CA2123242A1 - Derivatives of 3-fluorophenol, processes for preparing them, and the use of these compounds - Google Patents
Derivatives of 3-fluorophenol, processes for preparing them, and the use of these compoundsInfo
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- CA2123242A1 CA2123242A1 CA002123242A CA2123242A CA2123242A1 CA 2123242 A1 CA2123242 A1 CA 2123242A1 CA 002123242 A CA002123242 A CA 002123242A CA 2123242 A CA2123242 A CA 2123242A CA 2123242 A1 CA2123242 A1 CA 2123242A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C215/76—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
- C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
- C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
- C07C217/86—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C265/00—Derivatives of isocyanic acid
- C07C265/12—Derivatives of isocyanic acid having isocyanate groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
- C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Abstract of the disclosure Novel derivatives of 3-fluorophenol, processes for their preparation, and their use The present invention relates to compounds of the formula (I)
Description
~OECHST AKTIENGESELLSCHAFT HOE 93/F 133 Dr.Bl/PP
Description 2 1 2 3 2 ~ 2 Novel derivatives of 3-fluorophenol, proce~ses for preparing them, and the use of these compound The pre~ent invention relates to novel derivatives of 3-fluorophenol, to proce~ses for preparing them, and to the use of these compounds.
.. . .
Derivatives of 3-fluorophenol are useful intermediates in the preparation of plant protection agents, pharmaceu-ticals and industrial products, such as, for example, liquid crystals. Owing to the general importance, and numerous uses, of this substance class, it represents a rewarding object to prepare novel compounds from this group of substances in order not only to supplement the spectrum of their posslble applications, but also to 15 enxich and extend it by giving nuances to material i-;~
properties.
: .
This object is achieved by compounds of the formula (I) ORl ~R 2 in which is hydrogen, (C1-C8~-alkyl or CH2-phenyl, where the alkyl radical or the phenyl group can be substituted by one to three ( Cl-C4 ) -alkoxy groups, fluorine, chlorine or bromine atoms~ nitrc groups, cyano groups, trifluoromethyl grcups or (C1 C4 ) -alkoxy-! carbonyl groups, and ¦25 RZ is -CW, -CON~2, -NH2, -NCO or -N~CooR3, where R3 has Ithe m~anings of R1 other than that of hydrogen.
¦Cyclic, straLght-chain or singly or multiply branched f ~ 2 1 2 3 2 ~ 2 alkyl radicals are generally suitable as alkyl radicals.
Examples of ~uch radicals are the methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-pentyl, i~pentyl, n-hexyl, i-hexyl, n~heptyl, i-heptyl, n-octyl, i-octyl, 2-chloroethyl, 2-bromoethyl, 2-methoxyethyl, 2-ethoxy-ethyl, 3-methoxypropyl, 3-ethoxypropyl, 4-methoxybutyl, ~- 3-chloropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohsxyl and methylcyalohexyl radicals.
In addition to unsubstituted phenyl, phenyl radicals which are substituted one to three times ars generally suitable as phenyl radicals.
.1 Those which may be mentioned here by way of example are 2-methylphenyl~ 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluoro-phenyl, 4-trifluoromethylphenyl, 2,5-dichlorophenyl, 2,4-dichlorophenyl, 3-nitrophenyl, 4-cyanophenyl, 3,5-dimethoxyphenyl, 2-nitrophenyl and2,4,5-trichlorophenyl.
is, in particular, hydrogen, a linear or branched l(Cl~C~)-alkyl group or a CH2-phenyl group.
j20 A certain importance i~ attached to the phenols of the ,formula I (~l = H) in which R2 iB -CONH2 or NH2, in par-ticular 2-amino-3-fluorophenol and 2-hydroxy-6-fluoro-benzamide.
The compounds of the foxmula I in which Rl is CH2-phenyl and R2 is -CN, -CONH2, NH2 or NHCooR3, in particular 2 1 benzyloxy-6-fluorobenzamide, 2~benzyloxy-6-1uoroaniline, j 2-benzyloxy-6-fluoro-N-benzyloxycarbonylaniline and ~-benzyloxy-6-fluorobenzonitrile, are also valuable inter-mediates.
.,~
The compound~; of the formula I in which R' i6 (C,-Ca)-alkyl and R2 is -CN or -CON~2, in paxticular 2-ethoxy-6-fluorobenzonitrile and 2-ethoxy-6-fluorobenzamide, are of interest.
, `I
~ 2~23242 ~ ,~
Description 2 1 2 3 2 ~ 2 Novel derivatives of 3-fluorophenol, proce~ses for preparing them, and the use of these compound The pre~ent invention relates to novel derivatives of 3-fluorophenol, to proce~ses for preparing them, and to the use of these compounds.
.. . .
Derivatives of 3-fluorophenol are useful intermediates in the preparation of plant protection agents, pharmaceu-ticals and industrial products, such as, for example, liquid crystals. Owing to the general importance, and numerous uses, of this substance class, it represents a rewarding object to prepare novel compounds from this group of substances in order not only to supplement the spectrum of their posslble applications, but also to 15 enxich and extend it by giving nuances to material i-;~
properties.
: .
This object is achieved by compounds of the formula (I) ORl ~R 2 in which is hydrogen, (C1-C8~-alkyl or CH2-phenyl, where the alkyl radical or the phenyl group can be substituted by one to three ( Cl-C4 ) -alkoxy groups, fluorine, chlorine or bromine atoms~ nitrc groups, cyano groups, trifluoromethyl grcups or (C1 C4 ) -alkoxy-! carbonyl groups, and ¦25 RZ is -CW, -CON~2, -NH2, -NCO or -N~CooR3, where R3 has Ithe m~anings of R1 other than that of hydrogen.
¦Cyclic, straLght-chain or singly or multiply branched f ~ 2 1 2 3 2 ~ 2 alkyl radicals are generally suitable as alkyl radicals.
Examples of ~uch radicals are the methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-pentyl, i~pentyl, n-hexyl, i-hexyl, n~heptyl, i-heptyl, n-octyl, i-octyl, 2-chloroethyl, 2-bromoethyl, 2-methoxyethyl, 2-ethoxy-ethyl, 3-methoxypropyl, 3-ethoxypropyl, 4-methoxybutyl, ~- 3-chloropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohsxyl and methylcyalohexyl radicals.
In addition to unsubstituted phenyl, phenyl radicals which are substituted one to three times ars generally suitable as phenyl radicals.
.1 Those which may be mentioned here by way of example are 2-methylphenyl~ 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluoro-phenyl, 4-trifluoromethylphenyl, 2,5-dichlorophenyl, 2,4-dichlorophenyl, 3-nitrophenyl, 4-cyanophenyl, 3,5-dimethoxyphenyl, 2-nitrophenyl and2,4,5-trichlorophenyl.
is, in particular, hydrogen, a linear or branched l(Cl~C~)-alkyl group or a CH2-phenyl group.
j20 A certain importance i~ attached to the phenols of the ,formula I (~l = H) in which R2 iB -CONH2 or NH2, in par-ticular 2-amino-3-fluorophenol and 2-hydroxy-6-fluoro-benzamide.
The compounds of the foxmula I in which Rl is CH2-phenyl and R2 is -CN, -CONH2, NH2 or NHCooR3, in particular 2 1 benzyloxy-6-fluorobenzamide, 2~benzyloxy-6-1uoroaniline, j 2-benzyloxy-6-fluoro-N-benzyloxycarbonylaniline and ~-benzyloxy-6-fluorobenzonitrile, are also valuable inter-mediates.
.,~
The compound~; of the formula I in which R' i6 (C,-Ca)-alkyl and R2 is -CN or -CON~2, in paxticular 2-ethoxy-6-fluorobenzonitrile and 2-ethoxy-6-fluorobenzamide, are of interest.
, `I
~ 2~23242 ~ ,~
The present invention additionally relates to processes ~, for preparing the compound3 according to the in~ention.
. Thus, compounds of the formula I, in which R1 is hydrogen, ~Cl-C8)-alkyl or CH2-phenyl, where the alkyl radical or the phenyl group can be sub3tituted by one to -~ three (C,-C4)-alkoxy group , fluorine, chlorine or bromine atom~i, nitro groups, cyano groups, trifluoromethyl group3 ! or (C1-C4)-alkoxycarbonyl groups, and R2 i8 -NH2 or ~ -NHCooR3~ can be prepared by reacting compounds of the ;i 10 formula (II) ~ .
~ C ~ N H 2 ., .
in which X i5 OR', in a~ueous-alkaline medium, with i chlorine, bromine, sodium hypochlorite or sodium hypo-I bromite in the presence of alcohols and at temperatures i of from -15C to ~80~C, in the ~en~ie of a ~ofmann j 15 degradation. : -In many ca6es, it ha3 proved to be of value to employ, as the alcoh~l component, compounds of the formula ~oR3, where R3 is ( C1_CB ) -a1kY1 or CH2-phenyll where the alkyl radical or the phenyl group can be substituted by one to ~ . :
three (C1-C4)-alkoxy groups, fluorine, chlorine or bromine ~: atoms, nitro groups, cyano groups, trifluoromethyl groups :: -;1: or (C1-C~]-alkoxycarbonyl groups.
~ The compound o the formula (I') ,~
~N H C O O R ~ ~:
:~ resulting fro:m the reaction can be isolated. However, it ~ :
25 i8 also possi.ble to cleave the carbamate group and/or, for X = OR1, the group OR1 (when R1 i8 not hydrogen) ' ~' .
i ~1 :
` ` 2123242 . ~
~ hydrogenolytically or hydrolytically without undertaking '~! any intermediate isolation. It is likewise po6sible to ~elect the reaction condition~ such that the cleavage already takes placP to a large extent at the same time a~
the rearrangementa s The compounds of the formula II are prepared by convert-ing the corresponding nitriles into the benzamides by methods which are generally known in the literature (J.
March, Advanced Organic Chemistry [1985], 788).
In this context, preference is given to the reaction of 2,6-di~luorobenzonitrile in aqueous~alkaline medium with hydrogen peroxide (JP-OS 60-132 942), where appropriate in correspondan~e with the pre~ent invention, in the presence of from about 1 to about 20 mol, preferably from about 0.1 to 10 mol, particularly preferably between about 1.05 mol and 5 mol, of alcohol per 1 mol of 2,6-difluorobenzonitrile. In this context, alkan-(C,-C8)-ols of any structure, which can additionally be substituted ^~ by alkoxy(Cl-C4) groups, fluorine, chlorine or bromine atoms, nitro groups, cyano groups, trifluoromethyl groups or alkoxylCl-C4)-carbonyl gr~ups, or phenylmethanols, where the phenyl radical can be substituted by alkyl(Cl-C4 ) groups, alkoxy~Cl-C4~ groups, fluorine, chlorine or bromine atoms, nitro groups, cyano groupY, trifluoro-methyl groups or alkoxy(CI-C4)-carbonyl groups, can be used as Rl-OH alcohols; primary alcohol~ are preferred, `with methanol, ethanol and benzyl alcohol being particu-larly preferred.
.~
2,6-Difluorobenzamide can be isolated; however, it is l 30 also possi~le to obtain the compounds of the formula II
having X = ORl immediately in a one-pot process. Thi~ can be achieved, in particular, by raising the reaction il temperature.
The work is carried out at temperatures of between about 0 and about 90C, preferably of between about 20 and ;'j '1 !
~ 2123242 s about 70C.
