 70 (3H.s). 4.83 (2H.bs).
6.50 (2H.d.J: 9Hz). 6.66 (
2H. d. J=9Hz). 6.80 (4H.s)M
ass: 216 (M+1), 215 (M).
m/e 2G0. 172 Higashi' Mutai Mutual a. 4′-diaminodiphenyl ether (5.5g)
and concentrated hydrochloric acid (2811Q) and acetic acid (55111
> and water (55111') in a mixed solvent,
Sodium nitrite (4g) in water (2G+11') solution
is added dropwise at a temperature below 5°C while stirring with water cooling. Mixture at 5℃
Stir for 1 hour. Stannous chloride (3(I)
A solution of g) in concentrated hydrochloric acid (1 oom) was stirred while cooling with ice and salt.
The reaction mixture was stirred for 3 hours and then brought to room temperature.
Leave it warm overnight. Filter the precipitate and wash with water. Bee solid
Transfer to a car, dilute with water, and add dilute sodium hydroxide under water cooling with stirring.
pHlo with mu aqueous solution! l Adjust. Filter the precipitate, wash with water,
Vacuum dry to obtain 4,4'-dihydrazino diphenyl ether.
ter (3.0 g, yield 47.4%) was obtained. Melting point: 175°C IR (Suzir) 3300. 1610.
1590. 1505. 13g0.1255
c1' NMR (DMSO-d6.90MHz.ppm) 3
．． 83 (4H.bs). 6.37 (2H.bs).
6.50-7.0 (8H, m) Mass: 23
1 (M+1), 230 (M). story 21
5. 200,183. 170 Kennoban 4-nitro-4'-methanesulfonylaminodiphenyl
Ether (5.5g) methanol (150m) and
Mixture solution of tetrahydrofuran (150111)
at room temperature in the presence of 10% palladium-carbon (1.5 g)
Hydrogenate at atmospheric pressure for 1 hour. The catalyst is filtered off and then
The filtrate was concentrated under reduced pressure to give 4-amino-4'-methanesulfonate.
Nylamino diphenyl ether (4.9 g, yield 98,
8%). Melting point 140"C IR (Suji Shinichiru) 3400. 3320.
1610. 1505. 1380.1320
cab-' NMR (DMSO-d6.90MHz.ppa+)
2.90 (3H.s). 4.90 (2H.s).
6.50 (2H.d.J=9Hz). 6.67 (
2H. d. J-9Hz). 6.77 (2H.d.J
=9Hz). 7.10 (28.d, J=9Hz).
9.31 (IH.s)Mass: 279 (M
a1). 278 (M). lIIle 213.
199 Higashi Jl 4 4-Amino-4'-methoxydiphene produced in Example 7
A 47% aqueous solution of hydrobromic acid (2.5 g)
The mixture in 251Q) was refluxed for 1 hour while stirring. reaction mixture
After pouring the mixture into water, the solution was poured into 20% carbonated water with water cooling and stirring.
Adjust the pH to 8 with an aqueous sodium solution! It is. Filter the precipitate
, washed with water, dried under vacuum to obtain 4-amino-4'-hydroxy
Diphenyl ether (2.14g, yield 91.6%)
obtain. Melting point: 157-158℃ IR (Suji Chinichiru): 3380, 33
10. 1605. 1575, 1505 am-
l NMR (DM50-d6.90MHz.ppa+)
4.75 (2H.bs), 6.47 (2H, d, J
-9Hz). 6.60 (2H, d.J=9Hz>
, 6.80 (4H.a+). 8.96 (lH
．． s) Mass: 202 (M◆1). 2
01 (M). m/e 172 1u4u 4-hydrazino-4' ditrodiphenyl ether salt
A solution of the acid salt (3.08g) in methanol (100mQ)
At room temperature in the presence of 10% palladium-carbon (1.5 g)
Hydrogenate under atmospheric pressure for 1 hour. Filter off the catalyst. filtrate
Concentrate under reduced pressure, then dilute with water. Sodium hydroxide solution
Adjust the pH to 8 with an aqueous thorium solution under water cooling and stirring. precipitation
It was collected by filtration, washed with water and n-hexane, and dried in vacuum.
, 4-amino-4'-hydrazino diphenyl ether (
1.57 g, yield 66.7%) was obtained. Melting point 170℃ IR (Sujisil> 3450. 3400-
3100. 1640, 1510.1500 a
m-1 NMR (DMSO-d6.90MHz, ppm) 3
．． 28 (IH.bs), 4.70 (4H, bs).
6.40-6.80 (8}1.m)Mass
: m/e 211. 200. 171 days
'12 4-(4-aminophenoxy)-4'
Nylether (6.8g). Ammonium chloride (0.6
g) and iron powder (6 g, 60 mesh) in ethanol (
In a mixed solvent of 60111Q) and water (151Q)
Mixture a with stirring l. Reflux for 5 hours. Filter off insoluble matter,
The filtrate is then concentrated under reduced pressure. Grind the residue in water-cooled sewage
．． The precipitate was collected by filtration, washed with water, and dried in vacuum to give 4-(4-amino
phenoxy)-4'-aminodiphenyl ether (5
．． 42 g, yield 87.8%). Melting point 170℃ IR (nuji*-4)' 3400, 33
20. 3200. 1610. 1495.1
380 am-1 NMR (DMSO-d6.90M}Iz.ppm)
4.83 (4H,s). 6.50 (4H, d.J=
9Hz>, 6.68 (4H.d.J=9Hz).
6, 76 (61, s) Mass: 293 (M+1), 292 (M
). m/e 263. 184, 146, 1
08 Sulfurized 4-nitro-4'-methanesulfonylaminodiphene
(5.5g) of tetrahydrofuran (toomi
) and methanol (100mQ)
in the atmosphere at room temperature in the presence of 10% palladium-carbon (4 g)
Hydrogenate under reduced pressure for 4.5 hours. Filter off the catalyst and remove the filtrate.
Concentrate under reduced pressure to obtain 4-amino-4-methanesulfonyl sulfide.
Obtained ruminodiphenyl (4.7 g, yield 94.2%)
Ru. Melting point tSS℃ IR (Streak I-4) 3400. 1630.
1600, 1320. 1270.1160
cm-' NMR (DMSO-d6.60MHz.ppm) 2
．． 90 (3H, s), 5.50 (2H, bs).
6.80 <2H. d. J=6Hz), 7.06
(4Hs). 7.17 (2H.d.J-6Hz
), 9.67 (IH,s)Mass: 2
95 (M+1>. 294 (M), m/e
4-acetamido N-[4-
(4-aminophenyl) phenyl] benzenesulfate
Honamide (3.5g) in ethanol (70mQ)
and concentrated hydrochloric acid (7 ml) and refluxed the mixture under stirring for 3 hours.
Ru. Concentrate the reaction mixture under reduced pressure and dissolve the residue in water. melt
The solution was adjusted to pH 5.5 with a 10% aqueous sodium hydroxide solution while cooling with water.
0 to 11#! I do. Collect the precipitate by filtration, soak in water, and dry under vacuum.
, 4-amino-N-[4-(4-aminophenyl)
phenyl]benzenesulfonamide (3.0 g, yield 9
5.3%). Melting point 188-190°C (decomposition) IR (streak i4) 3350. 3100.
1620. 1595, 1380.1150
am-1 NMR (DMSO-d6, 90MHz, ppm) 5
．． 35 (2H.bs). 5.88 (2H.bs>,
6.48 (2H, d.J=9Hz). 6.55
(21, d.J-9Hz). 6.90 (4H.bs
), 7.05 (2B, d, J=9Hz). 7.3
2 (2H, d.J=9Hz) Mass: 372
(M+1), 371 (M). m/e 215,
183 Higashi 14 Iron powder (7 g, 60 mesh) and ammonium chloride (
0.7g) of ethanol (7Qml), tetrahydrogen
Closed flan (70mQ) and water (401011
) in a mixed solvent, 4-acetamido N-[
4-(4nitrophenyl)phenyl]benzenesulfate
Honamide (6.6g) was divided into small portions at 80°C with stirring.
and add. Reflux the mixture for 2 hours. Aspirate the reaction mixture.
The filtrate was concentrated under reduced pressure, and then the residue was filtered under water-cooled water.
Smash. The precipitate was collected by filtration, vacuum dried, and 4-acetamide
DoN-[4-(4-aminophenylde)phenyl]
Benzene sulfonamide (3.5 g, yield 56.9%)
obtain. Melting point: 192-195°C IR (Stripe i-IL) 3500. 3400
, 3350. 3200, 1685, 162
5. 1595. 1495. 1330 cm-'N
MR (DMSO-d6.60MHz, ppm) 2.
05 (3H.s). 5.50(2}1.bs).
4.40-6.70 (3H, m). 6.83-7.
35 (61, m>, 7.67 (3H, bs), 1
0.07 (1M, s). 10.27 (IH.s) Mass: 414 (M+1). 413
(M). m/e 290, 215 dog'tatami' iron powder (6g 160 mesh) and ammonium chloride (0.
6g) of ethanol (13Qml), tetrahydride
of Lofuran (40ml) and water (.40mQ)
4-nitro-4'-methanesulfonate was added to the mixture in the mixed solvent.
Nylaminodiphenyl sulfoxide (6 g) was added under stirring.
Disassemble and add little by little at 0°C. Stir the mixture for 4 hours.
Reflux. The reaction mixture was concentrated under reduced pressure, and the residue was washed under water-cooled water.
Smash. Collect the precipitate by filtration, wash with water, and air dry to obtain a solid. solid
Cover the body with silica gel (silica gel 60, 70-230 mesh)
Column chroma using (120 g)
The mixture of chloroform and methanol was
Elute with solution (5:1). Combine the fractions containing the target compound.
and evaporated to dryness to give 4-amino-4'-methanesulfonyl
Ruminodiphenyl sulfoxide (4.3g, yield
Rate 7s. o%). Melting point 198-200℃ IR (Stripe I1-4) 3500. 3400
．． 1635. 1595.1505 cm-' NMR (DMSO-d6.'70MHz.ppm>
3.02 (3H, s), 5.69 (2H, s).
6.56 (2H, d, J=9Hz). 7.23
(2H, d.J=9Hz>. 7.26 (2H.
d. J=9Hz), 7.47 (2H.dJ=9H
z＞． 10.00 (LH.s)Mass:
295 (M+1>. 294 (M),
m/e 215 large 1d 4-acetamido N-[4-
(4-aminobenzenesulfinyl)phenyl]ben
Zensulfonamide (2.5g) in concentrated hydrochloric acid (5111
1) and ethanol (501111) mixed solvent
The medium mixture is refluxed for 3.5 hours while stirring. Reduce reaction mixture
Concentrate under pressure. Dissolve the atrocities in water and carbonate the solution under water-cooling stirring.
Adjust the pH to 7.0 with sodium hydrogen. Filter the precipitate,
Washed with water, dried in vacuum, and 4-amino-N-[4-(4-a
Benzene sulfinyl) phenyl] benzene sulfonyl
Nami}? (1.7 g, yield 75.4%) was obtained. Melting point 198-200℃ IR (Suji Sanichiru) 3450. 3350,
3250. 1630. 1600, 1500
．． 1380. 1320 cm-'NMR (DMS
O-d6.90MHZ. ppm>5.60 (2H.
bs), . 5.90 (2H.bs), 6.46
(2H, d.J=9Hz). 6.53 (2H, d
．． J=9Hz>. 7.10 (2H.d.J=9H
z), 7.18 (2H.d, J=9Hz),
7.35 (4H.d.J=9Hz>. 11.20
(IH.s)Mass: m/e 371.2
48.215 1d4 iron powder (6 g, 60 mesh) and ammonium chloride (0.
6g) ethanol C 60fflQ), tetra
Hydrofuran (60ml!) and water C 4011
112) in a mixed solvent, 4-acetamido
N-[4-(4-nitrobenzenesulfinyl)pheni
]benzenesulfonamide (4.2 g) under stirring.
Add in small portions at ℃. Stir the mixture for 1.5 hours.
Reflux for a while. Filter the reaction mixture with suction. Concentrate the filtrate under reduced pressure.
Shrink and triturate the residue with water. Filter the precipitate, wash with water, and air dry.
to obtain a solid (4.0 g). The solid is silica gel (1
20g, 270-400 mesh, on Menolekne
Column chromatography using
Elute with a mixture of lolomethane and acetone (3:1).
