CA1264763A - Process for the preparation of diphenyl ethers - Google Patents
Process for the preparation of diphenyl ethersInfo
- Publication number
- CA1264763A CA1264763A CA000423736A CA423736A CA1264763A CA 1264763 A CA1264763 A CA 1264763A CA 000423736 A CA000423736 A CA 000423736A CA 423736 A CA423736 A CA 423736A CA 1264763 A CA1264763 A CA 1264763A
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- compound
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
ABSTRACT
An improved process for the preparation of herbicidal diphenyl ethers of the generic formula I
(I) in which R1, R2, X1,and X2 have a range of possible meanings. The described process reacts a compound of formula IV with a phenol of formula VI
(IV) (VI) in the presence of a base and of a phase transfer catalyst. The resulting product is reacted with an amine of formula NHR2 in an alcohol containing ether groups, such as diethylene glycol, to provide a compound of formula I.
This process avoids the impurities, particularly coloured ones, and by-products obtained by the known processes for compounds ot this type.
An improved process for the preparation of herbicidal diphenyl ethers of the generic formula I
(I) in which R1, R2, X1,and X2 have a range of possible meanings. The described process reacts a compound of formula IV with a phenol of formula VI
(IV) (VI) in the presence of a base and of a phase transfer catalyst. The resulting product is reacted with an amine of formula NHR2 in an alcohol containing ether groups, such as diethylene glycol, to provide a compound of formula I.
This process avoids the impurities, particularly coloured ones, and by-products obtained by the known processes for compounds ot this type.
Description
The invention relates to an improved process for the preparation of diphenyl ethers of general formula Xl NHR2 ( l)n ~ X~ ~I2 (I) wherein n is an integer from 1 to 3, Rl represents hydrogen, halogen, alkyl or alkoxy with 1 to 8 carbon atoms, trifluoromethyl, acetyl or cyano, R2 represents hydrogen; alkyl, alkenyl or alkynyl with up to 16 carbon atoms; an alkyl group with 2 to 6 carbon atoms substituted by hydroxyl Cl 4 alkoxy, phenoxy, halophenoxy, Cl 4 alkylphenoxy, Cl 4 alkoxyphenoxy, nitrophenoxy, cyanophenoxy, amino or Cl 4 alkylthio;
optionally halosubstituted benzyl, NR3R4, CHR3-COOR~
or CHR3-CONR4R5, wherein R3, R4 and R5, which may be the same or different, represent hydrogen or Cl 8 alkyl groups, and Xl and X2, which may be the ~-same or di~ferant/
represent hydeogen or halogen arld Xl a~ rep~e(3~nt~s methy 1 .
n will only assume the values 2 and 3 if R
represents halogen or alkyl. The term "halogen"
refers to fluorine, chlorine, bromine and iodine.
The preferred halogens are fluorine, chlorine and bromine, particularly fluorine and chlorine. When Rl, R2, R3, R4 and R5 represent or contain hydrocarbon gro~ps, these may possibly also be branched. However, these groups preferably contain 1 to 2 carbon atoms.
.,j ,.
` ` ~2~;~7~:3 Within the scope of the definitions given herein-before, Rl preferably represents hydrogen, fluorine, chlorine, bromine or methyl, R2 represents hydrogen, Cl 4 alkyl, allyl, 2-hydroxyethyl, 4-fluoro- or 4-chlorobenzyl or dimethylamino. R3 is preferably hydrogen or methyl whilst R4 is Cl 4 alkyl. The preferred definitions of Xl/X2 are chlorine/hydrogen, methyl/hydrogen, chlorine/bromine and bromine/chlorine.
If n represents 2 or 3, there may be different groups Rl present at the same time. Some of the compounds of general formula I are known (DE-OS P 29 38 595).
They are distinguished by their excellent herbicidal action.
According to DE-OS 29 38 595 the compounds of general formula I can be obtained by reacting a nitrodiphenoxybenzene of general formula (Rl)n~
wherein n, Rl, Xl and X2 are a~ hereinbefore defined, with an amine of formula H2NR2 (III) wherein R2 is as hereinbefore defined, at elevated temperature. The compounds of formula II are prepared by reacting a compound of general formula ~ Ei4763 Xl Cl Ll Cl ~ NO2 ~IV) wherein Xl and X2 are as hereinbefore defined, for example 2,3,4-trichlorobenzene, 2,4-dichloro-3-methyl-nitrobenzene and 2,3,4,5-tetrachloronitrobenzene, with a corresponding phenoxide of general formula (Rl)2 ~ OKat (V) (wherein Kat is one equivalent of a cation). Preferably, the alkali metal phenoxides are used, particularly the sodium phenoxide, or the phenol and, for example, an alkali metal carbonate. In the case of simple phenols, particularly unsubstituted phenol, the corres-ponding phenol may servc ~s a rea~tion mec~lum. Ilowever, it is par~icul~rly pre~crred to use dlmeth~lsulphoxide as solvent The two chlorine atoms in the 2- and 4-positions, which can be exchanged for phenoxy groups, show a clearly graduated reactivity.
The known process is less suitable for use on an industrial scale. In the production of the starting substances of formula II, strongly coloured by--products are formed which make it difficult or ~2~497~i3 impossible to carry out further processing directly.
further problem is presented by phenolic by-products, e g. cleavage products of the type Xl OH
(Rl)n X~
An extensive purifying operation is needed to eliminate the by-products.
The reaction of the compounds of formula II
to yield the end products of formula I according to the prior art requires, in some cases, an autoclave reaction in solvents such as toluene, dioxan or chlorinated hydrocarbons. Substantial reaction times (about 12 to 20 hours) are generally required.