If 2,6-difluorobenzamide, which has been isolated as an intermediate, i~ employed for preparing the compounds ~f the formula II having X - ORl, the work i~ preferably carried out, in accordance with the invention, in excess alcohol, as described above, and reaction takes place, in the temperature range which has likewise already been defined, with about 1 mol to about 1.8 mol, particularly preferably with about 1.1 mol to about 1.5 mol, of alkali metal or alkaline earth metal compounds having an alkaline effect. Ex~mples of such compounds having an 1 alkaline effect are hydroxides, carbonates, hydrogen carbonates, phosphatesl hydrogen phoæphates, dihydrogen phosphates, oxides, or similar compounds, or mixtures ~
15 thereof; sodium or potassium hydroxide or carbona$e are -1 1 preferred. The reaction times amoun to from about 1 to '1 about 16 h, with the reaction product generally being ¦ isolated, in the event that isolation is ~esired, by diluting the reaction mixture with water and filtering off (extraction, crystallization, chromatography).
~ Alternatively, it is possible to react 2,6-difluorobenzo-`1 nitrile, as explained below, or 2,6-difluorobenzamide i with the above-describ2d quantities and types of ~ ~
~ compounds having an allcaline ef~ect and al~ohols in ~ -¦ 25 dipolar, aprotic solventsr Acetone, tetrahydrofuran (THF), acetonitrile, 1,2-dimethoxyethane (DMAc), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl ~ulfoxide (DMS0), dimethyl ~ulfone, diphenyl sulfoxide, diphenyl sulfone, tetramethylurea, tetra-n-l 30 butylurea or 1,3-dimethylimidazolidin-2-one (DMI), or 3 mixtures thereof, can be used as dipolar, aprotic solvents. Such solvents are u~ed in ~uantities of about li 50 to 500 ~ by mass, based on 2,6-difluorobenzamide or J 2,6-difluoroblenzonitrile, preferably in quantities of I 35 between about 80 and about 250 % by mass. The use of !l these solvent:s makes it possible to ~eparate off by ~ filtration the alkali metal or alkaline earth metal ~ .
21232~2 fluoride which i~ formed in the reaction; the product i8 ' crystallized from the mother liquor by adding water and the solvent is recovered by di~tillation. In this variant of the process, the work is carried out at reaction 5 temperatures of between about 30 and about 150C, preferably of between about 40 and about lOO~C. A~
l compared with aqueous variants of the process, this ! variant has the advantage of higher yields.
The preparation of 2-(primary-alkoxy)-6-fluorobenzamides is preferred, with that of 2-methoxy-6-fluorobenzamide, 2-ethoxy-6-fluorobenzamide and 2-benzyloxy-6-fluoro-benzamide being particularly preferred.
In the sase of 2-benzyloxy-6-fluorobenzamide, 2-hydroxy-6-fluorobenzamide can be obtained by hydrogenolytic elimination OI the benzyloxy group.
i Compounds of the formula I (R' ~ hydrogen) having R2 = CN
i can be obtained in an analoyous mannerc For this purposs, 2,6-difluorobenzonitrile is reacted with R30H alcohols in aqueous-alkaline or dipolar, aprotic medium in the presence of alkali~.
In this context, alkan-(CI-C8)-ols of any ~tructure, which can additionally be substituted by alkoxy(C1-C4~ groups, fluorine, chlorine or bromine atoms, nitro groups, cyano group~, trifluoromethyl gxoups or alkoxy-(Cl-C~)-carbonyl groups, or phenylmethanol~, where the phenyl radical can be 0ub~tituted by alkyl( C,-C4 ) groups, alkoxy(Cl-C4) groups, fluorine, chlorine or ~romine atom~, nitro roups, cyano groups, trifluoromethyl group~ or alkoxy-~C,-C~)-carbonyl groups, can be u~ed a~ Rl-OH alcohols;
! 30 primary alcohols are preferred, with methanol, ethanol and benzyl alcohol being particularly preferred.
~ It i8 al~o pos~ible to obtain compounds of the formula I
¦ (Rl ~ hydrogen) having R2 - NH2 in a one-pot process by ¦ reacting either 2,6-difluorobenzonitrile or 2,6-difluoro-,, :
~123242 benzamide in aqueous-alkaline medium with alcohols to form compounds of the formula II having X = OR1 ~R1 ~
hydrogen), and then reacting the latter~ after inter-~mediate isolation, but preferably without any '!5 intermediate isolation~ in a one-pot proces3, with chlorine, bromine, sodium hypochlorite or sodium hypo-bromite, at temperatures of from -15C to ~80C and in ~the presence of alcohols, in the sense of a Hofmann ddegradation, and ~ubsequently, where appropriate, `i,10 cleaving ~arbamates which have been formed hydrolytically ~or hydrogenolytically.
j':!In this context, (C,-C8)-alkanols or phenylmethanols, `Alwhere the alkyl radical or the phenyl radical can be `'substituted by one to three (Cl-C4)-alkoxy groups, fluorine, chlorine or bromine atoms, nitro groups, cyano groups, trifluoromethyl groups or (Cl-C4)-alkoxycarbonyl groups, in particular primary alcohols, can also be employed as alcohols.
jIn many cases, the use of methanol, ethanol or benzyl alcohol has proved to be advantageous.
These alcohols are employed in mixtures with aqueous solutions having an alkaline effect, a~ described above, ipreferably sodium or potassium hydroxide solutions. The compounds having an alkaline effect are used, dissolved or su~pended in water, in quantities, based on the amide to be dsgraded, of between about 1 mol and about 30 mol, preferably of between about 3 mol and about 15 mol, particularly preferably of between about 5 mol and about 10 mol. While the concentrations of the aqueous solutions depend on the amide employed, the concentrations are typically between about 1 mol/l and about 20 mol/l, ~;~preferably between about 3 mol/l and about 10 mol/1. In ¦practice, the quantity of the aqueou~ suspension having an alkaline effect i~ chosen such that it is still possible to stir the reaction mixture.
.1 `` 2~23242 The procedure can be carried out using hypohalite solu-tions (bleaching liquors), which is completely equivalent to metering elemental halogen into solutions having an I alkaline effect. An indication of the quantity of halogen 5 employed is suPficient to describe the reaction ,~ondi-tions since, in situ, hypohalite solution~ are formed when halogen makes contact with the aqueous solutions having an alkaline effe,ct which are employed. Chlorine or ~ bromine are used, therefore, in quantities of between i 10 about 1 mol and about 5 mol, preferably of from about 1.01 mol to about 2 mol, particularly preferably of between about 1.02 mol and about 1.2 mol, in each case based on 1 mol of amide to be degraded. Chlorine is preferably used since it is more readily available 15 industrially. The halogen can be added dropwise (bromine) or passed in in gaseous form (chlorine). In thi~ regard, suitable metering times on a laboratory ~cale are, ~ depending on the reaction temperature, between about 1 0.5 h and about 8 h, preferably from about 1 h to about 20 4 h. Owing to the reaction being exothermic, the metering times on an industrial scale mu~t be adapted to the cooling capacities available.
The reaction in the ~en~e of the Hofmann degradation is carried out at temperatures of between about -15C and about 100C, preferably of between about 0C and about 60C, particularly preferably of between about 10C and about 40~C.
::
If bleachin~ liquor~ e. aqueous hypohalite solutions, are metered in, which generally has operational advan-tage~ as ~ompared with the use of elemental halogen, ~ solutions are then used having a content of active 1 chlorine of from about 30 to about 250 ~ per kg of solution, preferably of between about 100 and about 160 g of active ch~orine per kg of solution, or from about 60 to about 550 g o~ active bromine per kg of solution,preferably oP between about 200 and about 350 g per kg of solution. These solutions may be obtained by metering the , . .~
, ~ 9 corresponding quantities of chlorine or bromine into aqueous solutions having an alkaline effect.
~.~
In the variant according to the invention, the primary reaction product of the reaction in the ~en3e of a i 5 Hofmann degradation is pressmably the alkyl carbamate of the desired aniline, ~ince the isocyanate ari~ing as an intermediate i8 probably captured by the alcoholates, i nucleophilic under the reaction conditions~
The anilines can be obtained from the carbamates by 10 processes known in principle from the literature (T.W. Greene, P.G.M. Wuts, Protective Group~ in Organic ¦ Chemistry (1991), 317-348). As a rule, liberation of the amino group is achieved by heating the reaction mixture according to the invention, once any excesses of chlorine 15 or bromine have been destroyed. Optionally sub~tituted , benzyl carbamates can be hydroly~ed under alkaline 3 conditions in less than 10 h at from 80 to '00C, whereas ¦ simple alkyl carbamates require reaction times of up to 96 h at the same temperatures. ~he use of optionally 20 substituted benzyl alcohol is therefore particularly ~ preferred since the resulting benzyl carbamates can be I cleaved without any great difficulty, and therefore cost-effectively, by hydrogenation (T.W. Greene et al., loc.
cit., 335-341). The hydrogenolytic cleavage is preferably 25 carried out in the presence of transition metal catalyst~, in particular platinum, nickel or palladium cataly~ts. In general, the reaction products can ~e ~ i~olated simply by phase separation, resulting in I mixtures with the alcohols employed. The phase separation 30 can be improved or induced by adding additional solvents, such a~ t for example, toluene or xylene.
. .
The resulting solutions of the free amine~ can, provided they contain compounds which posse s benzyl group~, be hydrogenated by methods which are generally known from 35 the literature (T.W. Greene et al., loc~ cit., 47-68, 156-160, 335-341). Hydrogenation u~ing hydrogen gas in ,:! .
- 1o_2~23242 the presence of transition metal catalysts, preferably palladium catalysts, particularly preferably palladium on active charcoal, is preferred. An alternative option is to use the so-called transfer-hydrogenation method for ~l 5 synthesizing the novel intermediates (T~W. Greene et al., -lj loc. cit., 156-160). Besides palladium, nickel or ,! platinum, in particular, are suitable for employment as transition metals. The hydrogenations proceed smoothly under a hydrogen pressure of between about 1~1 bax and about 100 bar at temperatures of between about 10 and about 80C in lower aliphatic alcohols or simple aromatic or aliphatic hydrocarbons, such as, for example, hexane, methylcyclohexane, toluene, xylene, methanol, butanol, isopropanol or ethanol as solvent, or mixtures thereof.
The precious metal catalysts are employed in quantikies of between about 0.05 and about 3, preferably of from i about 0.3 to about 1, % by mass (calculated as pure transition metal). The concentration of the end product (in particular 2-amino-3-fluorophenol) in the hydrogena-`1 20 tion mother liquor is typically between about lD and j about 500, preferably between about 100 and about 300, '37 g/l. If the unsubstituted benzyl compounds are employed , under these circumstances, the free hydroxyl groups and !~7 toluene are obtained during the hydrogenation. Toluene is ~3 25 therefore preferred as the ~iolvent ~or the hydrogenation.
j The end product, 2-amino-3-fluorophenol, can be i~iolated by concentrating the solutions, from which, where appro-priate, the catalyst has been filtered off while the 3 solutions were hot, and subsequently filtering them. In 30 this context, it is advi~able to carry out the procedure `i in the presence of oxidation-preventing additivPs, such l I as hydrazine or hydrazinium Ralts, or 2,6-di-tert-butyl-~7 4-methylphenol, since the end product exhibits a high `~l degree of lability towards atmospheric oxygen, particu-j 35 larly on heating. Other phenol ether groupings, such as the methyl ethers or ethyl ethers which can prefferably be prepared according to the invention, may be cleaved by methods known from the literature (T.W~ Greene, loc.
cit., 14.68, 145-161) before or after hydrogenating any ~` ff,;~
: .
benzyl groups which may be present.
In the process according to the invention, the use of benzyl alcohol is particularly preferred in those reaction steps which proceed in the presence of alcohols.
6-Fluorosalicylamide can be prepared in high yield by cleaving the phenyl ether grouping in 2-alkoxy-6-fluoro-benzamides by the methods which have already been described. The compound can be reacted, likewise in the ,described manner and optionally in the presence of 110 alcohols, with halogens in alkaline iolutions in the sense of a Hofmann degradation. Under these circum-~stances, the reaction proceeds as far as 2-amiino-3-¦fluorophenol, as described above, provided that it involves formation of the carbamates. Otherwise, 6-fluorobenzoxazolone i6 obtained as an intermediate and has to be hydrolyzed in acid solution to yield the product, resulting in lower yields being obtained.