The fractions containing the target compound were combined and condensed under reduced pressure to obtain 4-a
Cetamide N-[4-(4-aminobenzenesulfide)
phenyl]benzenesulfonamide (2.1 g,
A yield of 53.5% was obtained. Melting point: 225-228℃ (decomposition) IR (stripe): 3350, 32
00, 3100. 1675. 1630,1
595, 1500, 1380, 1340, 116
5 am' NMR (DMSO-d6, 60 MHz, ppm) 2
．． 10 (38, s), 5, 73 (2H.bs),
6.63 (2H.d.J:9Hz), 7.20 (
2H. d. J=9Hz>. 7.25 (2H.d.J
=9Hz), 7.33 (2H.d, J=9Hz>,
7.73 (41, bs). 10.33 (IH,
s)Mass: m/e 413. 341, 29
0. 248 large' self M19 4,4'-diamino-3-methoxy constructed in Example 32
dichloromethane of sidiphenylsulfone (1.2g)
(100mQ) and cooform (100II
Add boron tribromide (10g) to a solution of the mixture of
Place the methane (30ffLQ) solution on dry ice.
Add dropwise at -10°C with stirring while cooling with setone. Mixture at room temperature
Stir for 10 hours, then at 40°C for 2 hours. reaction
Concentrate the mixture under reduced pressure. Dilute the residue with water and then mix
Reflux the mixture under stirring for 1 hour. Dilute the reaction mixture with sodium hydroxide
Adjust the pH to 5 with aqueous lium solution! 11, and stirred for 1 hour under water cooling.
do. The precipitate was collected by filtration, washed with water, and dried in vacuum to obtain 4.4'-di
Amino-3-hydroxydiphenylsulfone (0.8
g, yield 70.2%). Melting point: 260°C (decomposition) IR (suji-seiichiru) 3450. 3400.
1630. 1595. 1520.1380
．． 1290 cm' NMR (CF3GOOD.90MHz.ppm)7.
50-7.70 (LH, m). 7.73 (2H.
d. J=8Hz). 7.83 (2H.d.J=8Hz
), 8.15 (2H.d.J=8Hz)Mass
: 265 (M+1). 264 (M). m/a
200. 156 Trap Peeling In the same manner as in Example 21, the 4-1 ace manufactured in Example 29 was
Cetamido-4'-hydrazinodiphenylsulfone (3
Starting from g), 4-amino-4'-hydrazinodif
Obtain phenyl sulfone (1.7 g, yield 57.7%). Melting point 160-165°C IR (Skul) 3200-3450. 1
630. 1595. 1505.1385. 1
285 am' NMR (DMSO-d6.90MHz.ppm) 6
．． 00 (4H, bs), 6.35-6.90 (3
H. m), 7.00-8.00 (5H.m) Mas
s: m/e 248. 4-acetamido-4' (methane) produced in Example 28
Concentrated salt of sulfonylamino) diphenyl sulfone (6 g)
in acid (aomQ) and water (40+1111)
The mixture is refluxed under stirring for 2.5 hours. Water-cool the reaction mixture
Adjust to pHlo with potassium carbonate powder. Filter the precipitate
, washed with water, dried under vacuum to obtain 4-amino-4' (methane sulfate).
honylamino) diphenyl sulfone (4.5 g, yield 8
4.7%). Melting point 190℃ IR (streak a-'L): 3350-340
0. 1635. 1595.1500 cm-' NMR (CF3COOH.60MHz, ppm) 3
．． 55 (3H.s). 7.67-8.00 (6
H. m). 8.06-8.40 (4}1, m)
Mass: 327 (Ma1), 326
(M), m/e 248. 183 Dog 1d Iza 4-acetamido-2'-methanesulfonylamino-4
'1 ditrodiphenyl sulfone (6 g) in methanol (
200ml), tetrahydrofuran (300ml)
) and N,N-dimethylformamide (60
mR ) mixed solvent solution was mixed with 10% palladium-carbon (
Hydrogenate in the presence of 2g) at room temperature and atmospheric pressure for 6 hours.
．． The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 4-acetic acid.
Toamide-4'-amino-2'-methanesulfonylamine
Obtain nodiphenyl sulfone (4.0 g). 4-Aceto
Amido4″-amino2′-methanesulfonylua
Minodiphenylsulfone (4.0 g) and concentrated hydrochloric acid (
40111) in water (aom++).
Reflux for 2 hours. The reaction mixture was diluted with sodium hydroxide under water cooling.
Adjust the temperature to 5.0 with an aqueous solution of aluminum, and stir at 5°C for 4 hours under water cooling.
Stir. The precipitate was collected by filtration, washed with water, and dried in vacuum to obtain a yellow solid.
Ru. The solid is silica gel (silica gel 60, 70-2
30 mesh, manufactured by Merck & Co.) (300g)
Lamb chromatography and chloroform and methane
Elute with a mixture of 10:1 and 10:1. Contains the target compound
The fractions were combined and concentrated under reduced pressure to give 4,4'-diamino
-2'-methanesulfonylaminodiphenylsulfone (
t. tg, yield 22.2%). Melting point 210℃ (decomposition) IR (Stripe 1-L> 3450. 3350-
3200. 1625. 1595, 1380.
1335 cm-' NMR (DMSO-d6.60MHz.ppm) 2
．． 97 (3H, s). 6.33 (4H.bs),
6.60-7.06 <38. m>. 7.40 (L
H. d. J=8Hz). 7.15 (LH.d.J=
8Hz). 7.59 (IH, d, J=8Hz>,
8.03 (IH.d.J: 8Hz), 8.97 (I
H. bs) Mass 2 342 (M+1), 341
(M), m/e 314. 285.263 4-(2-acetoxybenzoyl produced in Example 36)
)hydrazino]-4'-(penzylhydrazino)
amino) diphenyl sulfone (4.8 g)
Dokufuran (751Q) and methanol (12
511111) was mixed with 10% palladium on charcoal.
(7.4 g) at room temperature and atmospheric pressure for 11 hours.
Add element. The catalyst was filtered off and the filtrate was evaporated under reduced pressure.
Dry to obtain a solid. Extract the solid with ethyl acetate and carbonate
Wash with saturated aqueous sodium solution and dry with magnesium sulfate.
Dry. After removing magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure.
4-(2-acetoxybenzoyl)hydrazino]
-4'-aminodiphenylsulfone (2.8g,
Yield 78.0%), melting point 206-208°C IR (Skul) 3400. 3340.
1755. 1680. 1625.1590.
1310. 1285. 1200 cca-1NM
R (DMSO-d6.90MHz.ppm>2.1
6 (3H.s). 6.40-7.97 (15H
). 10.23 (IH.bs) Mass +
426 (M+1>. 425 (M). m/e
383. 289.248
Nilsulfone (6.74 g), ammonium chloride (0.
67 g) and iron powder (6.74 g, 60 mesh)
ethanol (601IQ), tetrahydrofura
(60 mA) and water (30111) in a mixed solvent.
The mixture is refluxed under stirring for 2 hours. Insoluble matter was removed by filtration, and then
Concentrate the filtrate under reduced pressure. Add methanol to the residue and stir
Reflux for 3 minutes. Filter the precipitate and wash with methanol.
, air-dried, 4-acetamido-2'chloro-4'-a
Minodiphenylsulfone (5.06g 1 yield 82.0%
). Melting point 277-288°C IR (suji-kuru) 3480. 3350-
3150. 1685. 1640, 15g5.
1520. 1300 era-'NMR (DMSO
-d6.90MHz. ppm) 2.07 (3H,s
). 6.06-6.76 (3H.m), 7.43
-8.10 (4H, m). 10.25 (IH.bs
) Mass: 326 (M+1>. 325
(M). m/e 324. 284.282,
218. 174? 10''4-acetamido-2'chloro prepared in Example 24
4'-aminodiphenyl sulfone (6.1 g) and
N. of ethylamine (7.6 g) N-dimethylform
Add methanesulfonyl chloride to amide (6G111) solution.
(6.45 g) was added dropwise at 5°C while stirring. mixture
Stir at room temperature for 5 hours. The reaction mixture a is condensed under reduced pressure, and the residue is
Pour into ice water. The precipitate was collected by filtration, washed with water, and air-dried to form a solid (4
-acetamido 2'-chloro 4'-methanesulfony
Ruamino diphenyl sulfone and 4-acetamido 2'
-chloro4' -dimethanesulfonylaminodipheni
A mixture with rusulfone) is obtained. Tetrahydrof solid
Orchid (420fflJ+) and water (70111Q)
) and add it under stirring to the mixture with IN* sodium oxide aqueous solution.
liquid p}19. Adjust to 5. Mixture at 50”C
Stir for an hour. The reaction mixture PTT was further diluted with IN hydroxyl.
9. Add the sodium oxide aqueous solution. 0-9. Maintain at 5
hold. The reaction mixture was concentrated under reduced pressure, and the residue was stirred with water cooling.
pH 2.0 with 0% hydrochloric acid. Adjust to 0. Filter the precipitate and wash with water
, air dry to obtain a solid. The solid is silica gel (Wako Gel C)
-200, 100-200 mesh, manufactured by Wako Pure Chemical Industries) (
180 g) was subjected to force 2 μm chromatography using
, dissolved in a mixture of chloroform and methanol (30:1).
Put out. Combine both parts containing the target compound and concentrate under reduced pressure.
, 4-acetamido-2'-chloro-4'-methanesulfate
Honylaminodiphenylsulfone (3.74g, yield 4
9.4%). Melting point 201-202°C IR (Nugital) 3400-3250.
3100, 1680. 1595.1535.
1408. 1325. 1305,1150 cm-
'NMR (DMSO-d6.90MHz, ppm>2
．． 06 (3H.s). 3.13 (3H.s). 7
．． 16-7.43 (21, m). 8.00-8.2
3 (IH.m). 10.29 (IH.s), 10
．． 40-10.75 (IH.bs) Mass: 404 (M+1). 403 (M)
, rn/e 362. 360.324. 282 Dai 1d 艷中4-acetamido-4'-aminodiphenylsulfone (
13.9g) of tetrahydrofuran (400mQ) and
Stirring the pH of the mixture solution of water and water (140+IL11)
Adjust the pH to 8-9 with saturated aqueous sodium carbonate solution while stirring.
．． Stir carbobenz chloride (36.8 g) into the mixture.
Add dropwise at 5°C while stirring. The reaction mixture was stirred at 5°C for 2.5 hours.
Stir. Further reaction using saturated sodium carbonate aqueous solution
Maintain the pH of the mixture at 8-9. The reaction mixture was diluted with acetic acid.
Extract with chill, wash with water and dry with magnesium sulfate.
After filtering off the magnesium sulfate, the filtrate is evaporated to dryness under reduced pressure.
Ru. Then, the residue was transferred to a 500 mQ flask, and n-hex
Stir for 20 minutes in a saline solution (3QQmQ). absorb the sediment
Filter, wash with n-hexane, air dry, and remove 4-acetate.
Amido-4' pendyl groupponylaminodiphenylene
Lusulfone (19.95 g, yield 98.2%) was obtained.
Ru. Melting point 213-214'C IR (Stripe 1-L) 3330. 3250.
1745, 1650. 1595.1580.
1540. 1410. 1320 crtr-'N
MR (DMSO-d6, 90MHz.ppm) 2.
05 (3H.s>. 5.12 (2H.s), 7
．． 17-7.43 (5H.m). 7.46-7
．． 86 (8H.m>, 10.06-10.33
(2H.m)Mass: 425 (M+1>
,424 (M>.m/e 407,380,316
, 300. 290 4-acetamido-4'penzyl prepared in Example 26
Ponylaminodiphenyl sulfone (19.
9g) and 6N hydrochloric acid (3011Q) (7)
Compound a in tanol (400ml1) was stirred for 5 hours.
Reflux. The reaction mixture was concentrated under reduced pressure and diluted with water, then
Adjust the pH to 8 with a saturated aqueous solution of sodium hydrogen carbonate.
The precipitate was collected by filtration, washed with water, and air-dried to obtain 4-amino-4'-beta.
Ponylaminodiphenylsulfone (1)
7.0 g, yield 94.8%). Melting point 198-2
00℃ IR (Streak 3-L) 3480. 3390.
3330, 1730. 1635, 1595
．． 1535, 1410. 1300, 1230 c
m-' NMR (DMSO-d6, 90MHz.ppm>5
．． 13 (2}1.s). 5.50 (2H.d, J=
9Hz>. 7.18-7.80 (13H.m),
10.10 (11, bs) Mass: 383 (M+1), 382
(M), m/e 33g. 274,248.
210 Tai1 Seiki 4-acetamido-4'-aminodiphenylsulfone
(5g) and triedelamine (3g)
To the mixture in chloroformamide (IOOIIQ), salt
Methanesulfonyl chloride (12.3 g) was added dropwise at 5°C with stirring.
Go down. The reaction mixture was stirred at 5°C for 2 hours and concentrated under reduced pressure.
to obtain an oily residue. Add water to the oily residue and filter the precipitate.
, washed with water, dried in vacuum, and prepared 4-acetamide-4'-(
Methanesulfonylamino) diphenyl sulfone (8.