It has now been found that the compounds of formula I can be obtained with greater purity, in a shorter time and with less elaborate apparatus, if a nitrobenzene of formula IV is heterogeneously reacted, in the presence of a phase transfer catalyst, with a phen~l of formula (Rl)n Ol~ ~VX) wherein Rl and n are as hereinbefore defined, with the addition of an aqueous alkaline or alkaline earth metal base, at elevated temperature, to ~orm the corresponding 2,4-diphenoxy compound of formula II, which i5 then reacted, in a hiyh-boiling alcohol ~L26~7~i3 containing ether groups, with an amine o~ formula III to form the corresponding compound of formula I.
If desired, the first reaction step, which produces the diphenoxy compounds of formula II, may also be carried out with the addition of inert, water-immiscible solvents. The critical advantage of the reaction according to the invention consists in the use of a conventional phase transfer catalyst. Thanks to the addition of such a catalyst, a very pure product of formula II is obtained in an excellent yield at temperatures of between 60 and 150C, preferably between 80 and 120C, more particularly between 90 and 110C. The phase transfer catalyst can be recovered almost totally. The reaction components of formulae IV and VI are used in a molar ratio of from 1:1.8 to 1:2.5. Preferably, the phenol is used in a slight excess (molar ratio 1:2.1 to 1:2.4) and a quantity of a~ueous base, preferably strong sodium or potassium hydroxide solution, corresponding to the quantity of phenol is used. The quantity of phase transfer catalyst may vary within wide limits. It has proved advantageous to use about 0.005 to 0.12, preferably from 0.01 to 0.06 mol of catalyst per mol of phenol.
Suitable phase transfer catalysts include, for example, triethylbenzylammonium chloride or bromide; tetrabutyl-ammonium chloride, bromide, hydrogen sulphate, hydroxide;
methyl trioctylammonium chloride; tetra~u~ylphos~honium bromide. Nllmerous other ~iuitahle ~ha~.se t.~nsE@r catalysts arè mentioned in the monograph by E.V.
Dehmlow and S.S. Dehmlow, "Phase Transfer Catalysis", Verlag Chemie, Weinheim (1980), particularly page 38 and pages 39-43.
The second reaction step, the reaction of the diphenoxy compounds of formula Il to yield the end products of formula I, is, surprisingly, particularly successful if ether alcohols are ~sed as the reaction medium. Suitable compounds of this kind include, ~264763 in particular, aliphatic or cycloaliphatic compounds, e.g. diethylene glycol, triethylene glycol, dipropylene glycol, diethylene glycol monomethyl ether, monoethy~
ether, monopropyl ether, monobutyl ether, monobenzyl ether, lower monoalkyl ethers of triethylene glycol or of dipropylene glycol and partial ethers of other polyhydric alcohols. The reaction temperature is between about 20 and 180C, preferably between about 40 and 170C; it depends largely on the amine of formula III used. Whereas methylamine, for example, can be reacted at ambient temperature, a higher temperature is required when ammonia is used so that the reaction can be completed with a few hours. A slight increase in the ammonia pressure to 3 to 4 bar can be used to per~orm the reaction at temperatures of about 120 to 130C without taking any longer.
The end products are obtained in very pure form and in very good yields.
In the Examples which follow, the process is described more fully, without being restricted to the embodiments described.
~ 6;~
Preparation of diphenoxy__ompounds of formula II
Example (a)
optionally halosubstituted benzyl, NR3R4, CHR3-COOR~
or CHR3-CONR4R5, wherein R3, R4 and R5, which may be the same or different, represent hydrogen or Cl 8 alkyl groups, and Xl and X2, which may be the ~-same or di~ferant/
represent hydeogen or halogen arld Xl a~ rep~e(3~nt~s methy 1 .
n will only assume the values 2 and 3 if R
represents halogen or alkyl. The term "halogen"
refers to fluorine, chlorine, bromine and iodine.
The preferred halogens are fluorine, chlorine and bromine, particularly fluorine and chlorine. When Rl, R2, R3, R4 and R5 represent or contain hydrocarbon gro~ps, these may possibly also be branched. However, these groups preferably contain 1 to 2 carbon atoms.
.,j ,.
` ` ~2~;~7~:3 Within the scope of the definitions given herein-before, Rl preferably represents hydrogen, fluorine, chlorine, bromine or methyl, R2 represents hydrogen, Cl 4 alkyl, allyl, 2-hydroxyethyl, 4-fluoro- or 4-chlorobenzyl or dimethylamino. R3 is preferably hydrogen or methyl whilst R4 is Cl 4 alkyl. The preferred definitions of Xl/X2 are chlorine/hydrogen, methyl/hydrogen, chlorine/bromine and bromine/chlorine.
If n represents 2 or 3, there may be different groups Rl present at the same time. Some of the compounds of general formula I are known (DE-OS P 29 38 595).
They are distinguished by their excellent herbicidal action.
According to DE-OS 29 38 595 the compounds of general formula I can be obtained by reacting a nitrodiphenoxybenzene of general formula (Rl)n~
wherein n, Rl, Xl and X2 are a~ hereinbefore defined, with an amine of formula H2NR2 (III) wherein R2 is as hereinbefore defined, at elevated temperature. The compounds of formula II are prepared by reacting a compound of general formula ~ Ei4763 Xl Cl Ll Cl ~ NO2 ~IV) wherein Xl and X2 are as hereinbefore defined, for example 2,3,4-trichlorobenzene, 2,4-dichloro-3-methyl-nitrobenzene and 2,3,4,5-tetrachloronitrobenzene, with a corresponding phenoxide of general formula (Rl)2 ~ OKat (V) (wherein Kat is one equivalent of a cation). Preferably, the alkali metal phenoxides are used, particularly the sodium phenoxide, or the phenol and, for example, an alkali metal carbonate. In the case of simple phenols, particularly unsubstituted phenol, the corres-ponding phenol may servc ~s a rea~tion mec~lum. Ilowever, it is par~icul~rly pre~crred to use dlmeth~lsulphoxide as solvent The two chlorine atoms in the 2- and 4-positions, which can be exchanged for phenoxy groups, show a clearly graduated reactivity.
