US20080139795A1 - Preparation of halogenated 4-aminophenols - Google Patents
Preparation of halogenated 4-aminophenols Download PDFInfo
- Publication number
- US20080139795A1 US20080139795A1 US12/011,550 US1155008A US2008139795A1 US 20080139795 A1 US20080139795 A1 US 20080139795A1 US 1155008 A US1155008 A US 1155008A US 2008139795 A1 US2008139795 A1 US 2008139795A1
- Authority
- US
- United States
- Prior art keywords
- amino
- phenol
- formula
- fluoro
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- RZXMPPFPUUCRFN-UHFFFAOYSA-N CC1=CC=C(N)C=C1 Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 4
- 0 CC1C(CC2C3C2)C3C2C1CC*2 Chemical compound CC1C(CC2C3C2)C3C2C1CC*2 0.000 description 4
- BEYOBVMPDRKTNR-UHFFFAOYSA-N OC1=CC=C(N=NC2=CC=CC=C2)C=C1 Chemical compound OC1=CC=C(N=NC2=CC=CC=C2)C=C1 BEYOBVMPDRKTNR-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N CC1=CC=CC=C1 Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N NC1=CC=CC=C1 Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N OC1=CC=CC=C1 Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- XRGPFNGLRSIPSA-UHFFFAOYSA-N C#CC(C)=O Chemical compound C#CC(C)=O XRGPFNGLRSIPSA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/02—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides
- C07C245/06—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings
- C07C245/08—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings with the two nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings, e.g. azobenzene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
-
- 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
Definitions
- the invention relates to a process for preparing a compound of the formula (I):
- n 0, 1, 2 or 3 and
- n 1, 2, 3 or 4
- R 1 is hydrogen, C 1 -C 12 -alkyl or C 5 -C 15 -arylalkyl and
- R 2 is in each case independently C 1 -C 12 -fluoroalkyl, C 1 -C 12 -fluoroalkylthio or C 1 -C 12 -fluoroalkoxy and
- Hal is in each case independently bromine, chlorine or fluorine.
- the invention relates to a compound of the formula (I):
- n 0, 1, 2 or 3 and
- n 1, 2, 3 or 4
- R 1 is hydrogen, C 1 -C 12 -alkyl or C 5 -C 15 -arylalkyl and
- R 2 is in each case independently C 1 -C 12 -fluoroalkyl, C 1 -C 12 -fluoroalkylthio or C 1 -C 12 -fluoroalkoxy and
- Hal is in each case independently bromine, chlorine or fluorine,
- the compound of formula (I) excludes a compound selected from the group consisting of 4-amino-3,5-difluorophenol, 4-amino-2,5-difluorophenol, 4-amino-2,6-difluorophenol, 4-amino-2-chloro-6-fluorophenol, 4-amino-2-chloro-3-fluorophenol, 4-amino-2-chloro-5-fluorophenol, 4-amino-2-bromo-5-fluorophenol, 4-amino-2-fluorophenol, 4-amino-3-fluorophenol, 4-amino-2-(trifluoromethyl)phenol, 4-amino-5-chloro-2-(trifluoromethyl)phenol, 4-amino-2-chloro-6-(trifluoromethyl)phenol ot 4-amino-3-(trifluoromethyl)phenol.
- the invention relates to a composition
- a composition comprising a compound of the formula (V),
- the compound of formula (V) excludes a compound selected from the group consisting of 3,5-difluoro-4-phenylazophenol, 3-fluoro-4-phenylazophenol, 3-fluoro-4-(4′-nitrophenylazo) phenol, 3-fluoro-4-(3′-nitrophenylazo)phenol, 3-fluoro-4-(4′-thiocyanatophenylazo)phenol, 3-fluoro-4-(4′-sulphophenylazo)phenol, ethyl 4-(2′-fluoro-4′-hydroxyphenylazo)benzoate, 2-fluoro-4-(4′-fluorophenylazo) phenol, 2-fluoro-4-(3′-fluorophenylazo)phenol, 2-fluoro-4-(4′-sulphophenylazo)phenol, ethyl 4-(3′-fluoro-4′-hydroxyphenylazo)benzoate, 2,3-difluoro-4-(4′-i
- the invention also relates to methods for using the above-mentioned compounds.