0 g, yield 94.6%). Melting point 230-235℃ (decomposition) NMR (DMSO-d6.60MHz.ppm) 2
．． 07 (3H.s). 3.63 (3H.s), 7
．． 50-8.07 (8H.m)Mass: 369
(M+1). 368 (M). m/e 326.
290.248 Bundle 1 dl gain 4-acetamido-4'-aminodiphenyl sulpon
(6 g) and concentrated hydrochloric acid (16 mQ) (y) acetic acid (1
26 mN) and water (26 mQ), nitrous acid
Add a solution of sodium (3g) to water (10+nll) to water.
Add dropwise at a temperature below 5°C with cold stirring. Mixture at 5℃
Stir for 1 hour. Add concentrated stannous chloride (20 g) to the mixture.
Hydrochloric acid (1 oomu) was dissolved in salt and ice at O℃ under stirring.
Drip. The reaction mixture was stirred at O″C for 2 hours, then
Leave it at room temperature for 3 days. The reaction mixture was diluted with 40% sodium hydroxide.
Adjust the pH to 12 with an aqueous solution of aluminum, then cool with water for 2 hours.
Stir. The precipitate was collected by filtration, washed with water, and dried to form 4-acetic acid.
toamide-4'-hydrazinodiphenyl sulfone (3
g1 yield of 42.6%). Melting point 260-270℃ IR (streak *-L> 3450. 3350-
3200. 1685. 1630, 1595.
1380. 1290 cm-'NMR (DMSO-
d6.90MHz. ppm>2.06<38,s)
, 4, 15 (LH.s). 5.93
(2H.s)6.75 (2H.d.J=9Hz),
7.65-7.95 (6H, m) Mass:
306 (M+1), 305 (M).
m/e 290, 263,248 Higashi'4-acetamido-3'-methoxy4'
enylsulfone (4.0 g) in tetrahydrofuran (
5011111) and methanol (tooma)
A mixture solution of in the presence of 10% palladium-carbon (1 g)
Next, hydrogenate at room temperature and atmospheric pressure for 2 hours. Filter off catalyst
The filtrate was then evaporated to dryness under reduced pressure to give 4-acetoacetate.
Mido-3'-methoxy4'-aminodiphenylsulfo
(3.5 g, yield 95.9%) was obtained. Melting point; 193-194°C IR (S9-4) 3500. 3350-3
150. 1680, 1615.1590, 1
515. 1380 cm-'NMR (DMSO-d
6.60MHz. ppm) 2.10 <3H. s),
3.85 (38,s). 6.57 (IH.d.J
=8Hz). 7.20 (IH.bs). 7.27
(LH.d.J=8Hz). 7.80 (4H,s
). 10.30 (l}l,s) 4-acetamido-2'chloro- produced in Example 25
4' Monomethanesulfonylaminodiphenylsulfone (
3.6 &) (7) 6N hydrochloric acid (5.4 ml!) and eta
The mixture was refluxed in alcohol (70 ma) for 5.5 h under stirring.
Flow. The reaction mixture was concentrated under reduced pressure, and the residue was poured with carbonated water under water cooling.
Adjust to ptts with basic sodium. Mixture with ethyl acetate
Extract with water, wash with water, and dry with magnesium sulfate. Yes
The organic layer was concentrated under reduced pressure to give 4-amino-2'-chloro-4
1-methanesulfonylaminodiphenylsulfone (2.
1g. Yield: 65.1%). Melting point 84-94℃ IR (single sound) 3520-3100.
1630. 1595, 1505. ! 340,
1310. 1160 cm-'NMR (DMSO-
d6.90MHz, ppm) 3.13 (3H, s)
．． 6.11 (2H.bs). 6.43-6.66
(2H.m), 7.13-7.50 (4H.m).
8.03 <18, d, J=9Hz). 10.20-
10.76 (IH.bs) Mass: 362 (M+1), 361 (M)
．． m/e 282. 278.205, 149 Mixture of stannous chloride (6 g) in concentrated salt # (61+LQ)
4-acetamido 3'-methoxy 4' nitrogen
Phenyl sulfone (2 g) wo JWt4' lower! warm
Divide into small portions and add. The mixture was brought to 100°C under stirring.
Heat for 3 hours. The reaction mixture was diluted with 40% sodium hydroxide under water cooling.
Adjust the pH to 12 using a lium aqueous solution. Filter the precipitate
, washed with water and dried in vacuum to give 4,4'-diamino-3-meth.
Xydiphenyl sulfone (1.40 g, yield 88.1%
) is obtained. Melting point 195°C (decomposition) NMR (CF3COOH, 60MHz, ppm) 4
．． 16 (3H, s). 7.83 (3H, s). 7
．． 67-7.90 (3H, m). 7.73 (2H
．． d, J-8Hz>. 8.27 (2H.d.J=8
Hz) Mass: 279 (M+1). 278
(M). m/e 263, 213.171 4-amino-4'-benzyl compound prepared in Example 27
Cycarbonylaminodiphenyl sulfone (ta.tg)
and acetic acid (HomQ) of concentrated hydrochloric acid (5511IQ)
and water (220 ml) in a mixed solvent,
Sodium nitrate (3.08g) water C 35ml'
) The solution was added dropwise at 5°C with stirring. The mixture was then heated to 5°C.
Stir for 0.5 hour. Add stannous chloride (
25. 12g) of concentrated hydrochloric acid <220+1Q) solution
Add dropwise at 0°C while stirring. The mixture was stirred at 0°C for 2 hours.
, leave at room temperature overnight. The precipitate was collected by filtration, washed with water, and air-dried.
4-hydrazino-41-pendinoreponino
Rareamodiphenylsulfone hydrochloride (14.5g,
yield of 90.6%). Melting point l60℃ (decomposition) IR (streak!-4> 3400-3250.
1735, 1720, 1705.1595.
1530. 1305. 1220 am-1NMR
(DMSO-d6, 90MHz, ppm) 5.17
(28, s). 5.30-5.93 (3}1.m>
．． 7.13-8.13 (13H, m). 10.2
3 (18, bs) Mass: m/e 364, 355, 323,
293, 258 4-acetamido N-[4-(
4-Aminobenzenesulfonyl)phenyl]benzene
Ruphonamide (5.2g) in concentrated hydrochloric acid (1smu)
and water (toomQ) under stirring for 3.5 hours.
Flow. Concentrate the reaction mixture under reduced pressure. Dissolve the residue in water
Then, the solution was adjusted to pH 7 with sodium hydrogen carbonate under stirring under water cooling.
．． Adjust to 0. The precipitate was collected by filtration, washed with water, and dried under vacuum.
-Amino-N-[4-(4-aminebenzenesulfonyl)
) phenyl]benzenesulfonamide (3.5 g, yield
74.3%). Melting point 235°C (decomposition) IR (streak 9-l) 3500. 3370.
1630. 1595. 1500.1380
．． 1300 cta-' NMR (DMSO-d6.90MHz.ppm)
5.50 (4H.bs). 6.51 (2H.
d. J=9Hz). 6.57 (2H.d.J=9}
1z). 7.13 (2H.d.J=9Hz). 7.
40 (2H.d.J=9Hz). 7.43 (2H,
d. J=9Hz). 7.61 (2H.d.J=9H
z＞． 10.40 (LH.s) 0 out of 4-acetamido N-[4-(4-nitrobenzene)
sulfonyl)phenyl]benzenesulfonamide (6&)
of tetrahydrofuran (200 mEI), methanol
(200mQ) and N,N-dimethylformamide
(50 mQ) of 10% palladium
- Water in the presence of carbon (3 g) at room temperature and atmospheric pressure for 1.5 hours.
Add element. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure.
, 4-acetamido N-(4-(4-aminobenzene
sulfonyl)phenylcobenzene sulfonamide (5.
2 g, yield 92.5%). Melting point 288-289°C IR (streak 1-l) 3400. 3350.
3270, 1675. 1630.1595
, 1535. 1380. 1300 cm-'NM
R (DMSO-d6, 90MHz.ppm) 2.0
7 (3H.s). 5.25 (2H.bs), 6
．． 62 (2H.d, J=9Hz). 7.23
(2H, d, J=9Hz), 7.50 (2H.d
．． J:9Hz). 7.73 (2H, d, J=2Hz
). 7.78 (4H.s). 10.27 (IH
．． s), 10.77 (IH.s) Mass: 445 (M). m/e 402
．． 370.289.248 East 101 song N,N-dimethylformamide (0.2g) and salt
Stir the mixture with phosphorus chloride (0.43 g) at 5°C for 30 minutes.
do. Add dry tetrahydrofuran (5.6 ntQ) to this
Add. Add acetylsalicylic acid (0.46g) to this.
The mixture was stirred at 5°C for 1 hour to activate the water.
Produce an acid solution. On the other hand, 4 produced in Example 33
-hydrazino-4' -benzyloxycanoleboninole
Aminodiphenylene hydrochloride (L.Og)
and tetrahydrofuran (201) and water (20m
l! ) under stirring at 5°C with saturated sodium carbonate.
Adjust the pH to 7-8 with an aqueous solution. A mixture was prepared above.
Add dropwise to the activated acid solution at 5°C while stirring. reaction mixture
Stir at 5°C for 2 hours. Plus saturated sodium carbonate
Maintain the pH of the reaction mixture at 7-8 with an aqueous solution. reaction mixture
was extracted with ethyl acetate and washed with saturated aqueous sodium carbonate solution.
Clean and dry with magnesium sulfate. magnesium sulfate
After filtering off, the filtrate was concentrated under reduced pressure to obtain 4-[(2-acetoxychloride).
cybenzoyl) hydrazinocor4'-(penzil saiki)
cycarbonylamino)diphenylsulfone (1.02g
, yield 79.1%). IR (Stripe 9-L)
3330. 3200. 1740. 170
5. 1655.1595. 1550. 1305
cm-lNMR (DMSO-d6.90MHz.p
pm) 2.16 (3H, s). 5.14 (2H.
s), 7.03-7.97 (18H.m). 10
．． 07-10.30 (2H) Mass: m/e 445, 384, 331.
274 衷 1 tatami 艷 V 4-acetamido N-(4-i) produced in Example 39
(bropylaminophenyl)-N-methylbenzenesul
of honamide (3g) and concentrated hydrochloric acid (3fflll)
Mixture in ethanol (40+1111) under stirring 2
Reflux for a time. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with concentrated hydrochloric acid.
under water cooling with an aqueous ammonium chloride solution}19. Adjust to 0
Ru. The precipitate was collected by filtration, washed with water, and dried under vacuum to obtain 4-amino N.
-(4-isopropylaminophenyl)-N-methylbase
Zenesulfonamide (1.50g 1 yield 84.9%)
obtain. Melting point 201-202°C (decomposition) IR (streak 9-l) 3500. 3400,
1625, 1615. 1600.1515
．． 1325 am-1 NMR (DMSO-d6, 90MHz, ppm) 1
．． 06 (6}1, d.J=6Hz>.2.90 (3
H,s). 3.43 (1H, q.J: 6Hz),
5.35<LH. d, J=9Hz). 5.90
(2H.s), 6.35 (28,d, J=9H
z＞． 6.50 (2H.d.J: 9Hz),
6.65 (2H.d, J=9Hz). 7.05
(2H.d.J=9Hz>Mass: 320
(Ma1). 319 (M). m/e 163
East 1u student 1 4-acetamido N-methyl-N-(4-nitrophe
methanol of benzenesulfonamide F (5.5 g)
(200IflQ) and tetrahydrofuran (z
oomQ) and 10% palladium-carbon.
Hydrogenate in the presence of hydrogen at room temperature and atmospheric pressure for 2 hours. catalyst
was removed by filtration, and the solution was concentrated under reduced pressure to obtain 4-acetamide.
Do-N-(4-aminophenyl)-N-methylbenzene
Obtain sulfonamide (5.0 g, yield 99.5%). Melting point 150-152℃ IR (Sujiwor) 3550. 3400-
3200. 1690, 1645.1615.
1590, 1540. 1515. 137
0.1340. 1320 crn-'
Tetrahydryl)benzenesulfonamide F (4.5g)
Dokufuran (roo-), methanol (100m
Q) and acetone (toomc) mixture solution
, at room temperature in the presence of 10% palladium-carbon (2 g)
Hydrogenate at atmospheric pressure for 2 hours. Filter off the catalyst and then
The filtrate was concentrated under reduced pressure to give 4-acetamido-N-(4-
Improvylaminophenyl)-N-methylbenzene
Ruhonami F (4.5 g, yield 96.7%) is obtained. Melting point 175℃ IR (Sujiru> 3350. 1695.