The compounds o~ the formula I, in particular compounds in which Rl ii hydrogen f methyl, ethyl or CH2 phenyl, and R2 is -CN, -CON~2, -NHCooR3 or NH2, with R3 being methyl, ethyl or CH2-phenyl, may be used for preparing liquid-crystalline compounds, plant protection agents and pharmaceuticals.
The following examples illustrate the invention without limiting it.
1~
~ Example 1 ! !
¦ 2-Amino-3-fluorophenol 180 g o~ benzyl alcohol and 269 g (6.725 mol) of sodium hydroxide are introduced into 450 g of water. 220 g 1 30 (0.9 mol) of 2-benzyloxy-6-fluorobenzamide are added at 20C, and chlorine i9 passed in (15 l/h) at 40C while stirring thoroughly. The reaction is monitored by gas chromatography and terminated after 2.5 h when conversiion is complete. The aqueou~ mother liquor is heated at 95C
for 3 h once any excess of chlorine has been destroyed ~ (sodium sulfite).
:, 5 At this point, 2-benzyloxy-6-fluoroaniline can be iEfolatsd as a pale brown-colored viscous oil by extract-ing with MTBE, drying over magnPff~ium sulfate and removing the ~olvent (see Example 3 a~ well); however, this ~tep is omitted here.
'I
'J
' 10 Procedure a , The organic phase is separated from ths aqueous phase, taken up in 200 ml of methanol, and then stirred ~- vigorously (15 h~ together with 5 g of Pd/C (5 % Pd, 50 f moist) under an H2 atmosphere (slight exaess pressure) 15 until compounds po~se~sing benzyloxy groupings can no longer be detected. The catalyst i6 filtered off and than washed with methanol. Most of the methanol is distilled ~ off under an inert qas, and 300 g of toluene are added.
3 After cooling (0C), 60.9 g tO.48 mol, 53 %) of 2-amino~
20 3-fluorophenol, which i~ colored pale-brown to dark-gray after drying, can be obtained (content (GC): 100 %). A
I further 24.2 g (0.19 mol, 21 %) of product are contained J in the black mother liquor, as is dstermi~ed by quanti-tative ga~ chromatography. The mother liquor i8 reU8ed 25 for further batches.
; .
3 Procedure b ~ I After some minutes without stirring, the phases can be i separated after adding 200 g of toluene, and 300 g of ;l methanol are added to the organic phase which is then ~l 30 ~tirred vigorously (20 h~ together with 5 g of Pd/C ~5 %
¦ Pd, 50 % moist) under an H~ atmosphere ~slight excess pressure). GC analysi~ reveals solvent and, apart from minor quantities of ~yproducts, 2-amino-3--fluorophenol, as the main component. The catalyst i5 filtered off and .1 1!
' 21232i~2 then washed with methanol. ~o~t of the methanol is ~ distilled off from the $iltrate under an inert gas, and ; 300 g of toluene are added. After cooling (0C), and -$~ drying, 65.3 g (0.51 mol, 57 %) of 2-iamino-3-fluoro-~ 5 phenol, which is colored pale-brown, can be obtained ;~ (content (GC): 100 %). A further 28.2 g (0.22 mol, 25 %) of product are contained in the mo~her liquor/ as was determined by quantitative gas chromatography The mother ~ liquor is reused for further batches.
¦ 10 2-Amino-3-fluorophenol:
M.p. 124-126C; 126.3C (DSC) :~ B.p. 250.7C (DSC) Solubility in water ~ 15 g/l Bulk density approximately 0.2 g/cm3 ,; : '.
1H-NMR [DMSO-d6/TMS, ppm]:
= 6.39 (C) (ddd, lH, JBC = 8.28 HZ~ JCD = 6-36 H~
JAC = 7.83 HZ, Ar-HS) 6.50 ~B) (ddd, lH, J8c = 8-28 Hz, Ji3D = 8-30 Hz, J~ = 1.48 Hz, Ar-H4) 6.52 (A) (ddd, lH, JAC = 7.83 ~Z~ JAD = 2-30 HZ, J~ = 1.48 Hz, Ar-H6) .: ' ',''.
'9F-NMR [DMSO-d6/CFCl3, ppm]: :
= -133.94 (D) (ddd, lF, JaD = 6.36 ~Z, JAD = 2-30 Hz, JCD = 636 H Z, Ar-F3 ) 13C-NMR [DMSO~d6/T~S, ppm]
= lQ6.1 (J = 19.1 Hz, Ar-C2), 110.5 (Ar-C6), 11504 (J = 9O4 Hz, Ar-C1), 124.5 (J = 14.8 Hz, Ar-C4) 146.1 (J = 7.9 Hz, Ar-C5), 151.5 (J = -234.2 Hz, Ar-C3) ~' .
MS: m/z (%) = 51 ~14), 52 (16), 57 ~2), 63 (3), 70 ~6), 71 ~7)/ 78 ~7), 79 ~13), ~0 ~5), 81 (4), 82 (8), 98 (57), 99 (5), 126 ~11), 127 (100, ~), 128 (7) : ~
-~ 21232~2 Example 2 A. Preparation of 2-benzyloxy-6-fluorobenzamide in j aqueous medium J (1) 261.2 g (1.66 mol) of 2~6-difluorobenzamide are su~pended in 232.3 g (2.15 mol) of benzyl alcohol/ and the su~pension is then heated to 55C and 233.3 g (2.08 mol) of 50 ~ potassium hydroxide ~olution are ad~ed dropwise within the space of 2 h. At the end c>f this time, the temperature i~ raisecl to 60C and the mixture is stirred for a further 3 h.
i ¦ (2) The entire reaction mixture i~ allowed to flow, ¦ while 6tirring~ i~to 1900 g of water, and the precipi-tated solid i8 filtered off with suction. Washing takes place 3 times with 200 ml of water on each occasion, and the product i8 dried at 70C in vacuo. 297.7 g (1.21 mol, 73 %) of 2-benzyloxy-6-fluorobenzamide are obtained from 381 g of moist product as a slightly yellowish powder (purity (GC) > 98 %).
B. Preparation in dipolar, aprotic ~olvents 165.~ g ~1.2 mol) of potassium carbonate are suspended in 230 g of N,N-dimethylacetclmide (DM~c), and 113.4 g (1.05 mol) of benæyl alcohol are added to thi~ suspen-sion. After the addition of 157.1 g (1 mol) of 2,6-difluorobenzc~mide, the mixture is heated at 130C for ~ 25 24 h, and the fine salt which has precipitated is then I filtered off and washed with 250 g of DMAc in several 'portions (184.5 g, dry). The organic phase (658.6 g) is added dropwiæe, while stirring, into 1100 g of water, resulting in the reaction product crystallizing out.
Filtration takes place, and the filter cake i8 washed three times with 150 g of water on each occasion. 405 g of moist product are obtained as is, after drying, 170.7 g (0.696 mol, 70 %) of 2-benzyloxy-6-fluorobenza-mide a~ a powder which is colored yellow-beige.
;-~ 2~232~2 2-Benzyloxy-6-fluorobenzamide:
N.p. 142.6C (DSC) H-NMR [DMSO-d6/~MS, ppm]:
8 = 5.15 (I) (s, 2H, Ar-CH2) ~l 5 6-81 (G) (ddd~ J~G = 8-2 Elz, JPG = 0-5 ~Z~
JGI~ = 8 9 HZ ~ HS
~J 6.95 (F) (d(dd), 1~, J~ ~- 8-5 ~Z~ JFG - 0-5 HZ~
JF~ = 0 - 5 HZ ~ Ar-~3) 7.31 (~) (tm, 2~, Ar(benzyl)~H3s) 7.33 (E) (ddd, lHI J~ = 8-5 HZt J~G ~ 8-~ ~Z~
J~K = -6-9 ~Z, Ar-H4) J 7.38 (D) (tm, 1~, Ar(benzyl)-~4) 7.45 (C) (dm, 2~, Ar(benzyl)-H26) 7.49 (B) (8(br), 1~, Ar-NH2Ci~/tr~n~) 7.80 (A) (s(br), 1~, ~r-N~2 i 9F-NMR [DMSO-d6/CFCl3, ppm~:
= -116-40 (K) (ddd~ 1F~ J~:R = -6~9 HZ~ JF~ = 0-5 HZ~
JG~ = 8 - 9 HZ ~ Ar_F6 ) ~S: m/z (%) = 63 (5), 65 ~17), 91 (100), 92 (8), 98(3), 110 (6), 1~3 (4), 138 (3), 139 (5), 155 (1), 199 (1), 200 (1), 2~8 (20), 229 (3), ~ 245 (8.1, M+), 246 (1) 3 Example 3 : 2-Benzyloxy-6-fluoroaniline 120 g of methanoll 70 g of water, 30 g (0.75 mol) of 60dium hydroxide and 24.5 g (0.1 mol) of 2-benzyloxy-6~
fluorobenzamide are initially introduced and heated to 40C. Chlorine is passed in (4 l/h), whereupon, after a short time, the colorless suspension assumes a slightly brownish color and the heating can be removed since the temperature i.s then maintained by the exothermic nature of the reaction. A~ter 25 min, the reaction i complete, as can be demonstrated by GC. A clear solution is : obtained in place of the initial su~pension. The methanol is distilled off (50C) under a weak vacuum, and the resulting suspension of 2-benzyloxy-6-fluoro-N-carbo-~l methoxyaniline is heated at 100C for 48 h. After 3 5 cooling, 50 g of toluene are added, the pha~es are ~eparated, and 2 g of MgS04 and 1 g of active ~harcoal are added to the organic pha~e, which is stirred for ~ome hours. After filtration and removal of the solvent on a rotary evaporator, 19.8 g (91 mmol, 91 ~ of 2-benzyloxy-10 6-fluoroaniline are obtained as3 a brownish, clear oil, which exhibits a purity (GC. > 95 %) which is excellent ! for subsequent reactions.
2-Benzyloxy-6-fluoroaniline:
H-NMR [DMS0-d6/TMS, ppm]:
a = 4.57 (H~ (s(br~, 2H, Ar-NH2~
5.13 ~G) (s, 2H, Ar(benzyl)-CH2) ~ 6.51 (F) (ddd, lH, J~ = 8-35 HZ~ JDF = 8-15 Hz~
I JIF = 6.35 Hæ, Ar-H4) ¦ 6-68 (E) (ddd, lH, JBF = 8-35 HZI JD~ = 1.30 ~Z~
¦ 20 JEI = 10.6 Hz, Ar-Hs) 6-77 (D) (ddd~ JED = 1-30 HZI JDF = 8.15 Hz, JDI 1 . 2 0 Hz, Ar-H3) 7.21 (C) (tm, lH, Ar(benzyl)-H4) 7.39 (C) (tm, 2H, Ar(benzyl)-H3s) 1 25 7.48 (B) (dm, 2H, Ar(benzyl)-~26) 9F-NMR rDMS0-d6/CFCl3, ppm]:
133.77 (I) (ddd, lF, J~;I = 10-6 HZI 3FI = ~;-35 ~Z~
JDI 1 . 2 0 ~ Z ~ Ar-F ) MS: m/z (%) = 51 (9), 63 (4), 65 (16), 91 (100), 92 (8), 98 ~16), 126 (10), 138 (0.5), 217 (17.6, M~), 218 (2.6) 2-Ben~yloxy-6-fluoro-N-carbomethoxyaniline can be iso-lated if the procedure indicated above i~ followed but the 48-hour long hydroly~is of the intermediate i~
omitted and the latter i~ isolated and purified in J2~23 accordance with customary methods (in particular filtration and recrystallization)~ -MS: m/z (%) = 51 (3.2), 59 ~1.7), 63 (3.0), 65 tl4.0), 70 (3.2), 83 (1.6), 89 (2.5), 91 (100), 92 (9.7), 112 (1.2), 152 (1.6), 153 (1.3), 216 (1-6), 243 (800~, 244 tl.3), 275 (15.0, M+), 276 (2.6) ..