- R 1 is hydrogen, C 1 -C 12 -alkyl or C 5 -C 15 -arylalkyl and R 2 is in each case independently C 1 -C 12 -fluoroalkyl, C 1 -C 12 — fluoroalkylthio or C 1 -C 12 -fluoroalkoxy and Hal is in each case independently bromine, chlorine or fluorine,
- R 3 is in each case independently fluorine, chlorine, bromine, iodine, cyano, thiocyanato, hydroxysulphonyl or alkali metal salts thereof, nitro, C 1 -C 12 -alkyl, C 1 -C 12 -fluoroalkyl, C 1 -C 12 -fluoroalkyoxy, C 1 -C 12 -fluoroalkylthio, C 1 -C 12 -alkoxy, C 1 -C 12 -alkoxycarbonyl, di(C 1 -C 12 -alkyl)amino, C 4 -C 14 -aryl or C 5 -C 15 -arylalkyl are converted to diazonium salts of the formula (III)
- the compounds of the formula (I) can be converted by reacting with compounds of the formulae (VIIa) or (VIIb)
- Step D) may be carried out in a manner known per se, for example similar to that described in U.S. Pat. No. 4,851,535.
- step E) may be carried out in a manner known per se, for example similar to that described in U.S. Pat. No. 4,851,535.
- R 1 , R 2 , R 4 , R 6 , Hal, n and m are each as defined above.
- reaction of the compounds of the formula (VII) with compounds of the formula (IX) to give compounds of the formula (X) may be effected, for example, by heating the two reactants in an organic solvent, preferably an aliphatic alcohol, for example methanol.
- alkyl and alkoxy are in each case independently a straight-chain, cyclic, branched or unbranched alkyl and alkoxy radical respectively. The same applies to the nonaromatic moiety of an arylalkyl radical.
- C 1 -C 4 -Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl
- C 1 -C 12 -alkyl is additionally, for example, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 1-ethylpropyl, cyclohexyl, cyclopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and n-dodecyl.
- fluoroalkyl in each case independently a straight-chain, cyclic, branched or unbranched alkyl, alkoxy and alkylthio radical respectively, each of which is singly, multiply or fully substituted by fluorine atoms.
- C 1 -C 12 -fluoroalkyl is trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, nonafluorobutyl, heptafluoroisopropyl, perfluorooctyl and perfluorododecyl.
- C 1 -C 12 -fluoroalkoxy is trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, nonafluorobutoxy, heptafluoroisopropoxy, perfluorooctoxy and perfluorododecoxy.
- C 1 -C 12 -fluoroalkylthio is trifluoromethylthio, 2,2,2-tri-fluoroethylthio, pentafluoroethylthio, nonafluorobutylthio, heptafluoroisopropylthio, perfluorooctylthio and perfluorododecylthio.
- Aryl is in each case independently a heteroaromatic radical having 5 to 14 skeleton carbon atoms of which nil, one, two or three skeleton carbon atoms per cycle, but at least one skeleton carbon atom in the entire molecule, may be substituted by heteroatoms selected from the group of nitrogen, sulphur and oxygen, and is preferably a carbocyclic aromatic radical having 6 to 14 skeleton carbon atoms.
- carbocyclic aromatic radical or heteroaromatic radical may be substituted by up to five identical or different substituents per cycle which are selected from the group of fluorine, cyano, nitro, C 1 -C 12 -alkyl, C 1 -C 12 -fluoroalkyl, C 1 -C 12 -fluoroalkoxy, C 1 -C 12 -fluoroalkylthio, C 1 -C 12 -alkoxy, di(C 1 -C 12 -alkyl)amino.
- Arylalkyl is in each case independently a straight-chain, cyclic, branched or unbranched alkyl radical as defined above, each of which may be singly, multiply or fully substituted by aryl radicals as defined above.
- n is preferably 1 or 2
- m is preferably 0 or 1
- R 1 is preferably hydrogen or methyl, more preferably hydrogen
- R 2 is preferably trifluoromethyl, trifluoromethoxy and trifluoromethylthio
- Hal is preferably bromine, chlorine or fluorine, and at least one Hal radical is more preferably fluorine.