1680. 1610. 1595.1515
．． 1380 cm-' NMR (CF3COOH.60MHz, ppm) 1
．． 50 (68, d.J: 6Hz). 2.40 (38
, s), 3.30 (38, s). 4.00 (I
H. q. J=6Hz), 7.35-7.57 (4H
．． m). 7.60-7.90 (4H.m), 8.7
0 (IH.m). 9.00 (LH,s) Mas
s: 361 (M) Rice 4-acetamido N-methyl produced in Example 42
N-(4-methanesulfonylaminophenyl)benzene
Sulfonamide (4.96 g) and 6N salt M (10 mu)
) in ethanol (100IfI2) stirred mixture
Reflux for 3.5 hours. The reaction mixture was concentrated under reduced pressure and diluted with water.
Dilute and then adjust to pH 9 with IN disodium hydroxide solution.
．． Adjust to 0. The mixture was extracted with ethyl acetate and washed with water.
and dry with magnesium sulfate. magnesium sulfate
After filtration, the filtrate was evaporated to dryness under reduced pressure to give 4-amino-N
-Methyl-N-(4-methanesulfonylaminophenyl
) Benzene sulfonamide (3.35 g, yield 75.5
%〉. Melting point 150-152°C IR (streak l-L) 3500. 3400-
3300. 1635. 1595.1505.
1340-1305. 1225. 1150 cm-
'MNR (DMSO-d6.90MHz, ppm>
”2.98 (3H,s). 3.00 (3H.s).
5.98 (2H, bs), 6.53 (
2H, d. J=9Hz). 6.90-7.20 (6
H. m) Mass: 356 (M+1>, 35
5 (M). m/e 275,199,156 Large 1 tatami mat 1 4-acetamido N-methyl-N-(4-aminophene
) benzenesulfonamide <5.2 g) and tri
N,N-dimethylforma of ethylamine (6.6g)
Methane sulfonate chloride was added to the mixture in
Niru (5.6 g) was added dropwise at 5°C with stirring. chamber the mixture
Stir at room temperature for 2 hours, concentrate under reduced pressure, and grind the residue under water-cooled water.
do. The precipitate was collected by filtration, washed with water, and air-dried to form 4-acetamide.
-N-methyl-N-(4-dimethanesulfonylaminof)
enyl)benzenesulfonamide (10.58g,
yield of 136.6%). Melting point 161-164℃ IR (streak) 3650-3100.
1695. 16g0. 1595.1540,
t505. 1350. 1250.1160 cm-
1 NMR (DMSO-d6, 90MHz.ppm> 2
．． 10 (3H.s). 3.15 (3H.s).
3.67 (3H.s). 5.34 (3H.s
). 6.90-7.84 (8H.m), 10
．． 3 (1N, bs) Mass: 476 (M
a1), 475(M), m/e 297,
296,200, 199, 198 4-acetamido N-methyl produced in Example 4l
N-(4-dimethanesulfonylaminophenyl)benze
sulfonamide (7.74 g) in tetrahydrofuran
(32011111) and water (50ffil!)
The mixture solution with 1N sodium hydroxide aqueous solution with stirring
pH10. 4-10. Adjust to 6. thirsty substance
Stir at 50°C for 6 hours. The pH of the reaction mixture is further adjusted to
10.4-10,6 using 1N sodium hydroxide
maintain. The reaction mixture was concentrated under reduced pressure, and the residue was stirred for 10 min.
% hydrochloric acid to pH 2.0. Mixture with ethyl acetate
Extract, wash with water, and dry with magnesium sulfate. sulfuric acid
After removing the magnesium by filtration, the filtrate was evaporated to dryness under reduced pressure.
-acetamide N-methyl-N-(4-methanesulfonate)
nylaminophenyl)benzenesulfonamide (5.0
6 g, yield 78.2%). Melting point 197-198℃ IR (Stripe a-1> 3350-3150.
1680. 1665. 1610.1595,
1550. 1405, 1330.1270 am' NMR (DMSO-d6.90MHz.ppm) 2
．． 12 (3H.s), 3.03 (31,s), 3
．． 10 (3H, s), 7.08 (4H, dd, J
=3Hz, 9Hz>, ? ．． 43 (2}1, d, J;
9Hz). 7.73 (2H.d, J=9Hz),
9.76 (LH.bs). 10.30 (LH.b
s) Mass: 39B (M+1>, 397 (
M), m/e 368, 254,199 4-acetamido N-(4-nitrophenyl)benze
methanol (50ml1)
) and acetone ( somQ) mixture solution at 10
% palladium-in the presence of carbon (2 g) at room temperature and atmospheric pressure.
Add hydrogen for 1 hour. The decomposition medium is filtered off and the filtrate is
Concentrate under reduced pressure to obtain 4-acetami}'-N-(4-iso
Propylaminophenyl)benzenesulfonamide (2
．． 13 g, yield 102.9%). Melting point 210-213℃ tR (Stripe A-4) 3350. 3250.
1670, 1610, 1595.1515
．． 1380. 1160 am-1MNR (DMS
O-d6, 90MHz. ppm> 1.06 (6H,
d, J=9Hz). 2.05 (3H, s). 3.1
0-3.50 (18,m). 5.20 (LH.bs
). 6.33 (2H, d.J; 9Hz). 6.6
6 (2H.dJ=9HZ). 7.48 (2H,d
, J=9Hz), 7.63 (21d, J=9Hz)
, 9, 23 (1}1,s). 10.16 (IH
,s)Mass: 348 (M+1). 347
(M>. m/e 149, 107 1d 4-methanesulfonylaminoaniline (5.4 g) N
, N-dimethylaniline (13111) in the mixture.
, 4-acetamidobenzenesulfonyl chloride (6.3g
) is added little by little at 100°C while stirring. blend
Heat to 100℃ for 4 hours while stirring. The reaction mixture was heated to 6N
Pour into hydrochloric acid while cooling with water and stirring. Filter the precipitate, wash with water, and vacuum dry.
After drying, 4-acetamido N-(4-methanesulfonyl)
lyaminophenyl)benzenesulfonamide (8.0
8 g, yield 78.4%). Melting point: 223-235°C IR (streak, -x) 3200. 1680.
1595. 1530. 1380.1330
．． 1155 cm-' NMR (DMSO-d6.90MHz.ppm>
2.06 (3H, s). 2.90(3H,s
), 7.00 (4H.s), 7.63 <4H.s.
s). 9.46(tH,s). 9.96 (I
H,s). 10.23 <1}1. s)Mass
: 384 (M+1), 383 (M). ml
e 304, 240,198 4-acetamido N- (4-methane) produced in Example 44
Tansulfonylaminophenyl)benzenesulfonamide
(8g) of concentrated hydrochloric acid (12mQ) and ethanol
(l6am) in a mixed solvent was refluxed for 4 hours with stirring.
Flow. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water.
Then, the solution was brought to pH 7 with sodium bicarbonate under water cooling and stirring.
adjust. The precipitate was collected by filtration, washed with water, and dried in vacuum to obtain 4-amino
No N-(4-methanesulfonylaminophenyl)ben
Zensulfonamide (6.53g, yield 9l.7%)
obtain. Melting point: 190-194℃ Engineering R (Shr) 3500. 3400,
3260, 1635, 1600.1380.
1315 cm” NMR (DMSO-d6, 90MHz, ppm) 2
．． 86 (3H.s), 5.86 (21,s).
6.50 (2H.d.J=9Hz>.7.00
(4H, s), 7.31 (2H, d, J=9Hz>.
9.40 (LH.s). 9.63 (LH.s
) Mass: 342 (M+1). 341 (
M), m/e 262. 185.157 Tai1sei 40 4-acetamido N-(4-i) produced in Example 43
sopropylaminophenyl)benzenesulfonamide (
5.6g) of concentrated hydrochloric acid (g, 4mQ) and ethanol (1
10+1111) in a mixed solvent under stirring.
Reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water.
Dissolve. The solution was cooled with water and stirred with sodium hydrogen carbonate to pH
7. Adjust to 0. Collect the precipitate by filtration, dry it in a vacuum, and
, 4-amino-N-(4-isobrobylaminophenyl
) Benzene sulfonamide (4.3 g, yield 87.6%
) is obtained. Melting point: 160-166℃ IR (Stripe s-J 3500. 3400.
1630. 1600, 1525, 1380.
1320. 1155 cm-'NMR (DMSO
-d6,90MHz,ppm) 1.07 (6H,d
, J=6Hz), 3.15-3.50 (IH.m).
5.66 (28, bs), 6.33 (2H.
d. J=9Hz). 6.46 (2H.d.J=9
Hz), 6.70<21,d, J=9Hz),
7.20 (2}1.d, J=9Hz>, 8.93
(1}1.s) Mass: 305 (M), m/e 20
2, 159, 149, 107 4. Acetic acid (5 g) of 4'-diaminodiphenylmethane (
50-) Add acetic anhydride (6 g) to the solution at 40'C while stirring.
Drop at a temperature below Stir the mixture at room temperature for 1 hour.
．． The precipitate was collected by filtration, washed with water, and dried in vacuum to obtain 4.4'-diacetate.
Toamidiphenylmethane (6.9g, yield 99.0%
) is obtained. Melting point 225℃ IR (streak m-4) 3200, 1650,
1595. 1520 cm-'NMR (D
MSO-d6, 60MHz. ppm) 2.03 (6
H. s). 3.82 (2H.s). 7.15 (4
H. d, J=6Hz>, 7.53 (4H.d, J=
6Hz). 9,87 (2H,s) Large 1 tatami chromium dioxide (35g) acetic acid (B,5mQ) and water
(1.8 ml) of 4,4'-diacetamide
Add dodiphenylmethane (1 g) little by little at 80°C with stirring.
Divide and add. Heat mixture a to 90°C for 1 hour while stirring.
Ru. Pour the reaction mixture into water-cooled, stirred water. Filter the precipitate,
Wash with water, dry in vacuum, and remove 4,4'-diacetamido diphene.
Nylketone (0.4 g, yield 38%) is obtained. Melting point 233-234"C IR (streak 9-4) 3550. 3350.
1690, 1635. 1600.1530
am' NMR (DMSO-d6.60MHz, ppm) 2
．． 12 (6M, s). 7.77(8}1.s).
10.30 (2H,s)Mass: 297
(M+1). 296 (M), m/e 254.
212.120 uM 4.4'-diacetamidodiphenylketone (4g)
Add hydrogenated fluoride to methanol (200ffLI+) solution.
Sodium urethane (1.8 g) was stirred at a temperature below 30°C.
Add with . The mixture is stirred at room temperature for 2 hours. reaction mixture
was compressed, and IA/iI was mixed with 10% hydrochloric acid under water-cooling and stirring.
pH2. Adjust to 0. Filter the precipitate, wash with water, and vacuum dry.
and 4,4'-diacetamidobenzohydrol (4
．． 0 g, yield 99.3%). Melting point 185°C IR (streak 3-l) 3150-3250.
1665. 1660. 1610 am-1N
MR (DMSO-d6.60MHz.ppm>2.
00 <6H, s), 5.30 (LH, s). 7.
30 (4H.d, J=8Hz). 7.77 (4H
．． d. J:81{z). 9.90 (2H.s)Ma
ss: M298. m/e 281. 239X
4.4゛-diaminosyphenyl ketone (5.1g> and O
-Allylhydroxylamine hydrochloride (13.3g)
methanol (150 ml!) and tetrahydride
A mixture of oral furan (sOmN) in a mixed solvent at room temperature.
Stir for 50 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added with water.
Add. The solution was adjusted to pH 9 with IN* sodium oxide aqueous solution.
．． 0 and stir for 1 hour under water cooling. Filter the precipitate,
Wash with water and dry to obtain a solid. The solid is treated with silica gel.
Kagenore 60, 70-230 mesh, manufactured by Merck) (
200g) was subjected to column chromatography using
, dissolved in a mixture of chloroform and methanol (20:1).
Put out. Combine both parts containing the target compound and concentrate under reduced pressure.
Obtain a solid (6.4 g). The solid was dissolved in ethyl acetate and n-hexane.
Recrystallized from dry solution (5:1) with 4.4'-di
Aminodiphenylketone allyloxime (4.1g,
yield of 70.2%). Melting point 144-145°C IR 3450. 3350,
1620. 1605.1510 ca+-' NMR (DMSO-da.90MHz, ppm)
4.50 (2H.d.J; 5Hz>.5.16 (2
H. d. J=10Hz). 5.30 (4H.s).
5.8-6.20 (IH.m). 6.46 (2
H. d. J=5Hz). 6.56 (2H.d.J=5
Hz), 6.95 (2H.d.J=5Hz). 7
．． 15 (2H.d.J=51{z) Mass 2 268 (Ma1), 267
(M). tm/e 226. 210.19
6 bundles 144u 4.4″-diaminobenzyl (5g) and 1 meth
Hydroxylamine hydrochloride (2.1g) in methanol
(IOOIIIQ) and tetrahydrofuran (10
ffIQ) in a mixed solvent was stirred at room temperature for 24 hours.
do. The reaction mixture is concentrated under reduced pressure. Add water to the residual liquid, a.