2-Benzyloxy~6-fluorophenyl isocyanate ari6es as an intermediate in the synthe~is elnd can be isolated if ~o desired.
MS: m/z (%) = 51 (4.2), 63 (3.1), 65 (15.1), 76 (5.3), 89 (3.2), 91 (100), 92 ~8.2), 9~ (2.6), 108 (1.1), 152 (8.9), 124 (3.7), 152 (1-6), 243 (15.9, M') Example 4 2-Ethoxy-6-fluorobenzamide 69.6 g (~.5 mol) of 2,6-difluorobenzonitrile and 237 g (2 mol) of 6-normal sodium hydroxide solution ~re ¦ initially introduced in 270 ml of ethanol. 221 g (1.95 mol) of 30 % hydrogen peroxide solution are added ~ dropwise to this mixture within the ~pace of 30 min, ¦ during which the temperature, which was 20~C at the beginning of the addition, rise~ to 50C and is then maintained at this value. After 5 h, the mixture is cooled and ths precipit~ted white solid i8 filtered off I ! with suction (1902 g, m.p. 187.8C)~ The latter i5 - recrystallized from aqueous ethanol, yielding 16.5 g (90 mmol, 18 ~) of pure, colorle~s 2-ethoxy-6-fluoro-benzamide. lB.6 g (0.118 mol, 24 %) of 2,6-difluoro-benzamide can additionally be isolated from the mother liquor by distilling off 62 g of ethanol, and a further 17.5 g of this compound can be obtained in impure form (purity about 60 ~) by extracting the mother liquor with 2123~2 ~ dichloromethane and removing the solvent.
-~, 2-Ethoxy-6-fluorobenzamide:
~. M.p. 195.5C (DSC) ., .~' l9F-NMR [DMSO-d6/CFCl3, ppm]:
r 5 ~ = -115.98 ~D) (ddd, lF, JAD = 6.65 HZ~ JCD = 9-07 E~Z, J9D = 0-70 EIZ, Ar_F6) ,, ., MS (EI~ 70 eV): m/z (%) = 40 (3), 44 (8), 57 (~), 63 . ~5), 74 (2), 82 (9), 81 (17), 9~ (4), 110 -(48), 111 (4), 123 (34), 124 ~3), 138 , 10 (10~), 139 (32), 140 (4), 151 ~16), 166 (39) ~ 168 137) ~ 169 (3), 183 (4.5, M~) H-NMR [Acetone-d6/TMS, ppm]:
8 = 1 . 3 6 ~ t, 3H, -CH2-CH3) 4 .1 2 ( qu , 2 H , -CH2 -C~3 ) 6- 7 (s(br), lH, Ax-NH2i~/tr3n~) 6.71 (C) (ddd, lH, JAC = 8-4 HZr JBC = 0-78 HZ~
JCD = 9 07 ~Z, Ar-~4 ) 6.84 (B) (ddd, 1H, J~ 0078 HZ, J~ = 8.4 ~Z, J~D = 0-70 ~Z, Ar-HS) 6.9 ( 8 ( br ), lH , Ar-NH2Ci~/tranD ) 7.31 (A) (ddd, lH, J~ = 6.65 Hz, J~ = 8.4 Hz, JAC = 8 4 Hz, Ar-~13 ) .~ .
IR (KBr, cm~l): 3375, 3190, 2990 (W), 2985 (w), 2940 (W), 1650, 1570, 1~90, 1460, 1400, 1390, 1270, 1240, 1115, 1060, 1000, 810, 785, :
~, 755, 700, 645, 620, 530, 420 Example 5 '~ .. . ' ' I 2-~enzyloxy-6-fluorobenzonitrile , .
100 g of benzyl alcohol and 55.6 ~ t0.4 mO1) Of 2,6-difluorobenzonitrile are initially introduced and heated to 40C. 49.2 g (0.44 mol) of 50 ~ potassium hydroxide ~ :
' .
', ~j .
~! 2 ~L 2 3 2 ~L 2 .~ - 19 - .
",j solution are then added dropwise, with stirring, in such a way that the temperature ca~ be maintained (cooling).
';
After 4 h, the mixture i~ diluted with 200 ml of water, the precipitated product is iltered off with suction, and 50 g of toluene are added to the mother liquor in a separating funnel. The yield of moist product ie 62.0 g, and, after drying, 56.2 g (0.247 mol, 62 ~) of 2-benzyl-oxy-6-fluorobenzonitrile (purity (GC) 99.3 %) remain in the form of a slightly yellowish solid. 31.5 g of 92.4 %
pure material (29.1 g, 0.128 mol, 32 %) are obtained ~rom the organic phase by removing the toluene in vacuo (up to 190C). After dissolving the crude products in ethanol/water and crystallizing without filtration, the yield of pure 2-benzyloxy-6-fluorobenzonitrile i 81.2 g (0.36 mol, 90 %); the product is obtained in the form of colorless shiny platelets.
,.: .
¦ 2-Benzyloxy-6-fluorobenzonitrile ~ M.p. 71.9C (DSC) 3 MS: m/z (%) = 50 (3), 51 (6), 57 (3), 63 (7), 65 (27), 89 (5), 91 (100), ~2 (15), 108 (7), 120 (1), 136 (1), 170 (1), 227 (M~, 13.7), ~28 (2.4) Example 6 6-Fluorosalicylamide ': ~, 24.3 g (0.1 mol) of 2-benzyloxy-6-fluorobenzamide are stirred vigorously (lS h), at 20C and under an H2 atmo~-phere (slight excess pressure), in 150 g of toluene together with 5 g of Pd/C (5 %, 50 % moist). After that, only the desired ~alicylamide can be detected in the ~ 30 mixture. The catalyst ie filtered off and then washed 3 with 100 ml of methanol in several portion~ in order to dissolve off undisfiolved product from the solid. The filtrate is concentrated (about 150 g) under a weak 232~2 ~' '' .
vacuum, and then cooled down to 0C, whereupon colorless crystals of 2-hydroxy-6-fluorobenzamide precipitate out.
~l ~hese latter are filtered off with ~uction and washed with cold toluene and hexane. After drying, 14.2 g (91.5 mmol, 92 %) of colorlesFi 6-fluorosalicylamide are obtained.
2-Hydroxy-6-fluorobenzamide (6--fluoro~alicylamide) M.p. 144-146.5C
,' MS: m/z (%) - 44 (14), 57 (20), 63 (19), 71 (5), 81 (12), 82 (24), ~i3 (25), 98 (5), 110 (100), 111 (11), 113 (8)/ 138 (~0~, 139 i~i (19), 141 (19), 155 (74.4, M~) t 156 (~.43, 157 (11.5) Example 7 ~i :
2-Amino-3-fluorophenol via 2-hydroxy-6-fluorobenzamide (6-fluorosalicylamide) -~
15.5 g (0.1 mol) of 6-fluorosalicylamide are introduced into 100 g of 30 ~ ~iodium hydroxide solution, and ~
chlorine ~ passed (4 l/h) into the resulting clear ~-solution. After 30 min, the chlorine str~am is shut off, and excess chlorine is destroyed (sodium sulfite). The p~
of the æolution is adjus~ed to 6 with sulfuric acid and -~
the precipitated 3-fluorobenzoxazolo~e is filtered off ~; with suction at 0C. The moist product (16.6 g) i heated ~at 130C for 3 h in 80 g of 70 % sulfuric acid, and, ~ -after cooling, the pH of the mixture i8 once again adju~ted to 6, and filtration with suction takes place at 0C. 7.3 g (57 mmol, 57 %) of dark-gray 2-amino-3-fluoro-phenol are obtained with a purity of 98 % (GC); the black mother liquor i5 discarded.
.............. .................................................................... ...
2-Hydroxy-6-fluoro N-carbomethoxyaniline, inter alia, i8 ,~ formed if a little methanol is added to the reaction mixture.
,i ~1232~2 :. f . -: ' ~ 21 ~
'~ MS ~ Z (%) = 51 (19.7) ~ 59 (18.8) ~ 70 (15.4) ~ 71 (lloO) ~ 97 (13~ 98 (69~2) r 109 (6-3) ~
126 (100) 1 127 (8~4) ~ 140 (5~9) ~ 153 (32~4) ~ 154 (5~3) ~ 185 (71~ 186 (6~4) Example 8 ' ;~
2-Amino-3-fluorophenol in a one-pot proce~s starting from 2,6-difluoroben amide .
The procedure described in Example 2A. (1) iB carried 10 out. After that, a further 600 g of water, 280 g (7 mol) of sodium hydroxide and 185 g (1.71 mol) of benzyl ¦ alcohol are added at 10C, and chlorine i~ passed in 15-18 l/h~ at 40C for 3 h. The phase~ are separated, and 500 ml of methanol and 7 g of Pd/C (5 %, 50 ~ moist) are added to the organic phase and hydrogenation is carried out as described in Exampl~ lb. After working up ~ ~ :
I in analogy to Example lb, 123.5 g (0.97 mol, 59 %) of 2~
i~ amino-3-fluorophenol are obtained a~ pale-gray shiny ~ platelets.
3~ 20 Example 9 ~ .
2-Amino-3-fluorophenol in a one-pot proces~ starting from 2,6-difluorobenzonitrile 69.6 g (0.5 mol) of 2,6~difluorobenzonitrile and 237 g (1.2 mol) of 6-noxmal sodi~m hydroxide solution are ~ ~ 25 initially introduced in 200 ml of benzyl alcohol. 221 g ! ( 1. 95 mol) of 30 ~ hydrogen peroxide solution are added ~ drQpwise to this mixture within the space of 30 min, ¦ during which the temperature, which was 20C at the ¦ beginning of the addition, rises to 50C ~nd i8 then maintained at this value. After 5 h (complete conversion to 2-benzyloxy~6-fluorobenzamide can be detected by means of GC), the mixture is cooled down and ~upplemented with 200 g o~ wate!r and 60 g ( 1~5 mol) of ~odium hydroxideO
2~23242 Chlorine is passed in (8 10 l/h) at 30~C for 2 h, with the reaction being monitored by gas chromatography and terminated when the amide has disappeared. The phases are separated, and 180 g of methanol are added to the organic 5 phase, and this is followed by further working up as 3 indicated in Example 8. 32.4 g (0.255 mol~ 51 %) of 2-amino-3-fluorophenol are obtained as a brown-black powder.
.
.,,,,~ ~ ,.
:~ .
' ~, .
;:~
1. '.:.
~,
. Thus, compounds of the formula I, in which R1 is hydrogen, ~Cl-C8)-alkyl or CH2-phenyl, where the alkyl radical or the phenyl group can be sub3tituted by one to -~ three (C,-C4)-alkoxy group , fluorine, chlorine or bromine atom~i, nitro groups, cyano groups, trifluoromethyl group3 ! or (C1-C4)-alkoxycarbonyl groups, and R2 i8 -NH2 or ~ -NHCooR3~ can be prepared by reacting compounds of the ;i 10 formula (II) ~ .
~ C ~ N H 2 ., .
in which X i5 OR', in a~ueous-alkaline medium, with i chlorine, bromine, sodium hypochlorite or sodium hypo-I bromite in the presence of alcohols and at temperatures i of from -15C to ~80~C, in the ~en~ie of a ~ofmann j 15 degradation. : -In many ca6es, it ha3 proved to be of value to employ, as the alcoh~l component, compounds of the formula ~oR3, where R3 is ( C1_CB ) -a1kY1 or CH2-phenyll where the alkyl radical or the phenyl group can be substituted by one to ~ . :
three (C1-C4)-alkoxy groups, fluorine, chlorine or bromine ~: atoms, nitro groups, cyano groups, trifluoromethyl groups :: -;1: or (C1-C~]-alkoxycarbonyl groups.