The known process is less suitable for use on an industrial scale. In the production of the starting substances of formula II, strongly coloured by--products are formed which make it difficult or ~2~497~i3 impossible to carry out further processing directly.
further problem is presented by phenolic by-products, e g. cleavage products of the type Xl OH
(Rl)n X~
An extensive purifying operation is needed to eliminate the by-products.
The reaction of the compounds of formula II
to yield the end products of formula I according to the prior art requires, in some cases, an autoclave reaction in solvents such as toluene, dioxan or chlorinated hydrocarbons. Substantial reaction times (about 12 to 20 hours) are generally required.
It has now been found that the compounds of formula I can be obtained with greater purity, in a shorter time and with less elaborate apparatus, if a nitrobenzene of formula IV is heterogeneously reacted, in the presence of a phase transfer catalyst, with a phen~l of formula (Rl)n Ol~ ~VX) wherein Rl and n are as hereinbefore defined, with the addition of an aqueous alkaline or alkaline earth metal base, at elevated temperature, to ~orm the corresponding 2,4-diphenoxy compound of formula II, which i5 then reacted, in a hiyh-boiling alcohol ~L26~7~i3 containing ether groups, with an amine o~ formula III to form the corresponding compound of formula I.
If desired, the first reaction step, which produces the diphenoxy compounds of formula II, may also be carried out with the addition of inert, water-immiscible solvents. The critical advantage of the reaction according to the invention consists in the use of a conventional phase transfer catalyst. Thanks to the addition of such a catalyst, a very pure product of formula II is obtained in an excellent yield at temperatures of between 60 and 150C, preferably between 80 and 120C, more particularly between 90 and 110C. The phase transfer catalyst can be recovered almost totally. The reaction components of formulae IV and VI are used in a molar ratio of from 1:1.8 to 1:2.5. Preferably, the phenol is used in a slight excess (molar ratio 1:2.1 to 1:2.4) and a quantity of a~ueous base, preferably strong sodium or potassium hydroxide solution, corresponding to the quantity of phenol is used. The quantity of phase transfer catalyst may vary within wide limits. It has proved advantageous to use about 0.005 to 0.12, preferably from 0.01 to 0.06 mol of catalyst per mol of phenol.
Suitable phase transfer catalysts include, for example, triethylbenzylammonium chloride or bromide; tetrabutyl-ammonium chloride, bromide, hydrogen sulphate, hydroxide;
methyl trioctylammonium chloride; tetra~u~ylphos~honium bromide. Nllmerous other ~iuitahle ~ha~.se t.~nsE@r catalysts arè mentioned in the monograph by E.V.
Dehmlow and S.S. Dehmlow, "Phase Transfer Catalysis", Verlag Chemie, Weinheim (1980), particularly page 38 and pages 39-43.
The second reaction step, the reaction of the diphenoxy compounds of formula Il to yield the end products of formula I, is, surprisingly, particularly successful if ether alcohols are ~sed as the reaction medium. Suitable compounds of this kind include, ~264763 in particular, aliphatic or cycloaliphatic compounds, e.g. diethylene glycol, triethylene glycol, dipropylene glycol, diethylene glycol monomethyl ether, monoethy~
ether, monopropyl ether, monobutyl ether, monobenzyl ether, lower monoalkyl ethers of triethylene glycol or of dipropylene glycol and partial ethers of other polyhydric alcohols. The reaction temperature is between about 20 and 180C, preferably between about 40 and 170C; it depends largely on the amine of formula III used. Whereas methylamine, for example, can be reacted at ambient temperature, a higher temperature is required when ammonia is used so that the reaction can be completed with a few hours. A slight increase in the ammonia pressure to 3 to 4 bar can be used to per~orm the reaction at temperatures of about 120 to 130C without taking any longer.
The end products are obtained in very pure form and in very good yields.
In the Examples which follow, the process is described more fully, without being restricted to the embodiments described.
~ 6;~
Preparation of diphenoxy__ompounds of formula II
Example (a)
2-Chloro-4-nitro-1,3-diphenoxybenzene 216.2 g (2.3 mol) of phenol, 226.5 g (1 mol) of 95.5% 2,3,4-trichloronitrobenzene and 10.0 9 of tetrabutylammonium hydrogen sulphate are heated to 100C in a flask with a stirrer. Within 10 minutes, 187.5 9 of 49% sodium hydroxide solution are added dropwise, with vigorous stirring. The reaction mixture is then kept at about 110C for 4 hours. After it has cooled to about 90C, 1 litre of toluene is added and then water is added. The aqueous phase is separated off. The toluene phase is extracted twice with 100 ml of 2N hydrochloric acid. The toluene layer is separated off and concentrated by evaporation ln vacuo. According to gas chromatography, 94.1% of the residue consists of the title compound. From the crude product, 97.4%
of theory of pure end product is obtained, m.p. 106-107C.
The catalyst can be recovered from the hydrochloric acid phase n a yield of more than 90% and sufficiently pure to be usecl again in the form of the hydrochloride.
Example (b)
of theory of pure end product is obtained, m.p. 106-107C.
The catalyst can be recovered from the hydrochloric acid phase n a yield of more than 90% and sufficiently pure to be usecl again in the form of the hydrochloride.
Example (b)
3-Methyl-2,4-diphenoxy-nitrobenzene 20.6 y (0.l mol) of 2,4-dichloro-3-methyl-nitro benzene, 21.6 g (a . ~25 mol) of phenol and 9.3 c~ o( 95% tetrabutylpllosE7honium chlc7rld~ ~0.03 mol) are placed in a stirring app~ratus and heated to 110C.