The mixture was adjusted to pH 9.0 with 1N aqueous sodium hydroxide solution.
do. The precipitate was collected by filtration, washed with water, dried in vacuum, and extracted from ethanol.
Recrystallized to give 4,4'-diaminobenzyl 7-methyl
Kisim (4.5 g, yield 80.3%) is obtained. Melting point 190-192℃ (decomposition) IR (streak s-4> 3450. 3350.
1625. 1610, 1580, 1545
．． 1515 a11 NMR (DMSO-d6.60MHz.ppm) 3
．． 85 (3H.s), 5.70 (48, broad
s), 6.67 (4H, dd.J=2Hz, 9
Hz>, 6.27 (2H.d.J=9Hz), 7.
63 (2H.d, J=9Hz) Mass: 2
70 (M+1). 2fi9 (M), m
/e 209, 120 East 1 mouth 4-acetamido-31-methyl-4' ditrodiphe
Nylketone (17.9g), ammonium chloride (
1.93g) and iron powder (19.2g, 60 mesh
) of ethanol (1gomc), tetrahydrofura
Mixture of water (901111!) and water (901111!)
The mixture in the solvent is refluxed under stirring for 2 hours. Filter the reaction mixture and concentrate the filtrate under reduced pressure with water cooling.
Grind with sewage. The precipitate was collected by filtration, washed with water, and dried under vacuum.
-acetamido 4'-amino-3' -methyl diphene
Nylketone (15.05g, yield 99.7%) was obtained.
Ru. Melting point: 233-238°C IR (Suzir) F 3400. 33
50, 3300. 1690. 1630,1
600. 1575. 1530. 1290 am-
INMR (DMSO-d6.60MHz.ppm)
: 2.00-2.15 (6H.m). 5.80 (
2H. bs). 6.67 (2H.d.J=8Hz)
．． 7.40 (3}1.d.J=8Hz), 7.63
-7.67 (4H.m). 10.20 (IH.bs
) Mass: 269 (MO>. 268 (M).
m/e 253. 226.211, 134 4-acetamido-4'-amino-3'-methyldiphenylene
Concentrated salt rim of nylketone (15.0g) (2511
19) and a mixture in ethanol (150 mA)
Reflux under stirring for 5 hours. Concentrate the reaction mixture under reduced pressure and dissolve the residue in water. M liquid
Adjust to pttto with 1N*fa sodium aqueous solution under water cooling.
Arrange. Collect the precipitate by filtration, wash with water, and air dry to obtain a solid. solid
Silica gel (silica gel 60, 230-400
Column chromatography using 400g (manufactured by Merck)
matographed with dichloromethane and acetone.
Elute with a mixed solution (30:1). Both parts containing the target compound
Combine and evaporate to dryness to give 4,4'-diamino-3-
Methyl diphenyl ketone (9.48 g, yield 74.9%
) is obtained. Melting point: 145-147"C IR (Skul) i 3350, 163
5, 1600. 1580. 1550,13
20. 1270 am-' NMR (DMSO-d6.90MHz.ppm):
2.13 <38. s), 5.27<2H. bs)
．． 5.85 (2H.bs). 6.63 (2
H. d, J=9Hz). 6.70 (IH.d.J
=9Hz>. 7.30-7.63 (4H.m) Mass: 227 (Ma1). 226
(M), m/e 211. 134-di chicken 4.41-diaminodiphenyl ketone (5g) and
Tertiary methoxyamine (3.9g)
Methanol (1 oomu), tetrahydrofuran (
50ml), N,N-dimethylformamide (5ml)
Q) and concentrated salt # (11111) in a mixed solvent.
Stir at room temperature for 48 hours. Concentrate the reaction mixture under reduced pressure to remove the residue.
Grind the residue with water. The precipitate was collected by filtration, washed with water, and vacuum dried.
1.1-bis(4-aminophenyl)-1-(tertiary butyl)
methane (6.9 g,
yield of 74.5%). Melting point i 145-146°C IR (streak a-x): 3450. 33
50. 3220. 1735. 1640.1
625. 1515 am' NMR <DMSO-d6.60MHz. ppm) :
1.47 (9H, s). 4.50 (2H.s).
5.40 (4H.bs). 6.50 (2H.d
．． J=9Hz). 6.57 (2H.d.J:9H
z). 7.10 (2H.d.J=9Hz>.
7.20 (2H.d.J:9Hz>Mass:
342 (tD1), 341 (M).
m/e 285. 200 Ura 1 Iseno 1.1-bis(4-aminophenyl)-1-(tertiary group)
methane (6.9g)
triflic acetic acid (28-) and anisole in a mixture of
(70 mQ) of dichloromethane (20 fflfi)
) was added dropwise at 5°C while stirring with water cooling. chamber the mixture
Stir at room temperature for 2.5 hours and evaporate the reaction mixture to dryness under reduced pressure.
do. Dissolve the residue in IN aqueous sodium hydroxide solution.
Wash the liquid with ethyl acetate. Water layer with large pore nonionic adsorption tree
Daiai Saiten HP-20J (trademark, Mitsubishi Chemical Industries, Ltd.)
Column chromatography using
Elute with 0% isopropyl alcohol aqueous solution. objectification
The fractions containing the compound were combined and concentrated under reduced pressure to half the volume.1.
1-bis(4-aminophenyl)-1-canoleboxime
Toximinomethane (4.1 g, yield 71.
1%). Melting point: 250-253°C (decomposition) IR (streak m-4)' 3450. 33
50, 2550. 2450. 1650.1
620. 1600. 1515. 1325 cm-
'NMR (DMSO-ds.90MHz): 4.
51 (2H, s). 6.40-6.65 (6}1
, m), 6.90-7.22 (6H.m) Mas
s: 286 (M+1), 285 (M)
．． 11/1! 227. 210 x 1 x 4 In the same manner as in Example 59 described below, 4-acetamido N
-(4-nitro-2-chlorophenyl)benzenesulfo
Starting from N-amide, 4-acetamido N-(2-
Chloro-4-aminophenyl)benzenesulfonamide F
(2.0 g, yield 94.7%) was obtained. Melting point: 228-230℃ IR (streak*-1>' 3475.33
50, 3300. 1690. 1630,1
595. 1530. 1505. 1160 cm'
NMR (DMSO-d6, 90MHz.ppm)'
2.07 (3H.s). 5.37 (2H.s).
6.3-6.50 (21, m). 6.75 (I
H. d, J=9Hz). 7.55 (2H.d.J=
9Hz>. 7.17 (2H.d, J=9Hz).
9.20 (LH.s). 10.22 (IH.s)
Mass; 341 (M+2). 340 (
M+1). 339 (M). m/e 304, 24
0, 220. 205㉉m{M迦4-aceamide N-(4-amino-2-chlorophenylene
) Benzenesulfonamide F (2.8g) in ethanol
(56IIII) and mixed in concentrated hydrochloric acid (4, 21IQ).
The mixture was refluxed under stirring for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with 10% sodium bicarbonate.
Adjust the pH to 8.5 with a water-cooled aqueous solution of NaCl under stirring. The precipitate was collected by filtration, washed with water, and dried in vacuum to give 4-amino-N-(
4-Amino-2-chlorophenyl)benzenesulfona
Mido (1.89 g, yield 77.1%) was obtained. Melting point: 140-142℃ IR (streak*-4>' 3350.32
50, 1625. 1600. 1500.1
315 crm-' NMR (DMSO-d6.60MHz.ppm) 7
5.33 (2H.s). 5.87 (2H.s),
6.40 (2H.d.J; 9Hz>. 6.57
(2H.d.J=9Hz). 6.80 (IH, d.
J=9Hz>. 7.33 (2H.d.J=9}1z
). 8.73 (IH.s)Mass:
301 (M+3), 300 (M+2).
299 (M+1). 298 (M). rn/e
231, 197, 143. 141 past 14th birthday
Higashi 4-acetamido N-1 (2-chloro-4-nitrophe)
Nyl)-N-methylbenzenesulfonamide (3.45
g) and concentrated salt H of stannous chloride (6.9 g) (35
+1111), tetrahydrofuran (25mQ)
and the mixture in methanol (25ffLQ) at 60
Stir at ℃ for 2 hours. Concentrate the reaction mixture by force and dilute with water.
diluted, and then diluted with 24% aqueous sodium hydroxide solution under water cooling.
Adjust U4 at H10.0. Filter the precipitate, wash with water, and vacuum dry.
to obtain a solid. The solid is silica gel (Wako Gel C-20
0, 100-200 mesh, manufactured by Wako Pure Chemical Industries, Ltd.) (100
g) and column chromatography using
Elute with loform. Combine the fractions containing the target compound,
Concentrate under reduced pressure to obtain 4-amino-N-(4-amino-2-k).
rolophenyl)-N-methylbenzenesulfonamide (
2.32 g, yield 82.8%) was obtained. Melting point i 135-136°C IR (streak 3-l'): 3480. 3
380, 1625, 1595. 134013
15. 115 (l cm-' NMR (DMSO-d6, 60MHz.ppm):
3.08 (3H, s>. 6, 05 (2H, bs)
, 6.60 (2H, d.J=8Hz), 7.
00-7.50 (7H.m) Mass i m/e 287.276.262.
156 forks I 4.41-dinitro-2-chlorodiphenylsulfoxy
(5.3 g) and ammonium chloride (1 g)
(') Engineering 1/-le (2001nQ), Tetrahydric mouth fuller
methanol (50III1), methanol (50III11) and
iron and water (501119) in a mixed solvent.
Add the powder (10g) in small portions at 80℃ while stirring.
．． The mixture is refluxed under stirring for 2.5 hours. Filter the reaction mixture.
filtrate and concentrate the filtrate under reduced pressure. Pour the residue into silica gel (silica
Gel 60. 70-230 mesh, manufactured by Merck & Co.)
Add chloroform to the column chromatography to be used.
Elute with a mixture (10:1) of methanol and methanol. the purpose
Fractions containing the compound were combined and evaporated to dryness under reduced pressure.
．． 4'-diamino-2-chlorodiphenyl sulfoxide
(4.2 g. Yield 97.2%) was obtained. Melting point: 190-193°C (decomposition) IR (nursion: 3450, 3350
．． 3200. 1630. 1595.131
0 am' NMR (DMSO-d6, 60MHz.ppm)
: 5.70 (2H.s). 5.88 (2
H. s), 6.50-6.80 (4H.m).
7.23 (2H.d.J=9Hz>, 7.5
0 (IH.d.J: 9Hz) Mass: 26
9 (M+3>, 268 (M+2). 2
67 (M+1), 266 (M). m/e 25
0,218 1 tatami mat In the same manner as in Example 59, 4,4'-dinitropene
Starting from zuanilide, 4,4'-diaminobenz
Obtain anilide (4.22 g, yield 80.8%). melting point
: 197-201°C (decomposition) IR (streak i4): 3400. 332
0. 3200. 1640, 1625.16
05. 1515 am-1 NMR (DMSO-d6.60MHz.ppm):
5.30 (4H, bs). 6.55 (2H.d.
J. 8Hz). 6.63 (2H.d, J=8HZ)
,7.37 (2H.dJ=8Hz). 7.73
(2H.d,J; 8Hz). 9.30 (IH,s
) Mass: 228 (M+1). 227
(M), rn/e 120. 108 squares 1 tatami mat 4 rainbow In the same manner as in Example 59, 2-chloro-4.4'-dini
Starting from Tropenzanilide, 21 Chlor 4.4
'-Diaminobenzanilide (5.lg, yield 79.0
%). Melting point: 188-191'c IR (Ua-1>' 3350, 32
50, 1635. 1605, 1505.1
495 cm-' NMR (DMSO-d6.90MHz, ppm):
5.23 (2}!, bs), 5.61 (2H, b
s). 6.59 (2f{, d.J=9Hz), 6
．． 61 (2H.d..C9Hz>.7.10
(LH.d,J; 9Hz3.7.66(2H,d
．． J=9Hz). 9.13 (lH.s)Mass
: 264 (M+3), 263 (M+
2), 262 (M+1), 261 (M>.
m/e 226. 142, 120 Example 62 4,4'-Diaminodiphenylketone (9.
0g) and methanesulfonyl chloride (5.34g) with stirring.
Add dropwise at 5℃. The reaction mixture was stirred at 5°C for 3 hours and concentrated under reduced pressure to leave an oily residue.
Get pickles. Remove the oily residue with Nrica Gel (Shinoriki Gel 60, 2)
30-400 mesh, manufactured by Merck & Co., Ltd.) (500g) was used.