~ The compound o the formula (I') ,~
~N H C O O R ~ ~:
:~ resulting fro:m the reaction can be isolated. However, it ~ :
25 i8 also possi.ble to cleave the carbamate group and/or, for X = OR1, the group OR1 (when R1 i8 not hydrogen) ' ~' .
i ~1 :
` ` 2123242 . ~
~ hydrogenolytically or hydrolytically without undertaking '~! any intermediate isolation. It is likewise po6sible to ~elect the reaction condition~ such that the cleavage already takes placP to a large extent at the same time a~
the rearrangementa s The compounds of the formula II are prepared by convert-ing the corresponding nitriles into the benzamides by methods which are generally known in the literature (J.
March, Advanced Organic Chemistry [1985], 788).
In this context, preference is given to the reaction of 2,6-di~luorobenzonitrile in aqueous~alkaline medium with hydrogen peroxide (JP-OS 60-132 942), where appropriate in correspondan~e with the pre~ent invention, in the presence of from about 1 to about 20 mol, preferably from about 0.1 to 10 mol, particularly preferably between about 1.05 mol and 5 mol, of alcohol per 1 mol of 2,6-difluorobenzonitrile. In this context, alkan-(C,-C8)-ols of any structure, which can additionally be substituted ^~ by alkoxy(Cl-C4) groups, fluorine, chlorine or bromine atoms, nitro groups, cyano groups, trifluoromethyl groups or alkoxylCl-C4)-carbonyl gr~ups, or phenylmethanols, where the phenyl radical can be substituted by alkyl(Cl-C4 ) groups, alkoxy~Cl-C4~ groups, fluorine, chlorine or bromine atoms, nitro groups, cyano groupY, trifluoro-methyl groups or alkoxy(CI-C4)-carbonyl groups, can be used as Rl-OH alcohols; primary alcohol~ are preferred, `with methanol, ethanol and benzyl alcohol being particu-larly preferred.
.~
2,6-Difluorobenzamide can be isolated; however, it is l 30 also possi~le to obtain the compounds of the formula II
having X = ORl immediately in a one-pot process. Thi~ can be achieved, in particular, by raising the reaction il temperature.
The work is carried out at temperatures of between about 0 and about 90C, preferably of between about 20 and ;'j '1 !
~ 2123242 s about 70C.
If 2,6-difluorobenzamide, which has been isolated as an intermediate, i~ employed for preparing the compounds ~f the formula II having X - ORl, the work i~ preferably carried out, in accordance with the invention, in excess alcohol, as described above, and reaction takes place, in the temperature range which has likewise already been defined, with about 1 mol to about 1.8 mol, particularly preferably with about 1.1 mol to about 1.5 mol, of alkali metal or alkaline earth metal compounds having an alkaline effect. Ex~mples of such compounds having an 1 alkaline effect are hydroxides, carbonates, hydrogen carbonates, phosphatesl hydrogen phoæphates, dihydrogen phosphates, oxides, or similar compounds, or mixtures ~
15 thereof; sodium or potassium hydroxide or carbona$e are -1 1 preferred. The reaction times amoun to from about 1 to '1 about 16 h, with the reaction product generally being ¦ isolated, in the event that isolation is ~esired, by diluting the reaction mixture with water and filtering off (extraction, crystallization, chromatography).
~ Alternatively, it is possible to react 2,6-difluorobenzo-`1 nitrile, as explained below, or 2,6-difluorobenzamide i with the above-describ2d quantities and types of ~ ~
~ compounds having an allcaline ef~ect and al~ohols in ~ -¦ 25 dipolar, aprotic solventsr Acetone, tetrahydrofuran (THF), acetonitrile, 1,2-dimethoxyethane (DMAc), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl ~ulfoxide (DMS0), dimethyl ~ulfone, diphenyl sulfoxide, diphenyl sulfone, tetramethylurea, tetra-n-l 30 butylurea or 1,3-dimethylimidazolidin-2-one (DMI), or 3 mixtures thereof, can be used as dipolar, aprotic solvents. Such solvents are u~ed in ~uantities of about li 50 to 500 ~ by mass, based on 2,6-difluorobenzamide or J 2,6-difluoroblenzonitrile, preferably in quantities of I 35 between about 80 and about 250 % by mass. The use of !l these solvent:s makes it possible to ~eparate off by ~ filtration the alkali metal or alkaline earth metal ~ .
21232~2 fluoride which i~ formed in the reaction; the product i8 ' crystallized from the mother liquor by adding water and the solvent is recovered by di~tillation. In this variant of the process, the work is carried out at reaction 5 temperatures of between about 30 and about 150C, preferably of between about 40 and about lOO~C. A~
l compared with aqueous variants of the process, this ! variant has the advantage of higher yields.
The preparation of 2-(primary-alkoxy)-6-fluorobenzamides is preferred, with that of 2-methoxy-6-fluorobenzamide, 2-ethoxy-6-fluorobenzamide and 2-benzyloxy-6-fluoro-benzamide being particularly preferred.
In the sase of 2-benzyloxy-6-fluorobenzamide, 2-hydroxy-6-fluorobenzamide can be obtained by hydrogenolytic elimination OI the benzyloxy group.
i Compounds of the formula I (R' ~ hydrogen) having R2 = CN
i can be obtained in an analoyous mannerc For this purposs, 2,6-difluorobenzonitrile is reacted with R30H alcohols in aqueous-alkaline or dipolar, aprotic medium in the presence of alkali~.
In this context, alkan-(CI-C8)-ols of any ~tructure, which can additionally be substituted by alkoxy(C1-C4~ groups, fluorine, chlorine or bromine atoms, nitro groups, cyano group~, trifluoromethyl gxoups or alkoxy-(Cl-C~)-carbonyl groups, or phenylmethanol~, where the phenyl radical can be 0ub~tituted by alkyl( C,-C4 ) groups, alkoxy(Cl-C4) groups, fluorine, chlorine or ~romine atom~, nitro roups, cyano groups, trifluoromethyl group~ or alkoxy-~C,-C~)-carbonyl groups, can be u~ed a~ Rl-OH alcohols;
! 30 primary alcohols are preferred, with methanol, ethanol and benzyl alcohol being particularly preferred.
~ It i8 al~o pos~ible to obtain compounds of the formula I
¦ (Rl ~ hydrogen) having R2 - NH2 in a one-pot process by ¦ reacting either 2,6-difluorobenzonitrile or 2,6-difluoro-,, :
~123242 benzamide in aqueous-alkaline medium with alcohols to form compounds of the formula II having X = OR1 ~R1 ~
hydrogen), and then reacting the latter~ after inter-~mediate isolation, but preferably without any '!5 intermediate isolation~ in a one-pot proces3, with chlorine, bromine, sodium hypochlorite or sodium hypo-bromite, at temperatures of from -15C to ~80C and in ~the presence of alcohols, in the sense of a Hofmann ddegradation, and ~ubsequently, where appropriate, `i,10 cleaving ~arbamates which have been formed hydrolytically ~or hydrogenolytically.
j':!In this context, (C,-C8)-alkanols or phenylmethanols, `Alwhere the alkyl radical or the phenyl radical can be `'substituted by one to three (Cl-C4)-alkoxy groups, fluorine, chlorine or bromine atoms, nitro groups, cyano groups, trifluoromethyl groups or (Cl-C4)-alkoxycarbonyl groups, in particular primary alcohols, can also be employed as alcohols.
jIn many cases, the use of methanol, ethanol or benzyl alcohol has proved to be advantageous.
These alcohols are employed in mixtures with aqueous solutions having an alkaline effect, a~ described above, ipreferably sodium or potassium hydroxide solutions. The compounds having an alkaline effect are used, dissolved or su~pended in water, in quantities, based on the amide to be dsgraded, of between about 1 mol and about 30 mol, preferably of between about 3 mol and about 15 mol, particularly preferably of between about 5 mol and about 10 mol. While the concentrations of the aqueous solutions depend on the amide employed, the concentrations are typically between about 1 mol/l and about 20 mol/l, ~;~preferably between about 3 mol/l and about 10 mol/1. In ¦practice, the quantity of the aqueou~ suspension having an alkaline effect i~ chosen such that it is still possible to stir the reaction mixture.
.1 `` 2~23242 The procedure can be carried out using hypohalite solu-tions (bleaching liquors), which is completely equivalent to metering elemental halogen into solutions having an I alkaline effect. An indication of the quantity of halogen 5 employed is suPficient to describe the reaction ,~ondi-tions since, in situ, hypohalite solution~ are formed when halogen makes contact with the aqueous solutions having an alkaline effe,ct which are employed. Chlorine or ~ bromine are used, therefore, in quantities of between i 10 about 1 mol and about 5 mol, preferably of from about 1.01 mol to about 2 mol, particularly preferably of between about 1.02 mol and about 1.2 mol, in each case based on 1 mol of amide to be degraded. Chlorine is preferably used since it is more readily available 15 industrially. The halogen can be added dropwise (bromine) or passed in in gaseous form (chlorine). In thi~ regard, suitable metering times on a laboratory ~cale are, ~ depending on the reaction temperature, between about 1 0.5 h and about 8 h, preferably from about 1 h to about 20 4 h. Owing to the reaction being exothermic, the metering times on an industrial scale mu~t be adapted to the cooling capacities available.
The reaction in the ~en~e of the Hofmann degradation is carried out at temperatures of between about -15C and about 100C, preferably of between about 0C and about 60C, particularly preferably of between about 10C and about 40~C.
::
If bleachin~ liquor~ e. aqueous hypohalite solutions, are metered in, which generally has operational advan-tage~ as ~ompared with the use of elemental halogen, ~ solutions are then used having a content of active 1 chlorine of from about 30 to about 250 ~ per kg of solution, preferably of between about 100 and about 160 g of active ch~orine per kg of solution, or from about 60 to about 550 g o~ active bromine per kg of solution,preferably oP between about 200 and about 350 g per kg of solution. These solutions may be obtained by metering the , . .~
, ~ 9 corresponding quantities of chlorine or bromine into aqueous solutions having an alkaline effect.
~.~
In the variant according to the invention, the primary reaction product of the reaction in the ~en3e of a i 5 Hofmann degradation is pressmably the alkyl carbamate of the desired aniline, ~ince the isocyanate ari~ing as an intermediate i8 probably captured by the alcoholates, i nucleophilic under the reaction conditions~
The anilines can be obtained from the carbamates by 10 processes known in principle from the literature (T.W. Greene, P.G.M. Wuts, Protective Group~ in Organic ¦ Chemistry (1991), 317-348). As a rule, liberation of the amino group is achieved by heating the reaction mixture according to the invention, once any excesses of chlorine 15 or bromine have been destroyed. Optionally sub~tituted , benzyl carbamates can be hydroly~ed under alkaline 3 conditions in less than 10 h at from 80 to '00C, whereas ¦ simple alkyl carbamates require reaction times of up to 96 h at the same temperatures. ~he use of optionally 20 substituted benzyl alcohol is therefore particularly ~ preferred since the resulting benzyl carbamates can be I cleaved without any great difficulty, and therefore cost-effectively, by hydrogenation (T.W. Greene et al., loc.
cit., 335-341). The hydrogenolytic cleavage is preferably 25 carried out in the presence of transition metal catalyst~, in particular platinum, nickel or palladium cataly~ts. In general, the reaction products can ~e ~ i~olated simply by phase separation, resulting in I mixtures with the alcohols employed. The phase separation 30 can be improved or induced by adding additional solvents, such a~ t for example, toluene or xylene.
. .
The resulting solutions of the free amine~ can, provided they contain compounds which posse s benzyl group~, be hydrogenated by methods which are generally known from 35 the literature (T.W. Greene et al., loc~ cit., 47-68, 156-160, 335-341). Hydrogenation u~ing hydrogen gas in ,:! .