27 g (0.3 mol) of 50~ sodium hydroxide solution are added dropwise to the mixture, with stirring, and the eesulting mixture is stirred for 2 to 3 hours at reflux temperature. After cooliny, 100 ml of toluene and 50 ml of water are added. The mixture is stirred thoroughly and then the phases are separated.
The toluene solution is extracted with 2N hydrochloric acid and then with 2N sodium hydroxide solution,
27 g (0.3 mol) of 50~ sodium hydroxide solution are added dropwise to the mixture, with stirring, and the eesulting mixture is stirred for 2 to 3 hours at reflux temperature. After cooliny, 100 ml of toluene and 50 ml of water are added. The mixture is stirred thoroughly and then the phases are separated.
The toluene solution is extracted with 2N hydrochloric acid and then with 2N sodium hydroxide solution,
4~7~;3 g then dried and concentrated by evaporation. A brown oil is obtained (yield 31.7 g = 99~ of theory) which crystallises when stirred with a little isopropanol.
The yellowish solid is suction filtered and dried, m.p. 55-57C.
Some of the tetrabutylphosphonium chloride is recovered from the acidic washing liquid.
~26~763 The following compounds may be Qbtained accoedingly.
R" ~ Ll ~ ~/` R
R " ' -r ''2 Example R ~ R." R" ' ;~ 2 Mp 3 H H H Cl Cl 152C
4 4-~ H H Cl H
4-CF3 H H Cl El 6 2-C1 4-Cl El Cl l-l 7 2-C1 4-C1 5-Cl Cl H
8 2-C1 4-Br 5-Cl Cl ri 9 2-CH3 4-Cl H Cl El 2-C1 4-SCEi3 5-Cl Cl H
11 2-CH3 4-CH3 H Cl E~
12 2-CI`I H H Cl H
13 4-F ll 11 Cl-l,, ll 14 4-CF~ El E~ Ct ~
2-F 4-CH~ El CH-~ H
16 2-CH~ 4-CH3 H Cl-l 17 ~ Cl 1~ ~I Cl~
18 2-C1 5-Cl E~. Ei3 I-i 19 4-oCH3 El ~I CH H
3-CF3 H u CH3 ~
~2~i4t76~
Exar~lple R ~ R" R!' r Xl X Mp roCl 21 4-CN H H CH~ T
2Z 4-Br H H CH3 H
4-oCH3 H H Cl H
26 2-CH3 4-oCH3 H Cl H
27 2-C1 4-Br 5-Cl Cl Cl 28 4-oCH3 H H Cl Cl 29 2-CH3 3-OCH3 4-oCH3 Cl H
2-CH3 4-Cl H Cl Cl 31 4-CH(CH3)2 H H Cl H
32 2-CH3 4-oC2H5 H CH3 33 4-OC3~7 H H Cl Cl 34 3-CF3 H H Cl Cl 2-C1 4-Br 5-Cl H Cl 36 4-Cl H H Cl H
37 4-Cl H H CH H
3a 3-C1 5-Cl H Cri 3 39 2-F H H CH~ t!
2-~
41 2-CI-~3 tl H CH~ H
42 3-CH3 H H CH~ ~T
126~7i~
P ration of the end roducts of formula I
re~a P
Example 1 2-Chloro-3- henoxv-6-nitroaniline P
173 9 of 2-chloro-4-nitro-1,3-diphenoxybenzene (crude product according to Example ~a)) are dissolved in S00 ml of triethylene glycol. At 165C, ammonia is passed through the solution for 6 hours. Thin layer chromatography then shows that none of the starting product remains. Whilst the solution is cooled with ice, 250 ml of 2N sodium hydroxide solution and 300 ml of water are added. The reaction product is precipitated and is then suction filtered. 95%
of theory of crude product is obtained, which is shown by gas chromatography to contain 95.8~ of the title compound. The total yield over both steps is 95.3% of theory, m.p. 81-82C (from isopropyl alcohol).
The same result is achieved using diethylene glycol or diethylene glycol monobutyl ether as the solvent instead of triethylene glycol.
In the case of less volatile or more reactive amines, it is sufficient if the components are reacted at temperatures of between ambient temperature and about 160C.
Example 2 2-Methyl-6-nitro-3-phenoxy-N-methylaniline N~C~I3 ~0~ ~
32.1 9 (0.1 mol) of 3-methyl-2,4-diphenoxynitro-~6~L76~
benzene are dissolved in 100 ml of diethylene glycol.
Methyl amine is slowly introduced into the solution, with stirring, at 100C. The progress of thè reaction is monitored by thin layer chromatography (ready-made TLC plates made by Merck of Darmstadt, silica gel 60 F254, toluene/heptan 1:1).
After 3L hours the reaction has ended. After cooling, the product is precipitated by the addition of 2N sodium hydroxide, with trituration, then suction filtered and washed with water. Yellow solid; m.p.
60-62C.