Apply column chromatography using chloroform.
Elute with a mixture of 50:1 and methanol (50:1). objectification
Both parts containing the compound were combined and concentrated under reduced pressure to obtain 4-amino
4'-Methanesulfonylaminodiphenyl ketone (3
．． 03g. yield of 24.6%). M point: 195-197”c IR (streak 9-1): 3500, 34
00. 1645, 1595, 1575.1
550, 1340. 1315. 1295 cm-
'NMR (DMSO-d6.90MHz.ppm)
: 3.11 (3H.s). 6.06 (2H, bs
), 6.61 (2H, d, J=9Hz>, 7.3
0-7.73 (6H.m), 10.15 (LH,b
s) Mass: 291 (M+1). 2
90 (M). m/e 211. 198.18
2 Example 63 4-ureido-4' 1 ditrodiphenyl sulfoxide
(llg) and ammonium chloride (1g) in ethanol
(200ffllll'), tetrahydrofuran
(50+1112) and water (50mQ)
Iron powder (12 g) was added to the mixture in the combined solvent at 80°C with stirring.
Divide the amount into portions and add. The mixture a was refluxed for 4 hours, and the reaction mixture was
Filter the mixture with suction. Concentrate the filtrate under reduced pressure and triturate the residue with water.
Crush. The precipitate was collected by filtration, washed with water, and dried in vacuum to obtain 4-urei.
Do-4'-aminodiphenyl sulfoxide (7.5g,
yield of 75.6%). Melting point: 189-191'c IR (streak 9-4)' 3470, 33
50, 3200. 1690. 1635.1
595. 1585. 1540 cm-'NMR (
DMSO-d6.60MHz, ppm): 5.70
(2H, s). 6.1 (2H.s). 6.67
(2H.d, J=9Hz). 7.15-7.80 (6
H. m). 9.00 (IH.s)Mass: 2
75 (M+1). 274 (M), m/e 26
0. 248,216 4-Ureido-4' Nitology in the same manner as in Example 63
Starting from phenyl ketone, 4-ureido-4′ −
Aminodiphenyl ketone (4.2g, yield 63.7%)
obtain. Melting point: 190-193°C IR (Stripe A-4)' 3480. 34
00, 3320. 3200, 1660.1
635 am-1 NMR (DMSO-d6,90M}lz, ppm)
' 6.00 (4H.bs), 6.60 (2H.d
, J=9Hz), 7.30-7.65 (6H.m)
,8.83 (IH.s) Mass: 256 (M+1), 255 (M)
．． m/e 238. 212,120 Higashi'd 艷 4 In the same manner as in Example 59, 2.2'-dichloro-4.
Starting from 4'-dinitrodiphenyl ether, 2.
2'-dichloro-4.4'-diaminodiphenyleth
ether (5.6 g, yield 68.7%) 1%. Melting point: 117-118℃ IR (streak a-L>: 3400, 33
00. 3200. 1635. 160014
90 crn-' NMR (DMSO-d6, 60MHz, ppm>'
5.12 <4H. s), 6.45 (48, s).
6.73 (2H.d, J=3Hz)Mass
; 272 (M+4), 271 (M+3
). 270 (M+2), 269 (M+1).
26g (M). m/e 233. 198
．． 142 In the same manner as in dog 1dl competition Example 59, 3-methyl-4,4'-dini
Starting from trodiphenyl ether, 3-methyl-4
．． 4'-diaminodiphenyl ether (2.6 g, yield
38.5%). Melting point: 147-148°C IR: 3410. 33
30. 1625, 1495. 12B5.1
210. 1145 cm-' NMR (DMSO-d6, 90MHz.ppm):
2.02 <38. s). 4.51 (2H.bs)
．． 4.73 (21, bs). 6.40-6.73
(7H, m) Mass: 215 (M+1).
214 (M), m/e 185, 171.122 East 101 male 3.5-dimethyl-4.41
- Starting from dinitro diphenyl ether, 3.5
-dimethyl-4,4'-diaminodiphenyl ether (
3.4 g, yield 85.9%) was obtained. Melting point: 118-
120℃ IR (Stripe carbon dioxide): 3450, 33
50. 1630. 1600.1510 c11 NMR (DMSO-d6.90MHz.ppm):
2.04 (6H.s). 4.23 (2H.s).
4.70 (2H.s), 6.40-6.65 (
6H. m) Mass: 229 (M+1). 22
8 (M), m/e 213. 136 Inulin 4-Ureido-4' Nitrodiphenyl ether (7
g) methanol (100 mQ) and tetrahydride
A mixture solution of 10 Offlll was added to 1
In the presence of 0% palladium-carbon (2.5 g), at room temperature
Hydrogenate under atmospheric pressure for 3.5 hours. Filter off the catalyst and use the filtrate
was concentrated under reduced pressure to give 4-ureido-4'-aminodiphenylene.
ether (6.1 g, yield 97.9%) was obtained. Melting point: 164-166°C IR (Sujol'): 3400. 3
300. 3200. 1660, 1600.
1500 cm' NMR (DMSO-d6.60MHz.ppm):
5.20 (2H.bs), 5.73 (2H.s)
．． 6.50-6.90 (6H, m). 7.3
3 (21, d.J=9Hz>. 8.30 (IH.
s) Mass: 244 (Ma1). 2
43 (M). m/e 226. 200.17
1 In the same manner as in Example 59, 3.3'-dimethyl-4.4
'-'; Starting from nitrodiphenyl ether,
3.3'-dimethyl-4.4'-diaminodiphenyl
Ether (4.36 g, yield 86.0%) was obtained. Melting point: 100-102℃ IR: 3400, 33
50, 1630, 1600. 1505.14
95 cm” NMR <DMSO-d6.90MHz.ppm>:
2.00 (6B, s), 6.50 (48, s).
7.50 (6H.bs)Mass: 229
(M+1). 22g (M). m/e 213
．． 199.185. 122 4-acetamide-2' sulfurized in the same manner as in Example 59
-Chloro 4' Starting from diphenylcara, sulfur
4-acetamido 4'-amino-2'-chlorodi
Phenyl (10.7 g, yield 84.3%) is obtained. Melting point: 133-135℃ IR (Steel-1-4): 3425, 3
325. 1680, 1630. 16101
595. 1460 cm-' NMR (DMSO-d6, 60MHz.ppm)'
2.10 (3H.s). 5.77 (2H.s).
6.60 (IH.d.J=9Hz>. 7.10
(2H.d.J=9}1z), 7.27 (2H.d.
．． J=9Hz). 7.60 (2H, d, J=9Hz
). 9.97 (IH.s)Mass: 2
95 (M+3). 294 (M+2>.
293 (M◆1). 292 (M). m/e
250. 214"1l"4-amino-3'-cyano in the same manner as in Example 59.
Starting from 4' ditrodiphenyl ether, 4.
4'-diamino-3-cyanodiphenyl ether (
1. 11 g, yield 57.2%). NMR (
DMSO-d6.90MHz. ppm): 5.16
(2H.s), 6.50-6.90 (5}1.m>
．． 7.20 (IH.dd.J=3Hz, 6Hz).
8.30 (IH.d, J=9Hz) Mass:
256 (M+1), 255 (M). m/e 2
09. 108
Derived from honylamino-4' ditrodiphenyl ester
4-trifluor-romethanesulfonylamino-4
'-Aminodiphenyl ether (12.5g, yield 64
．． 9%). Melting point: 155-156°C IR (N9-4): 3420. 334
0. 1510. 1370.1200 cm-' NMR (DMSO-d6.60MHz.ppm):
6.00 (2H, bs), 6.50-6.80 <
4H. m). 6.83 (2H.d.J=9Hz),
7, 17 (2H.d, J=9Hz> Mass: 333 (M+1), 332 (M),
m/e 199 bundles 10 η 4.4'-diamino in pyridine (200 ml)
Benzyl (10.1g) and methanesulfonyl chloride (4
++1Q) was added dropwise at 5°C while stirring on ice. i1! Compound
Stir at 3-7°C for 5 hours and concentrate the reaction mixture under reduced pressure.
．． Grind the residue with water, wash with water, and dry under vacuum to obtain a solid.
The solid was immersed in silica gel (silica gel 60, 70-230 mesh).
Column chromatography using 500 g)
matographed with dichloromethane and acetone.
Elute with a mixed solution (5:1). Combine both parts containing the target compound.
4-amino-4'-methanesulfonate by concentrating under reduced pressure.
Nylaminobenzyl (5.9 g, yield 40.1%) was obtained.
Ru. IR (Skull) + 3450. 3
375. 3200. 1705. 16g0,
1655. 1510 c11 NMR (DMSO-d6.90MHz.ppm):
2.14 (3H.s). 6.49 (2H.s).
6.59 (IH.d.J=9Hz). 7.30
(28, d, J=9Hz). 7.41 (2H.q.
J; 9Hz). 7.77 (2H.d, J=9Hz)
．． 7.87 (2H.d.J=9Hz). 10.5
0 (IH.bs) Mass: 319 (M+1). 31B
(M). m/e 240. 224.198,
120 寞” U艷ha 4-Amino-4′-methanesulfonylaminobenzyl (
13.3g) and sodium hydrosulfite (20.5g)
g) methanol (zosmu), water (gzme
) and IN aqueous sodium hydroxide solution (82mQ
) The mixture was refluxed under stirring for 2 hours. Vacuum the reaction mixture
Concentrate and triturate the residue with ethyl acetate. Filter the precipitate,
The filtrate was filtered with silica gel (silica gel 50, 70-1230 mesh).
Column chromatography using 500 g)
matographed with dichloromethane and acetone.
Elute with a mixed solution (10:1). Fractions containing the target compound
Combine and evaporate to dryness to give 2-hydroxy-2-(4-alpha).
minophenyl)-1-(4-methanesulfonylaminof)
Enyl) ethanone (6.20 g, yield 44.6%) was obtained.
Ru. Melting point 285-90℃ IR (Stripe a-L>: 3450.33
50. 3200. 1710. 1660,1
595. 1465 cm-' NMR (DMSO-d6, 90MHz.ppm):
2.95 (3H.s). 5.51 (18, d, J
=6Hz), 5.83 (lH.d, J=6Hz
>. 6.03<28. s). 6.46 <2H
．． d. J=9Hz). 7.06 (2H.d.J=
9Hz), 7.30 (2H.d.J=9Hz>
．． 7.70 (2H.d.J=9Hz). 9
．． 70 (IH.s)Mass: 321 (M
+1). 32G (M). m/e 304.
275.200. 120 亥mJL4 In the same manner as in Example 59, 4-amino-3'-methoxy
-4' Starting from ditrodiphenyl ether, 4
．． 4'-diamino-3-methoxydi, phenyl ether
(5.23 g, yield 85.7%). Melting point: 100-103°C IR (x diw): 3475. 34
00, 3350. 1615. 1605,1
505 ctrr-' NMR (DMSO-d6, 90MHz.ppm):
3.70 (3H.s). 3.63 (4H.bs)
．． 6.20 (IH.dd.J=3Hz, 6
Hz), 6.40-6,70 (6H㊃〉 Mass: 231 (M+1). 230 (
M), m/e 215. 188 HigashijLIL4 In the same manner as in Example 59, 2.2'-dimethyl-4.4
'Starting from dinitrodiphenyl ether, 4.4
'-diami/-2.2' -dimethyldiphenyl ether
ter (5.33 g, yield 97.5%) was obtained. Melting point:
111-112℃ IR (Xdim-A)' 3400. 32
0G. 1660. 1605. 1495.1
305. 1240 am-1 NMR (DMSO-d6, 60MHz, ppm):
2.95 (6H.s). 4.60 (4H.bs).
6.07-6.90 (6H.m)Mass: 2
29 (M+1). 228 (M), m/e 12
2. 107 trap and ΔU In the same manner as in Example 59, 2-diphenylmethoxy force
Derived from Bonyl-4,4'-cinitrodiphenyl ether
2-diphenylmethoxycarbonyl-4.4'
-diaminodiphenyl ether (8.82 g, yield lo
t. 1%). Melting point: 133-135°C IR <Zdi m-L)' 3350, 17
00, 1625. 1495. 1330.1
310. 1270. 1245. 1225 cra
-'NMR (DMSO-d6.90MHz.ppm)
: 4.50-5.36 (4H.bs). 6.
45-7.50 (18H.m)Mass: 41
1 (M+1). 410 (M). m/e
318. 283.167 2-diphenylmethoxycarbonyl-4,41-diami
Nodiphenyl ether (8.80g) in dichloromethane
(441111!) and Anisole (17.6ffL
Triflic acetic acid (35
．． 2ffllll) was added dropwise at 5°C while stirring. blend
Stir at room temperature for 2 hours. Concentrate the reaction mixture under reduced pressure.