- 1o_2~23242 the presence of transition metal catalysts, preferably palladium catalysts, particularly preferably palladium on active charcoal, is preferred. An alternative option is to use the so-called transfer-hydrogenation method for ~l 5 synthesizing the novel intermediates (T~W. Greene et al., -lj loc. cit., 156-160). Besides palladium, nickel or ,! platinum, in particular, are suitable for employment as transition metals. The hydrogenations proceed smoothly under a hydrogen pressure of between about 1~1 bax and about 100 bar at temperatures of between about 10 and about 80C in lower aliphatic alcohols or simple aromatic or aliphatic hydrocarbons, such as, for example, hexane, methylcyclohexane, toluene, xylene, methanol, butanol, isopropanol or ethanol as solvent, or mixtures thereof.
The precious metal catalysts are employed in quantikies of between about 0.05 and about 3, preferably of from i about 0.3 to about 1, % by mass (calculated as pure transition metal). The concentration of the end product (in particular 2-amino-3-fluorophenol) in the hydrogena-`1 20 tion mother liquor is typically between about lD and j about 500, preferably between about 100 and about 300, '37 g/l. If the unsubstituted benzyl compounds are employed , under these circumstances, the free hydroxyl groups and !~7 toluene are obtained during the hydrogenation. Toluene is ~3 25 therefore preferred as the ~iolvent ~or the hydrogenation.
j The end product, 2-amino-3-fluorophenol, can be i~iolated by concentrating the solutions, from which, where appro-priate, the catalyst has been filtered off while the 3 solutions were hot, and subsequently filtering them. In 30 this context, it is advi~able to carry out the procedure `i in the presence of oxidation-preventing additivPs, such l I as hydrazine or hydrazinium Ralts, or 2,6-di-tert-butyl-~7 4-methylphenol, since the end product exhibits a high `~l degree of lability towards atmospheric oxygen, particu-j 35 larly on heating. Other phenol ether groupings, such as the methyl ethers or ethyl ethers which can prefferably be prepared according to the invention, may be cleaved by methods known from the literature (T.W~ Greene, loc.
cit., 14.68, 145-161) before or after hydrogenating any ~` ff,;~
: .
benzyl groups which may be present.
In the process according to the invention, the use of benzyl alcohol is particularly preferred in those reaction steps which proceed in the presence of alcohols.
6-Fluorosalicylamide can be prepared in high yield by cleaving the phenyl ether grouping in 2-alkoxy-6-fluoro-benzamides by the methods which have already been described. The compound can be reacted, likewise in the ,described manner and optionally in the presence of 110 alcohols, with halogens in alkaline iolutions in the sense of a Hofmann degradation. Under these circum-~stances, the reaction proceeds as far as 2-amiino-3-¦fluorophenol, as described above, provided that it involves formation of the carbamates. Otherwise, 6-fluorobenzoxazolone i6 obtained as an intermediate and has to be hydrolyzed in acid solution to yield the product, resulting in lower yields being obtained.
The compounds o~ the formula I, in particular compounds in which Rl ii hydrogen f methyl, ethyl or CH2 phenyl, and R2 is -CN, -CON~2, -NHCooR3 or NH2, with R3 being methyl, ethyl or CH2-phenyl, may be used for preparing liquid-crystalline compounds, plant protection agents and pharmaceuticals.
The following examples illustrate the invention without limiting it.
1~
~ Example 1 ! !
¦ 2-Amino-3-fluorophenol 180 g o~ benzyl alcohol and 269 g (6.725 mol) of sodium hydroxide are introduced into 450 g of water. 220 g 1 30 (0.9 mol) of 2-benzyloxy-6-fluorobenzamide are added at 20C, and chlorine i9 passed in (15 l/h) at 40C while stirring thoroughly. The reaction is monitored by gas chromatography and terminated after 2.5 h when conversiion is complete. The aqueou~ mother liquor is heated at 95C
for 3 h once any excess of chlorine has been destroyed ~ (sodium sulfite).
:, 5 At this point, 2-benzyloxy-6-fluoroaniline can be iEfolatsd as a pale brown-colored viscous oil by extract-ing with MTBE, drying over magnPff~ium sulfate and removing the ~olvent (see Example 3 a~ well); however, this ~tep is omitted here.
'I
'J
' 10 Procedure a , The organic phase is separated from ths aqueous phase, taken up in 200 ml of methanol, and then stirred ~- vigorously (15 h~ together with 5 g of Pd/C (5 % Pd, 50 f moist) under an H2 atmosphere (slight exaess pressure) 15 until compounds po~se~sing benzyloxy groupings can no longer be detected. The catalyst i6 filtered off and than washed with methanol. Most of the methanol is distilled ~ off under an inert qas, and 300 g of toluene are added.
3 After cooling (0C), 60.9 g tO.48 mol, 53 %) of 2-amino~
20 3-fluorophenol, which i~ colored pale-brown to dark-gray after drying, can be obtained (content (GC): 100 %). A
I further 24.2 g (0.19 mol, 21 %) of product are contained J in the black mother liquor, as is dstermi~ed by quanti-tative ga~ chromatography. The mother liquor i8 reU8ed 25 for further batches.
; .
3 Procedure b ~ I After some minutes without stirring, the phases can be i separated after adding 200 g of toluene, and 300 g of ;l methanol are added to the organic phase which is then ~l 30 ~tirred vigorously (20 h~ together with 5 g of Pd/C ~5 %
¦ Pd, 50 % moist) under an H~ atmosphere ~slight excess pressure). GC analysi~ reveals solvent and, apart from minor quantities of ~yproducts, 2-amino-3--fluorophenol, as the main component. The catalyst i5 filtered off and .1 1!
' 21232i~2 then washed with methanol. ~o~t of the methanol is ~ distilled off from the $iltrate under an inert gas, and ; 300 g of toluene are added. After cooling (0C), and -$~ drying, 65.3 g (0.51 mol, 57 %) of 2-iamino-3-fluoro-~ 5 phenol, which is colored pale-brown, can be obtained ;~ (content (GC): 100 %). A further 28.2 g (0.22 mol, 25 %) of product are contained in the mo~her liquor/ as was determined by quantitative gas chromatography The mother ~ liquor is reused for further batches.
¦ 10 2-Amino-3-fluorophenol:
M.p. 124-126C; 126.3C (DSC) :~ B.p. 250.7C (DSC) Solubility in water ~ 15 g/l Bulk density approximately 0.2 g/cm3 ,; : '.
1H-NMR [DMSO-d6/TMS, ppm]:
= 6.39 (C) (ddd, lH, JBC = 8.28 HZ~ JCD = 6-36 H~
JAC = 7.83 HZ, Ar-HS) 6.50 ~B) (ddd, lH, J8c = 8-28 Hz, Ji3D = 8-30 Hz, J~ = 1.48 Hz, Ar-H4) 6.52 (A) (ddd, lH, JAC = 7.83 ~Z~ JAD = 2-30 HZ, J~ = 1.48 Hz, Ar-H6) .: ' ',''.
'9F-NMR [DMSO-d6/CFCl3, ppm]: :
= -133.94 (D) (ddd, lF, JaD = 6.36 ~Z, JAD = 2-30 Hz, JCD = 636 H Z, Ar-F3 ) 13C-NMR [DMSO~d6/T~S, ppm]
= lQ6.1 (J = 19.1 Hz, Ar-C2), 110.5 (Ar-C6), 11504 (J = 9O4 Hz, Ar-C1), 124.5 (J = 14.8 Hz, Ar-C4) 146.1 (J = 7.9 Hz, Ar-C5), 151.5 (J = -234.2 Hz, Ar-C3) ~' .
MS: m/z (%) = 51 ~14), 52 (16), 57 ~2), 63 (3), 70 ~6), 71 ~7)/ 78 ~7), 79 ~13), ~0 ~5), 81 (4), 82 (8), 98 (57), 99 (5), 126 ~11), 127 (100, ~), 128 (7) : ~
-~ 21232~2 Example 2 A. Preparation of 2-benzyloxy-6-fluorobenzamide in j aqueous medium J (1) 261.2 g (1.66 mol) of 2~6-difluorobenzamide are su~pended in 232.3 g (2.15 mol) of benzyl alcohol/ and the su~pension is then heated to 55C and 233.3 g (2.08 mol) of 50 ~ potassium hydroxide ~olution are ad~ed dropwise within the space of 2 h. At the end c>f this time, the temperature i~ raisecl to 60C and the mixture is stirred for a further 3 h.
i ¦ (2) The entire reaction mixture i~ allowed to flow, ¦ while 6tirring~ i~to 1900 g of water, and the precipi-tated solid i8 filtered off with suction. Washing takes place 3 times with 200 ml of water on each occasion, and the product i8 dried at 70C in vacuo. 297.7 g (1.21 mol, 73 %) of 2-benzyloxy-6-fluorobenzamide are obtained from 381 g of moist product as a slightly yellowish powder (purity (GC) > 98 %).
B. Preparation in dipolar, aprotic ~olvents 165.~ g ~1.2 mol) of potassium carbonate are suspended in 230 g of N,N-dimethylacetclmide (DM~c), and 113.4 g (1.05 mol) of benæyl alcohol are added to thi~ suspen-sion. After the addition of 157.1 g (1 mol) of 2,6-difluorobenzc~mide, the mixture is heated at 130C for ~ 25 24 h, and the fine salt which has precipitated is then I filtered off and washed with 250 g of DMAc in several 'portions (184.5 g, dry). The organic phase (658.6 g) is added dropwiæe, while stirring, into 1100 g of water, resulting in the reaction product crystallizing out.
Filtration takes place, and the filter cake i8 washed three times with 150 g of water on each occasion. 405 g of moist product are obtained as is, after drying, 170.7 g (0.696 mol, 70 %) of 2-benzyloxy-6-fluorobenza-mide a~ a powder which is colored yellow-beige.
;-~ 2~232~2 2-Benzyloxy-6-fluorobenzamide:
N.p. 142.6C (DSC) H-NMR [DMSO-d6/~MS, ppm]:
8 = 5.15 (I) (s, 2H, Ar-CH2) ~l 5 6-81 (G) (ddd~ J~G = 8-2 Elz, JPG = 0-5 ~Z~
JGI~ = 8 9 HZ ~ HS
~J 6.95 (F) (d(dd), 1~, J~ ~- 8-5 ~Z~ JFG - 0-5 HZ~
JF~ = 0 - 5 HZ ~ Ar-~3) 7.31 (~) (tm, 2~, Ar(benzyl)~H3s) 7.33 (E) (ddd, lHI J~ = 8-5 HZt J~G ~ 8-~ ~Z~
J~K = -6-9 ~Z, Ar-H4) J 7.38 (D) (tm, 1~, Ar(benzyl)-~4) 7.45 (C) (dm, 2~, Ar(benzyl)-H26) 7.49 (B) (8(br), 1~, Ar-NH2Ci~/tr~n~) 7.80 (A) (s(br), 1~, ~r-N~2 i 9F-NMR [DMSO-d6/CFCl3, ppm~:
= -116-40 (K) (ddd~ 1F~ J~:R = -6~9 HZ~ JF~ = 0-5 HZ~
JG~ = 8 - 9 HZ ~ Ar_F6 ) ~S: m/z (%) = 63 (5), 65 ~17), 91 (100), 92 (8), 98(3), 110 (6), 1~3 (4), 138 (3), 139 (5), 155 (1), 199 (1), 200 (1), 2~8 (20), 229 (3), ~ 245 (8.1, M+), 246 (1) 3 Example 3 : 2-Benzyloxy-6-fluoroaniline 120 g of methanoll 70 g of water, 30 g (0.75 mol) of 60dium hydroxide and 24.5 g (0.1 mol) of 2-benzyloxy-6~
fluorobenzamide are initially introduced and heated to 40C. Chlorine is passed in (4 l/h), whereupon, after a short time, the colorless suspension assumes a slightly brownish color and the heating can be removed since the temperature i.s then maintained by the exothermic nature of the reaction. A~ter 25 min, the reaction i complete, as can be demonstrated by GC. A clear solution is : obtained in place of the initial su~pension. The methanol is distilled off (50C) under a weak vacuum, and the resulting suspension of 2-benzyloxy-6-fluoro-N-carbo-~l methoxyaniline is heated at 100C for 48 h. After 3 5 cooling, 50 g of toluene are added, the pha~es are ~eparated, and 2 g of MgS04 and 1 g of active ~harcoal are added to the organic pha~e, which is stirred for ~ome hours. After filtration and removal of the solvent on a rotary evaporator, 19.8 g (91 mmol, 91 ~ of 2-benzyloxy-10 6-fluoroaniline are obtained as3 a brownish, clear oil, which exhibits a purity (GC. > 95 %) which is excellent ! for subsequent reactions.