Yield: 23 g (89.2% of theory) ` 2~763 ~ ~ r-~
Ov a~ ~ ) ~ ~
CW~
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O xN c~ ~ ~ ~ r O
~ I X~ ~ ~ V ~: ~
' q q q q q ~ ~ ~ ~.C X ~: ~ r~
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~_ - 15 -O D D 1` 0 J N
($~ D
N N N N N3~N V V ~ _,~ ~\ ~T ~
X 3:: X ~ C ) X 3:~
'X C~ V ~ V V C~
~ 5 X ~ X ~ X r~
X rI~
r ~ rr~
r~ 1;~ r~ t ~ t rr~ ~J ,r~ --t N
~ r-l r-l r-l r-lr~l ~I r-l r I N' N N N t~' N
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~O 0 ," ~ 0 ~ 0 1~ ~ 0 r i a:
O
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O N t~ ~0 Ir~ ~~t--1 r~ (\1 (~ 15~ 0~ tD ~t N C~ ~/ .a~ 0 N
O ~ O O O O O
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a~ 1 4 I~r4 X ~ ~ ~ 4 ~ C~
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X~: X, ~ C ~ ~ ~ X X ~ ~ ~ ~ ~' t~ t ~ t~ t ~ t-~ t~ t~ ,~, t-~t ~ ~ ~ t~ t1 ~~.4 ~.4 ~ 4 X X ~ ~ ~ I; 3 ~ I T X ~ ~ ~ X
--_ ~ ~ X4 ~ X X X
~ N
~ o ~4 1_ X 3 ~ ~4 ~ S\ t ~4 1--4 ~<~
~t~ ~t~ r W I~ -4 ~ r.
O ~C.) t~ C) C.) C_) C.)~.~ ~'t~ ) r_ C~ C~
~ r~ \I r.~J N r~ 4 a t- ~ ~ ~ ~O ~ 0 ~ O ~ t~ C~ r.
t~ ~ ~ ~ ~ ~ ~ ~ ~ t.~ ~r~ lr~
~c r~
~L2~763 , ~
O ~ O N 0 0 ~ t C N ~ X
OO^O^O^O^ OOOOOyOOOO ~
~r N ~ N O
D ~ ~ X~ N ~0 C C~ V ~ ~
~8 X ~ ~ ~ C ~ -- ::C.,C~C~4 ~ X ~ ~ ~C 3:: ~ h ~e ~
X V ~ VC.) C.) C,)C C U ~ C ~ ~ ~~ . ~
~a~
~ l C ~ C XC~C ~X W l C ~ C ~ C l C ~ C ~ ~\ X
a) ~ ~
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-IW-~ ~ ~
C~ ~ ~ O
X ~ C~ C ~ C wCW ~ C ~ W W rl J
tU fd r. r' ~1 o 1 ~ rl c~ r,l vl ~I cl ~ r~
f~ w~ ~ J J N t~ ~ ~,;t ~t J J~t ;t N ,1 0 r~ ,~
fV O ~I N t~ J ~ ~ C0 C~O rl ~`Jr~ J ~ *
r~ ~o ~ ~o ~o ~o ~o ~o ~o ~o r~ .
64~63 Table ~I
Compounds of formula Cl l~nIR2 ~,~0 _~N02 (The compounds are obtained in the form of oils) No. R2 RF values 27C
Acetone/
Heptane Toluene 1: 1 1 C2HS 0.51 0.46 2 n-C3H7 0.615 0.47 3 i-C3H7 0.61 0.45 4 n-C4H9 0.625 0,50 i-C4H9 0.60 0.51 6 HO-CH2-CH2 0.445 0.01 7 CH( 2 5)2 8 -CH2-C-CH 0.31 * 5 toluene/cyclohexan~
~2~ 63 Table III
Compounds of formula Cl NHR2 C:l _~Q_~ N02 No. R2 X2 Properties/m.p.
1 CH3 Cl red crystals m.p. 101C
C H Cl light brown oil, 2 2 5 uniform according to thin layer chromatography 3 i-C3H7 Cl m p. 83C
Cl orange oil, uniform 4 n-C4Hg according to thin layer chromatography n C12 25 Cl m p. 43~C
6 n C18 37 Cl 47 - 48C
7 -cH2-cH2-oH Cl dark oil 8 -CH~C2H5)2 Cl CH =CH-CH H Rf 0.51 (ready-made 2 silica gel TLC plates, 6n F~5~, eluant toluene CH~C2H5)2 ~26~ii3 Table IV
From 1,3-diphenoxybenzenes of formula Cl O ~ Rl R ~ O ~ )/ _ NO2 wherein Rl has the meaning given below, the following compounds of formula Cl NH-R2 - Rl ~ O _'<~ NO 2 are prepared:
No. Rl R2 Rf values 27C
Acetone Toluene ~ Heptane 1 CH3 C~13 0.61 0.~5 2 CH3 C~l2~1~ 0.63 0.515 3 OCH3 n C3H7 0.29
The yellowish solid is suction filtered and dried, m.p. 55-57C.
Some of the tetrabutylphosphonium chloride is recovered from the acidic washing liquid.
~26~763 The following compounds may be Qbtained accoedingly.
R" ~ Ll ~ ~/` R
R " ' -r ''2 Example R ~ R." R" ' ;~ 2 Mp 3 H H H Cl Cl 152C
4 4-~ H H Cl H
4-CF3 H H Cl El 6 2-C1 4-Cl El Cl l-l 7 2-C1 4-C1 5-Cl Cl H
8 2-C1 4-Br 5-Cl Cl ri 9 2-CH3 4-Cl H Cl El 2-C1 4-SCEi3 5-Cl Cl H
11 2-CH3 4-CH3 H Cl E~
12 2-CI`I H H Cl H
13 4-F ll 11 Cl-l,, ll 14 4-CF~ El E~ Ct ~
2-F 4-CH~ El CH-~ H
16 2-CH~ 4-CH3 H Cl-l 17 ~ Cl 1~ ~I Cl~
18 2-C1 5-Cl E~. Ei3 I-i 19 4-oCH3 El ~I CH H
3-CF3 H u CH3 ~
~2~i4t76~
Exar~lple R ~ R" R!' r Xl X Mp roCl 21 4-CN H H CH~ T
2Z 4-Br H H CH3 H
4-oCH3 H H Cl H
26 2-CH3 4-oCH3 H Cl H
27 2-C1 4-Br 5-Cl Cl Cl 28 4-oCH3 H H Cl Cl 29 2-CH3 3-OCH3 4-oCH3 Cl H
2-CH3 4-Cl H Cl Cl 31 4-CH(CH3)2 H H Cl H
32 2-CH3 4-oC2H5 H CH3 33 4-OC3~7 H H Cl Cl 34 3-CF3 H H Cl Cl 2-C1 4-Br 5-Cl H Cl 36 4-Cl H H Cl H
37 4-Cl H H CH H
3a 3-C1 5-Cl H Cri 3 39 2-F H H CH~ t!