Add the residue to diimprovil ether (500-),
Then leave it in the freezer overnight. Filter the precipitate and diiso
Washed with probyl ether and diedel ether,
Dry in the air to obtain 2-carboxy-4,4'-diaminodiph.
Obtain phenyl ether (3.3 g, yield 64.5%). Melting point: 144-185°C IR: 3520. 34
50. 3350. 187G. 1625.1
56G. 1495. 1255. 1145 am-
1NMR (DMSO-d6, 90MHz, ppm)
: 5.30-7.10 (12H.m) Mass : 245 (M◆1), 244 (
M), m/e 200, 136'' In the same manner as in Example 59, 2-cyanol 4.4'-
Starting from the phenol ether, 4.4′ −
Diaminone-2-one anodiphenyl ether (3.32g
, yield 70. l%). Melting point: 104-106°C IR (X9-L): 3420. 335
0. 2250. 1630, 1515, 13
05. 1240 cm-1 NMR (DMSO-d6, 90MHz.ppm>:
4.93 (2H, bs). 5.20 (2H.bg
), 6.46-6.93 (7H.m>Mass:
227 (M+2). 226 (M+1>, 22
5 (M). m/e 196. 157, 149
．． 108 prongs 4.41-diamino-3-meterediphenylketone (1
5g) of vinegar # (150mQ) solution, acetic anhydride (
16g) was added dropwise at 10°C while stirring. 1 at room temperature
．． Stir for 5 hours. Pour the reaction mixture into ice water while stirring.
The precipitate is collected by filtration, washed with water, and dried in vacuum to obtain a solid. solids
A4 was recrystallized from tanol. 4'-diacetamido-3-methyldiphenylketone
(15.2 g, yield 73.9%) was obtained. Melting point: 21
7-218℃ IR (Xdi-i-4)' 3270. 31
70. 1665. 1600. 1550.1
530 crm-' NMR (DMSO-d6, 60MHz.ppa+)
'2.17 (3H.s). 2.20 (3H.s)
, 2.38 (38,s), ? , 73 (2H.d
, J=8Hz). 7.80 (5H.m). 9.47
(IH.s). 10.35 (LH,s)Mass
: 311 (Ma1), 310 (M), m/
e268. 253,226. 211 Higashi'0'4-acetamido-4'-
Starting from nitro-2'-chlorodiphenylketone
, 4-acetamido 4'-amino-2'-chlorodiph
Obtain phenyl ketone (7.70 g, yield 99.7%). Melting point + 162-185"C IR (streak i4): 3400. 3320
．． 3200. 1665. 1640,160
0, 1545. 1315 cm-'NMR (DM
SO-d6.60MHz. ppm>: 2.15 (
3}1. s>. 6.03 (2H.bs), 6.5
3-6.80 (2H, m), 7.23 (IH.
d. J=9Hz>. 7.70-7.80 (4H,
m), 10.30 <18, bs) Mass:
291 (M+3). 290 (M+2),
289 (M+1). 288 (M). m/
a 24g. 246. 154. 120 East''
In the same manner as in Example 53, 4-acetamido 4' -
Starting from amino-2'-chlorodiphenyl ketone,
4.4'-diamino-2-chlorodiphenylketone (
8. 98 g, yield 59.0%). Melting point: 87
-95℃ IR (Stripe a-4): 3350, 32
00, 1640, 1630. 1585,1
540. 1320, 1280. 1240 cm”
NMR (DMSO-d6, 90MHz.ppm):
5.47 (4}1.m). 6.50-6.77 (
4H, m). 7.07 (IH, d.J=9Hz>,
7.47 (2H.d.J=9Hz) Mass: 249 (M+3>, 248 (M+
2). 247 (M+1>.246 (M).
m/e 154. 120 East 1d In the same manner as in Example 52, 4-acetamido-2-methylene
Ru-4' Starting from 12trodiphenylketonekara, 4
-acetamido 2-methyl-4'-aminodiphenyl
Ketone (19.94 g, yield 94.7%) is obtained. IR (NEET): 3500. 335
0, 3230. 3010. 1680
-1500. 1440. 1410-1370. 1
330-1240. 1220. 1170 am'N
MR (DMSO-d6, 60MHz.ppm) 7
2.10 (3H.s). 2.20 (3H.s).
6.15 (2H.bs). 6.60 (2H.d.
J:9Hz>. 7.20 (LH.d.J=9Hz)
, 7.37-7.63 (4H, m), 10.03
(IH, bs) Mass: 269 (M+1).
269 (M). m/e 267. 251.225
．． 209,134,120 Higashi' tatami sinks Similarly to Example 53, 4-acetamido-2=methylene
Starting from 4'-aminodiphenyl ketone, 4.
4'-diamino-2-methyldiphenylketone (2.
9 g, yield 17.8%). Melting point: 138-13
9℃ IR (streak s-x): 3490, 34
20.1595. 1550, 1290 c1l 3330. 1440. 3220. 1320. 1635, NMR (DMSO-d6.60MHz.ppm):
2.18 (3H.s). 5.48 (2H.bs)
, 5.95 (2H.bs). 6.30-6.
77 (4H.m). 7.03 (2H.d.J=
9Hz>, 7.45 (2H.d, J=9HZ) Mass: 227 (M+1). 226 (M
). m/e 225. 210,209,!
34. 120 East 104 acetanilide (0.58g), anhydrous aluminum chloride
(3.41 g) and a mixture of nitrobenzene (1-)
Stir for 30 minutes at room temperature. Stir the mixture at 100°C
, then 4-acetamido-3-chlorobenzoyl chloride
(1.09g). Mixture too'c 2
．． Stir for 5 hours and pour into water-cooled stirring water. Filter the precipitate
Wash with water and saturated aqueous sodium bicarbonate solution and vacuum
Dry to give 4,4'-diacetamido-3-chlorodiph
Obtained enyl ketone (0.25 g, yield 17.6%)
Ru. Melting point 207-209'C IR (streak A4): 3400. 32g
0. 1710. 1655, 1595.15
10. 1305. 1265 cm-'NMR (
DMSO-d6, 60MHz. ppm) 2.12
(3H.s), 2, 20 (3H.s). 7.5
3-7.90 (6H.a+). 8.08 (IH.
d. J; 8Hz>. 9.67 (IH.bs). 1
0.32 (IH, bs) Mass: 332 (M
+2), 331 (M+1>. 330 (M).m
/a 294. 288, 246, 154, 12
0 Example 86 In the same manner as in Example 53, 4,4'-diacetamide
Starting from -3-chlorodiphenylketone, 4;4'
-diamino-3-chlorodiphenylketone (2.2g
, yield 68.6%). Melting point: 166-170°C IR: 3490. 33
50. 3200, 1630. 15g0,1
550. 1330. 1310, 1285.117
5 crtr-' NMR (DMSO-d6.60MHz.ppm):
6.93 (2}1.bs), 6.07 (2H.b
s). 6.55-6.92 (3H, m), 7.3
3-7.63 (4H.m) Mass: 248 (M+2). 247 (M
+1), 246 (M). m/e 199. 17
1, 156, 154, 126. 120
In the same manner as in Example 52, 4-acetamide-4'12
Starting from tro-3.3'-dimethyldiphenylketone
4-acetamido-4'amino-3,3'-dimethane
Rudiphenylketone (10.06g, yield 47.6%)
obtain. Melting point: 163-165°C IR (neat): 3450. 33
50, 3250. 1650. 163
0.1800. 1580. 1525, 1330.
1305.1280 am' NMR (DMSO-d6.60MHz.ppm>'
2.10 (3H.s). 2.30 (38,s).
5.87 (2H.bs). 6.68 (LH.d
．． J=9Hz), 7.45-7.83 (5H, m>
．． 9.42 (IH.bs)Mass: 283
(M+1>, 282 (M). m/e 267.
245,149. 134 In the same manner as in East JJL Competition Example 53, 4-acetamido 4″ −
Starting from amino-3.3'-dimedelphenyl ketone
4,4'-diamino-3,3'dimethyldiphenyl
Ketone (1.07 g, yield 39.3%) is obtained. Melting point: 126-131'C IR (streak@-L'): 3400. 3
330. 3200. 1625. 15g0.
1565. 1500. 1430. 1320. 1
300.1260 a1l NMR (DMSO-d6.60MHz.ppm):
1.93-2.10 (6H.m). 4.93 (2
H. bs), 5.67 (2H.bs). 6.47
-7.43 (6H.se) Mass: 241 (M+1). 240
(M). m/e 230. 134.106 In the same manner as in Example 85, acetanilide and chloride 4
- Starting from fluorobenzoyl, 4-acetamide
-4'-fluorodiphenyl ketone (4.43 g, yield
33.3%). IR (21!): 3
500, 3300, 3200. 31
00. 1700.1690, 1680.
1650. 1600. 1530.1510.
141G, 1370. 1315 cm-'NMR
(DMSO-d6, 90MHz.ppm): 2.1
3 (3H.s), 7.10-7.89 (8H.m)
．． 10.70 (LH.bs)Mass; 2
5g (M+1>. 257 (M).m/e 21
5.177.140 4-Acetamide-4'-
Starting from the full rhodiphenyl ketone, 4-amino
4'-fluorodiphenyl ketone (1.06 g, yield
28.8%). Melting point: 126-128°C IR (Sujisho-4): 3450. 33
50. 1630. 1600. 15g0.1
320. 1230 cm' NMR (DMSO-d6.60MHz, ppa+)
: 6.17 <2H, bs). 6.63 (2H.d
．． J=9Hz>. 7.13-8.00 (6H, m)
Mass: 216 (M+1>. 215 (M)
．． m/e 186. 120 Bundle 104 Salmon Same as Example 52, 3,5-dichloro-4-amino
Starting from no 4' ditrodiphenyl ketone, 3.
5-dichloro-4,4'-diaminodiphenyl ketone
(6.87 g, yield 88.8%) was obtained. melting point i
174-176°C IR (2-}): 3420. 3320
．． 1740-1700. 1580.1525.
t345. 1285. 1175 0ra-”NM
R (DMSO-d6.60MHz, ppm): 5
．． 77-6.27 (4H.bm). 6.53-6.
93 (2H.m). 7.33-7.66 (4H.
m) Mass: 282 (M+1), 2
81 (M). m/e 280. 248,
246, 211, 154. 120 101 4-acetamido-3,5-dimether-4'nitrogif
phenylketone (12.2 g) and ammonium chloride (
1.25 g) of ethanol (120Il111),
Tetrahydrofuran (6011111) and water (
60 mt ) of iron powder (12 mt ) in a mixture solvent.
Add 5 g) in small portions at 80°C while stirring. i1
! The mixture is refluxed under stirring for 1.5 hours. Aspirate the reaction mixture
Filter, and remove the solvent from the filtrate under reduced pressure. Add water to the residue
Extracted with ethyl acetate, washed with water, and extracted with magnesium sulfate.
dry. After filtration, the solvent of the filtrate was distilled off under reduced pressure, and 4
-acetamido 3,5-dimethyl-4'-aminodiph
Obtain enyl ketone (10.7 g, yield 97.0%). Melting point + 173-175°C IR (streak error): 3450. 33
50, 3250, 1730, 1670,1
645, 1620. 1585. 1315 cm”
NMR (DMSO-d6.60MHz.ppm):
2.00 (3H.s), 2.10 (3H,s),
2.27 (38,s). 6.22 (2H.b-
s). 6.60 (2}1.d.J=9Hz). 7.
03 (1}1.d..C8Hz>.7.23 (IH
．． d. J=8}1z). 7.50 (2H, d.J=
9Hz), 9.33 (LH.s) Mass: 283 (M+1). 282 (M)
．． m/e 2B7, 239,224 4-acetamido-3,5-dimedel-4'aminodiph
phenylketone (8.0g) in ethanol (1601d
) and concentrated salt # (60mQ) under stirring.
Reflux for 24 hours. The reaction mixture was diluted with 2N sodium hydroxide.
Aqueous solution with pH 9. llt to 0. water with water
Stir for 1 hour under cooling, and filter the precipitate under reduced pressure to obtain a solid.
．． The solid was immersed in silica gel (silica gel 60, 70-230 mesh).
Column chromatography using 250g
It was subjected to chromatography and mixed with methanol and chloroform.
Elute with a mixed solution (1:30). Fractions containing the target compound
Combine and concentrate under reduced pressure to give 4.4′-diamino-3.5
-dimethyl diphenyl ketone (2.8G., yield 54.
8%). Melting point: 202-204'C IR (Streak I-4> + 3470.33
50, 3200. 1625. 1590.1
320 am-1 NMR (DMSO-d6.60MHz.ppm)'
1.87 (3H, s). 2.10 (3H.s).