2-Benzyloxy-6-fluoroaniline:
H-NMR [DMS0-d6/TMS, ppm]:
a = 4.57 (H~ (s(br~, 2H, Ar-NH2~
5.13 ~G) (s, 2H, Ar(benzyl)-CH2) ~ 6.51 (F) (ddd, lH, J~ = 8-35 HZ~ JDF = 8-15 Hz~
I JIF = 6.35 Hæ, Ar-H4) ¦ 6-68 (E) (ddd, lH, JBF = 8-35 HZI JD~ = 1.30 ~Z~
¦ 20 JEI = 10.6 Hz, Ar-Hs) 6-77 (D) (ddd~ JED = 1-30 HZI JDF = 8.15 Hz, JDI 1 . 2 0 Hz, Ar-H3) 7.21 (C) (tm, lH, Ar(benzyl)-H4) 7.39 (C) (tm, 2H, Ar(benzyl)-H3s) 1 25 7.48 (B) (dm, 2H, Ar(benzyl)-~26) 9F-NMR rDMS0-d6/CFCl3, ppm]:
133.77 (I) (ddd, lF, J~;I = 10-6 HZI 3FI = ~;-35 ~Z~
JDI 1 . 2 0 ~ Z ~ Ar-F ) MS: m/z (%) = 51 (9), 63 (4), 65 (16), 91 (100), 92 (8), 98 ~16), 126 (10), 138 (0.5), 217 (17.6, M~), 218 (2.6) 2-Ben~yloxy-6-fluoro-N-carbomethoxyaniline can be iso-lated if the procedure indicated above i~ followed but the 48-hour long hydroly~is of the intermediate i~
omitted and the latter i~ isolated and purified in J2~23 accordance with customary methods (in particular filtration and recrystallization)~ -MS: m/z (%) = 51 (3.2), 59 ~1.7), 63 (3.0), 65 tl4.0), 70 (3.2), 83 (1.6), 89 (2.5), 91 (100), 92 (9.7), 112 (1.2), 152 (1.6), 153 (1.3), 216 (1-6), 243 (800~, 244 tl.3), 275 (15.0, M+), 276 (2.6) ..
2-Benzyloxy~6-fluorophenyl isocyanate ari6es as an intermediate in the synthe~is elnd can be isolated if ~o desired.
MS: m/z (%) = 51 (4.2), 63 (3.1), 65 (15.1), 76 (5.3), 89 (3.2), 91 (100), 92 ~8.2), 9~ (2.6), 108 (1.1), 152 (8.9), 124 (3.7), 152 (1-6), 243 (15.9, M') Example 4 2-Ethoxy-6-fluorobenzamide 69.6 g (~.5 mol) of 2,6-difluorobenzonitrile and 237 g (2 mol) of 6-normal sodium hydroxide solution ~re ¦ initially introduced in 270 ml of ethanol. 221 g (1.95 mol) of 30 % hydrogen peroxide solution are added ~ dropwise to this mixture within the ~pace of 30 min, ¦ during which the temperature, which was 20~C at the beginning of the addition, rise~ to 50C and is then maintained at this value. After 5 h, the mixture is cooled and ths precipit~ted white solid i8 filtered off I ! with suction (1902 g, m.p. 187.8C)~ The latter i5 - recrystallized from aqueous ethanol, yielding 16.5 g (90 mmol, 18 ~) of pure, colorle~s 2-ethoxy-6-fluoro-benzamide. lB.6 g (0.118 mol, 24 %) of 2,6-difluoro-benzamide can additionally be isolated from the mother liquor by distilling off 62 g of ethanol, and a further 17.5 g of this compound can be obtained in impure form (purity about 60 ~) by extracting the mother liquor with 2123~2 ~ dichloromethane and removing the solvent.
-~, 2-Ethoxy-6-fluorobenzamide:
~. M.p. 195.5C (DSC) ., .~' l9F-NMR [DMSO-d6/CFCl3, ppm]:
r 5 ~ = -115.98 ~D) (ddd, lF, JAD = 6.65 HZ~ JCD = 9-07 E~Z, J9D = 0-70 EIZ, Ar_F6) ,, ., MS (EI~ 70 eV): m/z (%) = 40 (3), 44 (8), 57 (~), 63 . ~5), 74 (2), 82 (9), 81 (17), 9~ (4), 110 -(48), 111 (4), 123 (34), 124 ~3), 138 , 10 (10~), 139 (32), 140 (4), 151 ~16), 166 (39) ~ 168 137) ~ 169 (3), 183 (4.5, M~) H-NMR [Acetone-d6/TMS, ppm]:
8 = 1 . 3 6 ~ t, 3H, -CH2-CH3) 4 .1 2 ( qu , 2 H , -CH2 -C~3 ) 6- 7 (s(br), lH, Ax-NH2i~/tr3n~) 6.71 (C) (ddd, lH, JAC = 8-4 HZr JBC = 0-78 HZ~
JCD = 9 07 ~Z, Ar-~4 ) 6.84 (B) (ddd, 1H, J~ 0078 HZ, J~ = 8.4 ~Z, J~D = 0-70 ~Z, Ar-HS) 6.9 ( 8 ( br ), lH , Ar-NH2Ci~/tranD ) 7.31 (A) (ddd, lH, J~ = 6.65 Hz, J~ = 8.4 Hz, JAC = 8 4 Hz, Ar-~13 ) .~ .
IR (KBr, cm~l): 3375, 3190, 2990 (W), 2985 (w), 2940 (W), 1650, 1570, 1~90, 1460, 1400, 1390, 1270, 1240, 1115, 1060, 1000, 810, 785, :
~, 755, 700, 645, 620, 530, 420 Example 5 '~ .. . ' ' I 2-~enzyloxy-6-fluorobenzonitrile , .
100 g of benzyl alcohol and 55.6 ~ t0.4 mO1) Of 2,6-difluorobenzonitrile are initially introduced and heated to 40C. 49.2 g (0.44 mol) of 50 ~ potassium hydroxide ~ :
' .
', ~j .
~! 2 ~L 2 3 2 ~L 2 .~ - 19 - .
",j solution are then added dropwise, with stirring, in such a way that the temperature ca~ be maintained (cooling).
';
After 4 h, the mixture i~ diluted with 200 ml of water, the precipitated product is iltered off with suction, and 50 g of toluene are added to the mother liquor in a separating funnel. The yield of moist product ie 62.0 g, and, after drying, 56.2 g (0.247 mol, 62 ~) of 2-benzyl-oxy-6-fluorobenzonitrile (purity (GC) 99.3 %) remain in the form of a slightly yellowish solid. 31.5 g of 92.4 %
pure material (29.1 g, 0.128 mol, 32 %) are obtained ~rom the organic phase by removing the toluene in vacuo (up to 190C). After dissolving the crude products in ethanol/water and crystallizing without filtration, the yield of pure 2-benzyloxy-6-fluorobenzonitrile i 81.2 g (0.36 mol, 90 %); the product is obtained in the form of colorless shiny platelets.
,.: .
¦ 2-Benzyloxy-6-fluorobenzonitrile ~ M.p. 71.9C (DSC) 3 MS: m/z (%) = 50 (3), 51 (6), 57 (3), 63 (7), 65 (27), 89 (5), 91 (100), ~2 (15), 108 (7), 120 (1), 136 (1), 170 (1), 227 (M~, 13.7), ~28 (2.4) Example 6 6-Fluorosalicylamide ': ~, 24.3 g (0.1 mol) of 2-benzyloxy-6-fluorobenzamide are stirred vigorously (lS h), at 20C and under an H2 atmo~-phere (slight excess pressure), in 150 g of toluene together with 5 g of Pd/C (5 %, 50 % moist). After that, only the desired ~alicylamide can be detected in the ~ 30 mixture. The catalyst ie filtered off and then washed 3 with 100 ml of methanol in several portion~ in order to dissolve off undisfiolved product from the solid. The filtrate is concentrated (about 150 g) under a weak 232~2 ~' '' .
vacuum, and then cooled down to 0C, whereupon colorless crystals of 2-hydroxy-6-fluorobenzamide precipitate out.
~l ~hese latter are filtered off with ~uction and washed with cold toluene and hexane. After drying, 14.2 g (91.5 mmol, 92 %) of colorlesFi 6-fluorosalicylamide are obtained.
2-Hydroxy-6-fluorobenzamide (6--fluoro~alicylamide) M.p. 144-146.5C
,' MS: m/z (%) - 44 (14), 57 (20), 63 (19), 71 (5), 81 (12), 82 (24), ~i3 (25), 98 (5), 110 (100), 111 (11), 113 (8)/ 138 (~0~, 139 i~i (19), 141 (19), 155 (74.4, M~) t 156 (~.43, 157 (11.5) Example 7 ~i :
2-Amino-3-fluorophenol via 2-hydroxy-6-fluorobenzamide (6-fluorosalicylamide) -~
15.5 g (0.1 mol) of 6-fluorosalicylamide are introduced into 100 g of 30 ~ ~iodium hydroxide solution, and ~
chlorine ~ passed (4 l/h) into the resulting clear ~-solution. After 30 min, the chlorine str~am is shut off, and excess chlorine is destroyed (sodium sulfite). The p~
of the æolution is adjus~ed to 6 with sulfuric acid and -~
the precipitated 3-fluorobenzoxazolo~e is filtered off ~; with suction at 0C. The moist product (16.6 g) i heated ~at 130C for 3 h in 80 g of 70 % sulfuric acid, and, ~ -after cooling, the pH of the mixture i8 once again adju~ted to 6, and filtration with suction takes place at 0C. 7.3 g (57 mmol, 57 %) of dark-gray 2-amino-3-fluoro-phenol are obtained with a purity of 98 % (GC); the black mother liquor i5 discarded.
.............. .................................................................... ...
2-Hydroxy-6-fluoro N-carbomethoxyaniline, inter alia, i8 ,~ formed if a little methanol is added to the reaction mixture.
,i ~1232~2 :. f . -: ' ~ 21 ~
'~ MS ~ Z (%) = 51 (19.7) ~ 59 (18.8) ~ 70 (15.4) ~ 71 (lloO) ~ 97 (13~ 98 (69~2) r 109 (6-3) ~
126 (100) 1 127 (8~4) ~ 140 (5~9) ~ 153 (32~4) ~ 154 (5~3) ~ 185 (71~ 186 (6~4) Example 8 ' ;~
2-Amino-3-fluorophenol in a one-pot proce~s starting from 2,6-difluoroben amide .
The procedure described in Example 2A. (1) iB carried 10 out. After that, a further 600 g of water, 280 g (7 mol) of sodium hydroxide and 185 g (1.71 mol) of benzyl ¦ alcohol are added at 10C, and chlorine i~ passed in 15-18 l/h~ at 40C for 3 h. The phase~ are separated, and 500 ml of methanol and 7 g of Pd/C (5 %, 50 ~ moist) are added to the organic phase and hydrogenation is carried out as described in Exampl~ lb. After working up ~ ~ :
I in analogy to Example lb, 123.5 g (0.97 mol, 59 %) of 2~
i~ amino-3-fluorophenol are obtained a~ pale-gray shiny ~ platelets.