2-~
41 2-CI-~3 tl H CH~ H
42 3-CH3 H H CH~ ~T
126~7i~
P ration of the end roducts of formula I
re~a P
Example 1 2-Chloro-3- henoxv-6-nitroaniline P
173 9 of 2-chloro-4-nitro-1,3-diphenoxybenzene (crude product according to Example ~a)) are dissolved in S00 ml of triethylene glycol. At 165C, ammonia is passed through the solution for 6 hours. Thin layer chromatography then shows that none of the starting product remains. Whilst the solution is cooled with ice, 250 ml of 2N sodium hydroxide solution and 300 ml of water are added. The reaction product is precipitated and is then suction filtered. 95%
of theory of crude product is obtained, which is shown by gas chromatography to contain 95.8~ of the title compound. The total yield over both steps is 95.3% of theory, m.p. 81-82C (from isopropyl alcohol).
The same result is achieved using diethylene glycol or diethylene glycol monobutyl ether as the solvent instead of triethylene glycol.
In the case of less volatile or more reactive amines, it is sufficient if the components are reacted at temperatures of between ambient temperature and about 160C.
Example 2 2-Methyl-6-nitro-3-phenoxy-N-methylaniline N~C~I3 ~0~ ~
32.1 9 (0.1 mol) of 3-methyl-2,4-diphenoxynitro-~6~L76~
benzene are dissolved in 100 ml of diethylene glycol.
Methyl amine is slowly introduced into the solution, with stirring, at 100C. The progress of thè reaction is monitored by thin layer chromatography (ready-made TLC plates made by Merck of Darmstadt, silica gel 60 F254, toluene/heptan 1:1).
After 3L hours the reaction has ended. After cooling, the product is precipitated by the addition of 2N sodium hydroxide, with trituration, then suction filtered and washed with water. Yellow solid; m.p.
60-62C.
Yield: 23 g (89.2% of theory) ` 2~763 ~ ~ r-~
Ov a~ ~ ) ~ ~
CW~
D
O xN c~ ~ ~ ~ r O
~ I X~ ~ ~ V ~: ~
' q q q q q ~ ~ ~ ~.C X ~: ~ r~
C~
~r: ~ ~ ~ J ;~
. r I r~ r ~ rl rl ~O~ _ ~ L~ r ~ X ~~l r I X
~I H
O
a Ll ~ r~ J ~ O C- 0 a~, o ~
~_ - 15 -O D D 1` 0 J N
($~ D
N N N N N3~N V V ~ _,~ ~\ ~T ~
X 3:: X ~ C ) X 3:~
'X C~ V ~ V V C~
~ 5 X ~ X ~ X r~
X rI~
r ~ rr~
r~ 1;~ r~ t ~ t rr~ ~J ,r~ --t N
~ r-l r-l r-l r-lr~l ~I r-l r I N' N N N t~' N
X
~_ o o~ ~ ~ C ~ O
._ I .i I I I ~ I
~O 0 ," ~ 0 ~ 0 1~ ~ 0 r i a:
O
L~
X~
~ ~ ~ W ~ ~ ~ ~ X ~:~ V
X ~ ~ V V ~ v ~ c~ V ~ ::C ~ X
~ ~ "~
X V C~ C~ V V C~ ~ V V V V V V V V C~ V
~-~
r~
_ ~ ~ J ~ ~ ~t ~ X ~~C X ~ ~ ~\U~
V C~ ~ V t~ r I O
O
~ ~O ~, 0 tJ~ Or t~ t~ ~ t~ t~ ~ C() ~<~ _t ~ -t F~
- 1 7 -` ~L26~63 U~
C~ O Lr~ ~1 o ~ ~ o~ ~ ~t~
`t I I o I I t~\
O N t~ ~0 Ir~ ~~t--1 r~ (\1 (~ 15~ 0~ tD ~t N C~ ~/ .a~ 0 N
O ~ O O O O O
~ t~
~J r~ I X
a~ 1 4 I~r4 X ~ ~ ~ 4 ~ C~
N
X~: X, ~ C ~ ~ ~ X X ~ ~ ~ ~ ~' t~ t ~ t~ t ~ t-~ t~ t~ ,~, t-~t ~ ~ ~ t~ t1 ~~.4 ~.4 ~ 4 X X ~ ~ ~ I; 3 ~ I T X ~ ~ ~ X
--_ ~ ~ X4 ~ X X X
~ N
~ o ~4 1_ X 3 ~ ~4 ~ S\ t ~4 1--4 ~<~
~t~ ~t~ r W I~ -4 ~ r.
O ~C.) t~ C) C.) C_) C.)~.~ ~'t~ ) r_ C~ C~
~ r~ \I r.~J N r~ 4 a t- ~ ~ ~ ~O ~ 0 ~ O ~ t~ C~ r.
t~ ~ ~ ~ ~ ~ ~ ~ ~ t.~ ~r~ lr~
~c r~
~L2~763 , ~
O ~ O N 0 0 ~ t C N ~ X
OO^O^O^O^ OOOOOyOOOO ~
~r N ~ N O
D ~ ~ X~ N ~0 C C~ V ~ ~
~8 X ~ ~ ~ C ~ -- ::C.,C~C~4 ~ X ~ ~ ~C 3:: ~ h ~e ~
X V ~ VC.) C.) C,)C C U ~ C ~ ~ ~~ . ~
~a~
~ l C ~ C XC~C ~X W l C ~ C ~ C l C ~ C ~ ~\ X
a) ~ ~
,~ a . .