4.63 (2H.s). 6.05 (2H.s)
．． 6.30 (IH.d.J=7Hz>.6.53
(2H.d.J; 9Hz>. 6.87 (IH.d.J
=7Hz). 7.40 (2H.d.J:9Hz)M
ass: 241 (M+1). 240 (M).
m/a 225. 210.120 Higashi 1kou U 4-N-ethylamino-3-methyl-4'1 ditrodiph
phenylketone (5.30 g) and ammonium chloride (
0.6 g) of ethanol (11G1d), tetrahydrogen
Dokufuran (55ffllll) and water (551
Iron powder (5.97 g) was stirred into the mixture of Q) in the mixed solvent.
Add in small portions at 80°C while stirring. stir the mixture
Reflux for 1 hour. Filter the reaction mixture under reduced pressure and reduce the filtrate.
Concentrate under pressure. Grind the residue with water and filter the precipitate. ethanol solid
Recrystallized from 4-N-ethylamino-3-methyl-
Obtain 4'-aminodiphenyl ketone (3.44 g). Melting point: 147-148℃ IR (streak m-IL)' 3400, 3
350. 3250. 1650. 1625,
1595. 1560. 1440. 1425.13
15 am-' NMR (DMSO-d6.60MHz.ppm):
1.25 (31, t.J=7Hz). 2.20
(3}1,s). 2, 97-3.50 (2H.m)
, 4.97 (1}1.t.J=6Hz). 6.07
(21, s). 6.67 (2H.d.J=9Hz)
．． 6.70-6.90 (2H.m). 7.
15 (LH, d.J=8Hz). 7.63 (2H
．． d. J=9Hz) Mass: 255 (M+
1). 254 (M), m/e 239.
225.180 Tom 4-acetamidobenzyl-4'-nitrophenyl tetrasulfide
(ts.Og) and ammonium chloride (2.0g)
Tetrahydrofuran (300111), ethano
Pool (300mQ) and water (100mQ)
(y) Stir iron powder (15.0g) into the mixture in the mixed solvent
Add in small portions at 80°C. stir fi hardware
Reflux for 2 hours, filter the reaction mixture with suction and reduce the filtrate.
Concentrate under pressure. Grind the residue with water, collect the precipitate by filtration, wash with water, and
Air-dried to give 4-acetamidobenzyl-4'-a sulfide.
Minophenyl (11.5 g, yield 63.8%) is obtained.
NMR (DMSO-d6, 60MHz.ppm):
2.06 (3}1.s). 3.90 (2H.s)
．． 5.30 (2H,s), 6.53 (2H.d
．． J=8Hz). 7. Go-7.30 (4B, m)
．． 7.50 (2H.d.J=8Hz>.9.90
(18,s) Mass: M+1273. M272, m/e
229. 216, 183.148. 106 Higashi 4-acetamidobenzyl-4-aminophenyl tetrasulfide
(4.0g) of ethyl acetate (15Qml) and
N. Mixing of N-dimethylformamide (39mQ)
Add 3-chloroperbenzoate a (6.0 g) to the acetic acid solution.
Add the chilled solution dropwise at 5°C while stirring. Mixture at room temperature 26
Stir for an hour. Reaction a compound dissolved in sodium bicarbonate water
Pour into a bowl and stir for 1 hour while cooling with water. Filter the mixture with suction
, the filtrate was treated with a mixture of ethyl acetate and tetrahydrofuran.
Extract. The organic layer was dissolved in aqueous sodium bicarbonate solution and water.
and then dried with magnesium sulfate. solvent
Concentrate under reduced pressure to obtain 4-(4-acetamidobesidyl sulfonate).
) aniline (4.0 g, yield 89.4%) was obtained.
Melting point: 240-245°C (decomposition) IR (suji-a-4)' 3500. 3
350, 3250, 1660, 1595.
1515 am-' NMR (DMSO-d6.60MHz, ppm):
2.00 (3H.s). 4.30 (2H.s),
6.00 (2H, s). 6.55 (2H.d.
J=8Hz). 7.15 (4H.dd.J=4Hz.
8Hz>. 7.46 (2H.d..C8Hz
). 9.90 (LH.s)Mass: M”
304. M 303. m/e 260, 240,
197,148. 106 or 104r 4-(4-acetamidobenzylsulfonyl)aniline
(4.4 g) of concentrated hydrochloric acid (201Q) and ethanol
Reflux the mixture in a 1001d bottle with stirring for 5 hours.
．． Concentrate the reaction mixture under reduced pressure and dissolve the residue in water. m liquid
was prepared in ptts with aqueous sodium hydrogen carbonate solution under water-cooling and stirring.
Arrange. The precipitate was collected by filtration, washed with water, and dried in vacuum to give 4-(4-
aminobenzylsulfonyl)aniline (2.5 g, yield
65.7%). Melting point: 245-250℃ (decomposition
) IR (School) i 3350. 325
0, 1630, 1610. 1595,15
15. 1280 am-' NMR (DMSO-d6.60MHz.ppm>'
4.13 (2H.s). 5.10 (2H.s),
6.00 (2H.s). 6.45 (2H.d.
J:8Hz). 6.67 (4H.dd.J=4}1z
．． 8Hz). 7.23 (2H.d.J=8Hz) Mass: M” 263. M 262. tal
e 211, 197, 156.106 bundle d-1,1-bis(4-aminophenyl)-1-hydroxy
Iminomethane (6.7g). Inbrovir iodide (lO.
2g) and potassium carbonate (6.2g). N-Jime
The mixture in chloroformamide (67 ml) was heated at room temperature.
Stir for 7 hours. Pour the reaction mixture into ice water and filter the precipitate.
Remove, wash with water, and dry under vacuum to obtain a solid. silica gel solid
(Silica gel 60, 70-230 mesh, manufactured by Merck & Co., Ltd.
) (500 g) for force ram chromatography using
A mixture of chloroform and methanol (10:1)
It elutes with Combine fractions containing the target compound and concentrate under reduced pressure.
and 1,1-bis(4-aminophenyl)-1-yne
Broboximinomethane (0.88g, yield 11.1%
) is obtained. NMR (CDCI3.90MHz, ppm>7 1
．． 20 (6H.d.J=3Hz>, 3.40-3.8
(4H.b-s), 4.00 (IH.m). 6
．． 40-6.70 (2H.m), 7.20-7.5
0 (2H.m>Mass: M+1270.M
269, m/e 254. 239, 210, 19
6. In the same manner as in Example 52, 4-acetamide-3.6-
Starting from dimethyl-4' ditrodiphenyl ketone
, 4-acetamido 3,6-dimethyl-4'-ami
Nodiphenylketone (12.6g, yield 89.9%)
obtain. Melting point: 211-213°C IR (Skyl): 3450, 335
0, 3280. 1655. 1590.15
25 cm" NMR (DMSO-d6.60MHz, ppm)'
2.13 (6}1.m). 2.20 (3H.s)
．． 6.17 (2H.b-s), 6.60 (2H.b-s)
．． d. J=8Hz). 7.07 (LH.s). 7
．． 40-7.60 (3H.m>.9.30 (lH.
b-s) Mass: M 282. m/e 2g1, 26
5, 239. 224 In the same manner as in Example 53, 4-acetamide = 3.6-
Starting from dimethyl-4'-aminodiphenyl ketone
, 3,6-dimethyl-4,4'-diaminodiphenyl
Ketone (3.84 g, yield 64.5%) is obtained. Melting point: 203-204℃ IR (Skul): 3500, 340
0, 3360, 3240. 1625.15
90. 1565 cm-' NMR (DMSO-d6.60MHz.ppm):
2.07 (3H.s), 2.20 (3H.s).
5.27 (2H.b-s). 5.97 (2H.
b-s). 6.53-6.80 (3H.m). 6.
97 (LH, s), 7.50 (2H.d, J=8}
12) Mass: M” 240, M 240, m/e
239. 223. 148 衷韮''4.4'-Diamino-3-methyldiphenylketone (5
．． 4g) of ethylene glycol diethyl alcohol (5g)
51112)! Add sodium borohydride (1
．． 81 g) and potassium hydroxide (0.12 g) in water (
IOIIIQ') mixture was added dropwise at 706C with stirring.
do. Stir the mixture at 70°C for 2 hours. reaction mixture
Pour into a saturated aqueous solution of sodium chloride under stirring. precipitation
4.4′-diamino-3- was collected by filtration, washed with water, and dried under vacuum.
Methylbenzohydrol (4.54g, yield 83.3%
), melting point: 62℃ IR (sujijiru): 3420, 33
50, 3170. 1615, 1510.1
280 cm-1 NMR (DMSO-d6, 90MHz.ppm):
2.00 (3H, s). 4.56 (2H.b-s
). 4.77 (2H.b-s), 5.07
(LH.d, J=4.5Hz). 5.29 (LH
．． d, J=4.5Hz). 6.30-6.53 (
3H. m). 6.67-6.97 <4H. m)M
ass: M228. m/e 226,224
, 214, 212. 210 衷韮 1 4.4'-Diamino-3-methyldiphenylketone
(6.1g) (7), 'tanol (61ml)
Add 〇1 methylhydroxylamine salt m salt (13
．． 5 g) at room temperature while stirring. The mixture was heated to room temperature for 18.
Stir for 5 hours. Concentrate the reaction mixture under reduced pressure. water the residue
and then diluted with IN aqueous sodium hydroxide solution under water cooling.
Adjust the pH to 12. The residue was extracted with ethyl acetate and extracted with water.
Wash and dry with magnesium sulfate. Concentrate the organic layer under reduced pressure
to obtain a solid. Triturate the solid with ethanol and water;
The precipitate was collected by filtration, washed with water, and dried in vacuum to give 4.4'-diami
No 3-methyldiphenyl-1-methoxyiminomethane
(5.75 g, yield 81.6%) was obtained. Melting point: 92-97"C IR (suji soda): 3400, 33
50. 3170, 1640, 1610.1
515 cab-' NMR (DMSO-d6.60MHz.ppm)'
2.05 (3H, s). 3.77 (3H.s),
5.10 (2H, b-s), 5.32 (21,
b-s), 6.43-7.20 (71, m) Mass: M 256. M255, m/e
225, 224 bundle Hendo beam 1.1-bis(4-acetamidophenyl)-1-hydro
Roxyiminomethane (5.0g) in ethanol (100g)
IIIQ) and IN aqueous sodium hydroxide solution (lo
omQ ) mixture was refluxed for 26 hours under F91 stirring. anti
The reaction mixture was concentrated under reduced pressure, and the residue was adjusted to pH 7 with hydrochloric acid under water cooling.
Arrange. The precipitate was collected by filtration, washed with water, and dried under vacuum.
(4-aminophenyl)1-hydroxyiminomethane
(3.0 g, yield 88.0%) was obtained. Melting point: 19g-200°C IR: 3475. 340
0,1520. 1325 NMR (DMSo-ds, 90 MHz
．． ppm >6.46 (2H.d.J=6}1z
), 6.95 (2H, d.J=6Hz). Mass
: M+1228. M 227.3250. 1
620. 1605, cm': 5.30 (4H, b-s). 6.53 (
2H. d. J=6Hz>,7.03 (2H, d.J
=6Hz>m/e 210.196.120

Claims (1)

[Claims] 1) Formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is a halogen, an amino group, a protected amino group, a hydrazino group, an aminobenzenesulfonylamino group , protected aminobenzenesulfonylamino group, lower alkanesulfonylamino group, aminophenoxy group,
hydroxy group or protected hydroxy group, R^2 is halogen, di(lower alkanesulfonyl) amino group, lower alkylamino group, amino group, protected amino group, hydrazino group, protected hydrazino group, halo (lower ) alkanesulfonylamino group or lower alkanesulfonylamino group, R^3 is hydrogen, lower alkyl group, halogen, cyano group, carboxy group, protected carboxy group, lower alkanesulfonylamino group, hydroxy group or protected hydroxy group , R^3^a is hydrogen or a lower alkyl group, R^4 is hydrogen, a lower alkyl group or a halogen, R^4
^a is hydrogen, lower alkyl group or halogen, A is -C
H(OH)-, -CH_2-, -CO-, -COCH(
OH)-, -COCO-, -CONH-, -O-, -S
-, -SO-, -SO_2-, -COC(=NOR^b
)-(in the formula, R^b means hydrogen or a lower alkyl group), -C(=NOR^a)-{in the formula, R^a represents hydrogen, a lower alkyl group, a lower alkenyl group, a carboxy (lower ) means an alkyl group or a protected carboxy (lower) alkyl group}, -SO_2N(R^C)- (wherein R^C means hydrogen or a lower alkyl group),
-CH_2S- or -CH_2SO_2-] and pharmaceutically acceptable salts thereof.