3~ 20 Example 9 ~ .
2-Amino-3-fluorophenol in a one-pot proces~ starting from 2,6-difluorobenzonitrile 69.6 g (0.5 mol) of 2,6~difluorobenzonitrile and 237 g (1.2 mol) of 6-noxmal sodi~m hydroxide solution are ~ ~ 25 initially introduced in 200 ml of benzyl alcohol. 221 g ! ( 1. 95 mol) of 30 ~ hydrogen peroxide solution are added ~ drQpwise to this mixture within the space of 30 min, ¦ during which the temperature, which was 20C at the ¦ beginning of the addition, rises to 50C ~nd i8 then maintained at this value. After 5 h (complete conversion to 2-benzyloxy~6-fluorobenzamide can be detected by means of GC), the mixture is cooled down and ~upplemented with 200 g o~ wate!r and 60 g ( 1~5 mol) of ~odium hydroxideO
2~23242 Chlorine is passed in (8 10 l/h) at 30~C for 2 h, with the reaction being monitored by gas chromatography and terminated when the amide has disappeared. The phases are separated, and 180 g of methanol are added to the organic 5 phase, and this is followed by further working up as 3 indicated in Example 8. 32.4 g (0.255 mol~ 51 %) of 2-amino-3-fluorophenol are obtained as a brown-black powder.
.
.,,,,~ ~ ,.
:~ .
' ~, .
;:~
1. '.:.
~,
Claims (21)
1. A compound of the formula (I) (I) in which R1 is hydrogen, (C1-C8)-alkyl or CH2-phenyl, where the alkyl radical or the phenyl group can be substituted by one to three (C1-C4)-alkoxy groups, fluorine, chlorine or bromine atoms, nitro groups, cyano groups, trifluoromethyl groups or (C1-C4)-alkoxycarbonyl groups, and R2 is -CN, CONH2, -NH2, -NCO or -NHCOOR3, where R3 has the meanings of R1 other than that of hydrogen.
2. A compound as claimed in claim 1, wherein R1 is hydrogen, (C1-C8)-alkyl or CH2-phenyl, R2 is -CN, -CONH2, -NH2, -NCO or -NHCOOR3, and R3 is (C1-C8)-alkyl or CH2-phenyl.
3. A compound as claimed in claim 1 or 2, wherein R1 is hydrogen and R2 has the meaning as claimed in claim 1, preferably -CONH2, or -NH2.
4. A compound as claimed in claim 1 or 2, wherein R1 is CH2-phenyl and R2 has the meaning as claimed in claim 1, preferably -CN, -CONH2, -NH2 or -NHCOOR3.
5. A compound as claimed in claim 1 or 2, wherein R1 is (C1-C8)-alkyl and R2 has the meaning as claimed in claim 1, preferably -CN or -CONH2.
6. A compound of the formula (I) as claimed in claim 1 from the group comprising 2-amino-3-fluorophenol, 2-hydroxy-6-fluorobenzamide, 2-benzyloxy-6-fluoro-benzamide, 2-benzyloxy-6-fluoroaniline, 2-benzyloxy 6-fluoro-N-benzyloxycarbonylaniline, 2-benzyloxy-6-fluorobenzonitrile, 2-ethoxy-6-fluoro-benzonitrile and 2-ethoxy-6-fluorobenzamide.
7. A process for preparing compounds of the formula (I) as claimed in claim 1, in which R1 has the meaning as claimed in claim 1 and R2 is -NH2 or -NHCOOR3, wherein compounds of the formula (II) (II) in which X is OR1, are reacted, in aqueous-alkaline medium, with chlorine, bromine, sodium hypochlorite or sodium hypobromite in the presence of alcohols and at temperatures of from -15°C to +80°C, in the sense of a Hofmann degradation.
8. The process as claimed in claim 7, wherein the reaction is effected in the presence of an alcohol, HOR3, where R3 has the same meaning as in claim 1.
9. The process as claimed in claim 8, wherein the compound of the formula (I') (I') resulting therefrom is either isolated, or the carbamate group and/or, for X = OR1, the group OR1 (when R1 is not hydrogen) is cleaved hydrogeno-lytically or hydrolytically.
10. The process as claimed in at least one of claims 7 to 9, wherein 2,6-difluorobenzonitrile is used as the starting compound for preparing the compounds (II) and the nitrile group is converted, in a manner known per se, into the amide group, and, in the case of compounds in which X is OR1, the corresponding F
atom is replaced by the OR1 group before, during or after this conversion.
atom is replaced by the OR1 group before, during or after this conversion.
11. The process as claimed in claim 10, wherein the replacement of the fluorine atom by an alkoxy group is effected at the same time as the conversion of the nitrile group into the amide group in such a way that the 2,6-difluorobenzonitrile is converted, in the presence of an alcohol, HOR3, where R3 has the same meaning as in claim 1 and preferably represents benzyl, into the corresponding benzamide, and the OR1 group (here R1 is different from hydrogen) is subsequently, where appropriate, cleaved hydrogeno-lytically.
12. The process as claimed in claim 10, wherein the 2,6-difluorobenzonitrile for preparing the compound of the formula (I) having R2 = CN is reacted with an alcohol, HOR3, where R3 possesses the same meaning a in claim 1, in aqueous-alkaline medium or in a dipolar, aprotic solvent in the presence of alkalis.
13. A process for preparing the compounds of the formula (I) as claimed in claim 1, in which R2 is NH2, wherein either 2,6-difluorobenzonitrile or 2,6-difluorobenzamide is reacted, in aqueous-alkaline medium, with alcohols to form compounds of the formula II having X = OR1, and these latter are then, after intermediate isolation, but preferably without any intermediate isolation, reacted, in a one-pot process, with chlorine, bromine, sodium hypochlorite or sodium hypobromite, at temperatures of from -15°C to +80°C and in the presence of alcohols, in the sense of a Hofmann degradation, and, where appropriate, carbamates which have been formed are subsequently cleaved hydrolytically or hydrogenolytically.
14. The process as claimed in claim 13, wherein (C1-C8)-alkanols or phenylmethanols, where the alkyl radical or the phenyl radical can be substituted by one to three (C1-C4)-alkoxy groups, fluorine, chlorine or bromine atoms, nitro groups, cyano groups, tri-fluoromethyl groups or (C1-C4)-alkoxycarbonyl groups, in particular primary alcohols, are employed as alcohols.
15. The process as claimed in claim 13 or 14, wherein the alcohols are methanol, ethanol or benzyl alcohol.
16. The process as claimed in at least one of claims 13 to 15, wherein the reactions to form the 2-alkoxy-6-fluorobenzamides are carried out in aqueous-alkaline medium or in one or more dipolar, aprotic solvents in the presence of alkalis.
17. The process as claimed in at least one of claims 13 to 15, wherein the reaction to form the compounds of the formula (II) having X = OR1 is effected at temperatures of from 0°C to 90°C, preferably of from 20°C to 70°C.
18. The process as claimed in claim 16, wherein the reaction is effected at temperatures of from 30°C to 150°C, preferably of from 40°C to 100°C.
19. The process as claimed in at least one of claims 13 to 18, wherein the carbamate groups, and, where appropriate, the OR1 groups as well, contained in the compounds obtained by the Hofmann degradation, are cleaved hydrogenolytically and/or hydrolyti-cally.
20. The process as claimed in claim 19, wherein the hydrogenolytic cleavage is carried out in the presence of transition metal catalysts, in particular platinum, nickel or palladium catalysts.
21. Use of the compounds of the formula (I), as claimed in claim 1, in particular compounds in which R1 is hydrogen, methyl, ethyl or CH2-phenyl, and R2 is -CN, -CONH2, -NH2 or -NHCOOR3, with R3 being methyl, ethyl or CH2-phenyl, for preparing liquid-crystalline compounds, plant protection agents or pharmaceuticals.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4315625.8 | 1993-05-11 | ||
| DE4315625A DE4315625A1 (en) | 1993-05-11 | 1993-05-11 | New 3-fluorophenol derivatives, process for their preparation and their use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2123242A1 true CA2123242A1 (en) | 1994-11-12 |
Family
ID=6487756
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002123242A Abandoned CA2123242A1 (en) | 1993-05-11 | 1994-05-10 | Derivatives of 3-fluorophenol, processes for preparing them, and the use of these compounds |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0624567B1 (en) |
| JP (1) | JPH0770007A (en) |
| CA (1) | CA2123242A1 (en) |
| DE (2) | DE4315625A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6420605B1 (en) | 1997-09-18 | 2002-07-16 | Basf Aktiengesellschaft | Benzamidoxim derivatives, intermediate products and methods for preparing and using them as fungicides |
| US7741426B2 (en) | 2003-06-23 | 2010-06-22 | Nippon Shokubai Co., Ltd | Method for production of fluorinated phenylenediamine |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9701396D0 (en) * | 1997-04-15 | 1997-04-15 | Astra Pharma Prod | Compounds |
| WO2000017156A1 (en) * | 1998-09-22 | 2000-03-30 | Basf Aktiengesellschaft | Novel benzamidoxime derivatives, intermediate products, methods for the production thereof, and their use as fungicides |
| DE10321269A1 (en) * | 2003-05-13 | 2004-12-02 | Bayer Cropscience Ag | Process for the preparation of dimethylcyanimidocarbonate |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63107990A (en) * | 1986-05-14 | 1988-05-12 | Nippon Shinyaku Co Ltd | Quinolinecarboxylic acid derivative |
| US4960767A (en) * | 1988-08-01 | 1990-10-02 | Hoechst-Roussel Pharmaceuticals Inc. | Isoxazolobenzoxazepines |
| GB8830182D0 (en) * | 1988-12-23 | 1989-02-22 | Shell Int Research | Heterocyclic herbicides |
| DE3919435A1 (en) * | 1989-06-14 | 1990-12-20 | Basf Ag | SALICYLALDEHYDE AND SALICYLSAEED DERIVATIVES AND THEIR SULFUR ANALOGUE, PROCESS FOR THEIR MANUFACTURE AS HERBICIDES AND BIOREGULATORS |
| CN1053921A (en) * | 1990-02-08 | 1991-08-21 | 布茨公司 | Therapeutical agent |
| NZ238576A (en) * | 1990-06-18 | 1994-12-22 | Merck & Co Inc | Pyridinone derivatives, preparation and pharmaceutical compositions thereof |
-
1993
- 1993-05-11 DE DE4315625A patent/DE4315625A1/en not_active Withdrawn
-
1994
- 1994-05-03 EP EP94106897A patent/EP0624567B1/en not_active Expired - Lifetime
- 1994-05-03 DE DE59408975T patent/DE59408975D1/en not_active Expired - Fee Related
- 1994-05-10 CA CA002123242A patent/CA2123242A1/en not_active Abandoned
- 1994-05-10 JP JP6096566A patent/JPH0770007A/en not_active Withdrawn
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6420605B1 (en) | 1997-09-18 | 2002-07-16 | Basf Aktiengesellschaft | Benzamidoxim derivatives, intermediate products and methods for preparing and using them as fungicides |
| US6509501B2 (en) | 1997-09-18 | 2003-01-21 | Basf Aktiengesellschaft | Benzamidoxime derivatives, intermediates and processes for their preparation, and their use as fungicides |
| US6680402B2 (en) | 1997-09-18 | 2004-01-20 | Basf Aktiengesellschaft | Benzamidoxime derivatives, intermediates and processes for their preparation, and their use as fungicides |
| US7741426B2 (en) | 2003-06-23 | 2010-06-22 | Nippon Shokubai Co., Ltd | Method for production of fluorinated phenylenediamine |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0770007A (en) | 1995-03-14 |
| EP0624567B1 (en) | 1999-12-08 |
| EP0624567A3 (en) | 1995-03-22 |
| DE59408975D1 (en) | 2000-01-13 |
| EP0624567A2 (en) | 1994-11-17 |
| DE4315625A1 (en) | 1994-11-17 |
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