-IW-~ ~ ~
C~ ~ ~ O
X ~ C~ C ~ C wCW ~ C ~ W W rl J
tU fd r. r' ~1 o 1 ~ rl c~ r,l vl ~I cl ~ r~
f~ w~ ~ J J N t~ ~ ~,;t ~t J J~t ;t N ,1 0 r~ ,~
fV O ~I N t~ J ~ ~ C0 C~O rl ~`Jr~ J ~ *
r~ ~o ~ ~o ~o ~o ~o ~o ~o ~o r~ .
64~63 Table ~I
Compounds of formula Cl l~nIR2 ~,~0 _~N02 (The compounds are obtained in the form of oils) No. R2 RF values 27C
Acetone/
Heptane Toluene 1: 1 1 C2HS 0.51 0.46 2 n-C3H7 0.615 0.47 3 i-C3H7 0.61 0.45 4 n-C4H9 0.625 0,50 i-C4H9 0.60 0.51 6 HO-CH2-CH2 0.445 0.01 7 CH( 2 5)2 8 -CH2-C-CH 0.31 * 5 toluene/cyclohexan~
~2~ 63 Table III
Compounds of formula Cl NHR2 C:l _~Q_~ N02 No. R2 X2 Properties/m.p.
1 CH3 Cl red crystals m.p. 101C
C H Cl light brown oil, 2 2 5 uniform according to thin layer chromatography 3 i-C3H7 Cl m p. 83C
Cl orange oil, uniform 4 n-C4Hg according to thin layer chromatography n C12 25 Cl m p. 43~C
6 n C18 37 Cl 47 - 48C
7 -cH2-cH2-oH Cl dark oil 8 -CH~C2H5)2 Cl CH =CH-CH H Rf 0.51 (ready-made 2 silica gel TLC plates, 6n F~5~, eluant toluene CH~C2H5)2 ~26~ii3 Table IV
From 1,3-diphenoxybenzenes of formula Cl O ~ Rl R ~ O ~ )/ _ NO2 wherein Rl has the meaning given below, the following compounds of formula Cl NH-R2 - Rl ~ O _'<~ NO 2 are prepared:
No. Rl R2 Rf values 27C
Acetone Toluene ~ Heptane 1 CH3 C~13 0.61 0.~5 2 CH3 C~l2~1~ 0.63 0.515 3 OCH3 n C3H7 0.29
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A two step process for the preparation of compounds of formula (I) (I) wherein n is an integer from 1 to 3, R1 represents hydrogen, halogen, alkyl or alkoxy with 1 to 8 carbon atoms, trifluoromethyl, acetyl or cyano, R2 represents hydrogen; alkyl, alkenyl or alkynyl with up to 16 carbon atoms; an alkyl group with 2 to 6 carbon atoms substituted by hydroxy, C1-4 alkoxy, phenoxy, halophenoxy, C1-4 alkylphenoxy, C1-4 alkoxyphenoxy, nitrophenoxy, cyanophenoxy, amino or C1-4 alkylthio; optionally halosubstituted benzyl, NR3R4, CHR3-COOR4 or CHR3-CONR4R5, wherein R3, R4 and R5, which may be the same or different, represent hydrogen or C1-8 alkyl groups, and X1 and X2, which may be thc same or different, represent hydrogen or halogen and X1 also represents methyl, in which process technical grade materials are used and in which the formation of undesirable colored by-products is substantially avoided, which comprises:
(a) in a first step reacting a nitrobenzene of formula (IV) (IV) in which X1 and X2 are as defined above, with a phenol of the formula (VI) (VI) in which R1 and n are as defined above, at a temperature between 60°C and 150°C, and in the presence of a phase transfer catalyst and of an aqueous alkaline or alkaline earth metal base to provide a compound of formula (II):
(II), and recovering the compound of formula (II), and (b) in a second step reacting the thus obtained compound of formula (II), if desired without further purification, in an alcohol containing ether groups as solvent, with an amine of the formula (III) H2NR2 (III) in which R2 is as defined above, to provide a compound of formula (I).
(a) in a first step reacting a nitrobenzene of formula (IV) (IV) in which X1 and X2 are as defined above, with a phenol of the formula (VI) (VI) in which R1 and n are as defined above, at a temperature between 60°C and 150°C, and in the presence of a phase transfer catalyst and of an aqueous alkaline or alkaline earth metal base to provide a compound of formula (II):
(II), and recovering the compound of formula (II), and (b) in a second step reacting the thus obtained compound of formula (II), if desired without further purification, in an alcohol containing ether groups as solvent, with an amine of the formula (III) H2NR2 (III) in which R2 is as defined above, to provide a compound of formula (I).
2. A process according to claim 1 wherein step (a) is carried out at a temperature between 80 and 120°C.
3. A process as claimed in claim 1, characterised in that, in step (a), 2,3,4-trichloronitrobenzene is used as the nitro-benzene of formula (IV) and phenol or 4-fluorophenyl is used as the phenol of formula (VI) and in step(b) arnmonia or methylamine is used as the amine of formula (III).
4. A process as claimed in claim 1, characterised in that, in step (a), 2,4-dichloro-3-methylnitrobenzene is used as the nitrobenzene of formula (IV), phenol or 4-fluorophenol is used as the phenol of formula (VI) and, in step (b), arnmonia or methyl-amine is used as the amine of formula (III).