- p is preferably 0.
- the process according to the invention is especially suitable for preparing 4-amino-2,3-difluorophenol, 4-amino-2,5-difluorophenol, 4-amino-2,6-difluorophenol, 4-amino-2-fluorophenol, 4-amino-3-chloro-5-fluorophenol, 4-amino-3-chloro-2-fluorophenol, 4-amino-5-chloro-2-fluorophenol, 4-amino-3-bromo-5-fluorophenol, 4-amino-2-(trifluoromethoxy)phenol and 4-amino-3-(trifluoromethoxy)phenol.
- Particularly preferred individual compounds of the formula (I) include: 4-amino-2,3-difluorophenol, 4-amino-3-chloro-5-fluorophenol, 4-amino-3-chloro-2-fluorophenol, 4-amino-5-chloro-2-fluorophenol, 4-amino-3-bromo-5-fluorophenol, 4-amino-2-(trifluoromethoxy)phenol and 4-amino-3-(trifluoromethoxy)phenol.
- the compounds of the formula (III) can be prepared from compounds of the formula (II) in a manner known per se.
- the compounds of the formula (II) are reacted with a nitrite source in the presence of water and acid.
- the acids used may be, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulphuric acid or tetrafluoroboric acid, or else organic sulphonic acids.
- the nitrite source used may be, for example, the alkali metal nitrites, especially sodium nitrite or potassium nitrite, and also organic nitrites, especially tert-butyl nitrite or methyl nitrite. Preference is given to alkali metal nitrites which are preferably used dissolved in water.
- the molar ratio of protons of the acid used to compounds of the formula (II) may be, for example, 1 to 15, preferably 2 to 10 and more preferably 2.5 to 6.5.
- the molar ratio of compounds of the formula (II) to the nitrite source may be, for example, 0.8 to 4, preferably 1.0 to 2.5 and more preferably 1.05 to 1.5.
- the reaction temperature in step A1) may be, for example, ⁇ 20° C. to 40° C., preferably ⁇ 10° C. to 20° C. and more preferably ⁇ 5° C. to 10° C.; the reaction pressure may be, for example, 0.5 to 100 bar, preferably ambient pressure; the reaction time may be 10 min to 5 hours, preferably 1 hour to 3 hours.
- the procedure is, for example, to initially charge the compounds of the formula (II) in water and acid and subsequently add an aqueous solution of the alkali metal nitrite.
- an excess of alkali metal nitrite may be destroyed by adding a primary amino compound, for example urea or amidosulphuric acid.
- the starting compounds of the formula (II) required for step A1) are known from the literature or can be synthesized in a similar manner to the literature.
- step A2) the compounds of the formula (III) obtained in step A1) are reacted with compounds of the formula (IV) in the presence of base to give compounds of the formula (V).
- Suitable bases are in principle all bases which are more basic than the compounds of the formula (IV), preferably by at least 2 pK units.
- alkali metal or alkaline earth metal hydroxides, carbonates and hydrogen carbonates Preference is given to using alkali metal hydroxides, carbonates and hydrogen carbonates, of which alkali metal hydroxides, such as sodium hydroxide in particular, are preferred.
- the base may either be initially charged or added in the course of the reaction in such a way that the reaction medium remains alkaline.
- the molar ratio of compounds of the formula (III) to compounds of the formula (IV) may be, for example, 0.3 to 5, preferably 0.5 to 2 and more preferably 0.6 to 0.9.
- the molar ratio of compounds of the formula (III) to base may be, for example, 1 to 15, preferably 3 to 10 and more preferably 4 to 7.
- the reaction temperature in step A2) may be, for example, ⁇ 20° C. to 50° C., preferably 0° to 40° C. and more preferably 50 to 30° C., the reaction pressure, for example, 0.5 to 100 bar, preferably ambient pressure.
- the reaction time may be, for example, 10 min to 15 hours, preferably 3 to 5 hours.
- the workup of the compounds of the formula (V) may be effected in a manner known per se by extraction and subsequent distillation, or, in the case of compounds of the formula (V) which are solid at 30° C., by filtration and crystallization.