5. A process according to claim 1 wherein, as a further step, the phase transfer catalyst is recovered and reused.
6. A process according to claim 1 wherein the alkali metal base is used.
7. A process according to claim 6 wherein the alkali metal base is sodium or potassium hydroxide.
8. A process according to claim 1 wherein the phase trans-fer catalyst is chosen from a triethylbenzylammonium, tetrabutyl-ammonium, methyltrioctylammonium, or tetrabutylphosphonium salt.
9. A process according to claim 8 wherein the phase transfer catalyst is chosen from tetrabutylammonium hydrogen sulphate, and tetrabutylphosphonium chloride.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823209878 DE3209878A1 (en) | 1982-03-18 | 1982-03-18 | METHOD FOR PRODUCING DIPHENYL ETHERS |
| DEP3209878.2 | 1982-03-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1264763A true CA1264763A (en) | 1990-01-23 |
Family
ID=6158603
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000423736A Expired - Lifetime CA1264763A (en) | 1982-03-18 | 1983-03-16 | Process for the preparation of diphenyl ethers |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0089517B1 (en) |
| JP (1) | JPS58170736A (en) |
| AT (1) | ATE20340T1 (en) |
| CA (1) | CA1264763A (en) |
| DE (2) | DE3209878A1 (en) |
| IL (1) | IL68142A0 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10144711B2 (en) | 2013-09-09 | 2018-12-04 | Peloton Therapeutics, Inc. | Aryl ethers and uses thereof |
| US10155726B2 (en) | 2015-03-11 | 2018-12-18 | Peloton Therapeutics, Inc. | Substituted pyridines and uses thereof |
| US10278942B2 (en) | 2015-03-11 | 2019-05-07 | Peloton Therapeutics, Inc. | Compositions for use in treating pulmonary arterial hypertension |
| US10335388B2 (en) | 2015-04-17 | 2019-07-02 | Peloton Therapeutics, Inc. | Combination therapy of a HIF-2-alpha inhibitor and an immunotherapeutic agent and uses thereof |
| US10512626B2 (en) | 2015-03-11 | 2019-12-24 | Peloton Therapeautics, Inc. | Compositions for use in treating glioblastoma |
| US10807948B2 (en) | 2015-03-11 | 2020-10-20 | Peloton Therapeutics, Inc. | Aromatic compounds and uses thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5424280A (en) * | 1993-10-07 | 1995-06-13 | American Cyanamid Company | Aryloxybenzene herbicidal agents |
| GB9622345D0 (en) * | 1996-10-28 | 1997-01-08 | Zeneca Ltd | Chemical process |
| US8071804B2 (en) * | 2007-10-24 | 2011-12-06 | Dow Agrosciences Llc | Process for the manufacture of R-(+)-2-(4-(4-cyano-2-fluorophenoxy)phenoxy)propionic acid esters |
| CN114349647B (en) * | 2021-10-29 | 2024-01-09 | 陕西菲尔特化工有限公司 | Synthesis method of aclonifen |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2311004A1 (en) * | 1975-05-13 | 1976-12-10 | Ciba Geigy Ag | PROCESS FOR PREPARING DIARYLIC COMPOUNDS OR HETEROARYLIC COMPOUNDS AND PRODUCTS OBTAINED BY THIS PROCESS |
| DE2938595A1 (en) * | 1979-09-24 | 1981-04-23 | Celamerck Gmbh & Co Kg, 6507 Ingelheim | METHOD FOR PRODUCING DIPHENYL ETHERS |
-
1982
- 1982-03-18 DE DE19823209878 patent/DE3209878A1/en not_active Withdrawn
-
1983
- 1983-02-28 AT AT83101949T patent/ATE20340T1/en not_active IP Right Cessation
- 1983-02-28 DE DE8383101949T patent/DE3364001D1/en not_active Expired
- 1983-02-28 EP EP83101949A patent/EP0089517B1/en not_active Expired
- 1983-03-15 JP JP58044033A patent/JPS58170736A/en active Granted
- 1983-03-16 CA CA000423736A patent/CA1264763A/en not_active Expired - Lifetime
- 1983-03-16 IL IL68142A patent/IL68142A0/en not_active IP Right Cessation
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10144711B2 (en) | 2013-09-09 | 2018-12-04 | Peloton Therapeutics, Inc. | Aryl ethers and uses thereof |
| US10597366B2 (en) | 2013-09-09 | 2020-03-24 | Peloton Therapeutics, Inc. | Aryl ethers and uses thereof |
| US10155726B2 (en) | 2015-03-11 | 2018-12-18 | Peloton Therapeutics, Inc. | Substituted pyridines and uses thereof |
| US10278942B2 (en) | 2015-03-11 | 2019-05-07 | Peloton Therapeutics, Inc. | Compositions for use in treating pulmonary arterial hypertension |
| US10512626B2 (en) | 2015-03-11 | 2019-12-24 | Peloton Therapeautics, Inc. | Compositions for use in treating glioblastoma |
| US10807948B2 (en) | 2015-03-11 | 2020-10-20 | Peloton Therapeutics, Inc. | Aromatic compounds and uses thereof |
| US10335388B2 (en) | 2015-04-17 | 2019-07-02 | Peloton Therapeutics, Inc. | Combination therapy of a HIF-2-alpha inhibitor and an immunotherapeutic agent and uses thereof |
| US10786480B2 (en) | 2015-04-17 | 2020-09-29 | Peloton Therapeutics, Inc. | Combination therapy of a HIF-2-α inhibitor and an immunotherapeutic agent and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0089517B1 (en) | 1986-06-11 |
| ATE20340T1 (en) | 1986-06-15 |
| JPH0480898B2 (en) | 1992-12-21 |
| IL68142A0 (en) | 1983-06-15 |
| DE3209878A1 (en) | 1983-09-29 |
| EP0089517A1 (en) | 1983-09-28 |
| DE3364001D1 (en) | 1986-07-17 |
| JPS58170736A (en) | 1983-10-07 |
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