- the compounds of the formula (V) are likewise encompassed by the invention as important intermediates, although the following are excluded: 3,5-difluoro-4-phenylazophenol, 3-fluoro-4-phenylazophenol, 3-fluoro-4-(4′-nitrophenylazo)phenol, 3-fluoro-4-(3′-nitrophenylazo)phenol, 3-fluoro-4-(4′-thiocyanatophenylazo)phenol, 3-fluoro-4-(4′-sulphophenylazo)phenol, ethyl 4-(2′-fluoro-4′-hydroxyphenylazo)benzoate, 2-fluoro-4-(4′-fluorophenylazo)phenol, 2-fluoro-4-(3′-fluorophenylazo)phenol, 2-fluoro-4-(4′-sulphophenylazo)phenol, ethyl 4-(3′-fluoro-4′-hydroxyphenylazo)benzoate, 2,3-difluoro-4
- the compounds of the formula (IV) are known from the literature or can be synthesized in a similar manner to the literature.
- step B compounds of the formula (V) are converted by reduction to compounds of the formula (I).
- the reduction may be effected, for example, by reducing agents such as sodium bisulphite, titanium(III) chloride or tin and hydrochloric acid. More advantageously, the reduction is carried out in the presence of hydrogen and catalyst.
- reducing agents such as sodium bisulphite, titanium(III) chloride or tin and hydrochloric acid. More advantageously, the reduction is carried out in the presence of hydrogen and catalyst.
- Preferred catalysts are, for example, metals or metal compounds, especially salts or complexes of nickel, palladium, platinum, cobalt, rhodium, iridium and ruthenium, and preference is given to metals such as nickel or palladium.
- Metals are preferably used in finely divided form, for example as Raney metal, or applied to a support material.
- the reduction in step B) may be carried out, for example, at a reaction temperature of 0° C. to 200° C., preferably at 10° C. to 80° C. and more preferably at 20° C. to 40° C.
- the partial hydrogen pressure in the reduction may be, for example, 0.1 to 180 bar, preferably 0.5 to 50 bar and more preferably 1 to 3 bar.
- the reduction may be carried out in the presence of solvents, as long as they are substantially inert under the reaction conditions selected.
- Suitable solvents are, for example, aliphatic, alicyclic or aromatic, optionally halogenated hydrocarbons, for example benzine, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl ether or ethylene glycol diethyl ether; alcohols, for example methanol, ethanol and isopropanol or mixtures of solvents.
- hydrocarbons for example benzine, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform or carbon
- the reduction is carried out in the presence of palladium on activated carbon and in the presence of methanol or ethanol at a partial hydrogen pressure of 1 to 3 bar.
- the reaction time in the reduction may be 10 min to 100 hours, preferably 2 to 20 hours.
- step C) the O-alkylation of compounds of the formula (I) in which R 1 is hydrogen, is undertaken.
- Suitable inorganic bases are in principle all bases which are more basic than the compounds of the formula (I) in which R 1 is hydrogen, preferably by at least 3 pK units.
- Preferred inorganic bases are alkali metal or alkaline earth metal carbonates, hydrogencarbonates and hydroxides, and also tetraalkylammonium hydroxides, of which preference is given to alkali metal carbonates and hydroxides.
- Suitable alkylating agents are in particular compounds of the formula (VI)
- R 1 is C 1 -C 12 -alkyl, C 5 -C 15 -arylalkyl and
- Act is iodine, bromine, chlorine or a sulphonate.
- Suitable solvents for carrying out the alkylation are in particular ethers such as methyl tert-butyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl ether or ethylene glycol diethyl ether; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, N-methylcaprolactam or hexamethylphosphoramide; sulphoxides such as dimethyl sulphoxide, sulphones such as tetramethylenesulphone or mixtures of such organic solvents.
- ethers such as methyl tert-butyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl ether or ethylene glycol diethyl ether
- amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanil
- the molar ratio of inorganic base to compounds of the formula (I) in which R 1 is hydrogen may be, for example, 0.3 to 5, preferably 0.5 to 3 and more preferably 0.9 to 1.3.
- the molar ratio of alkylating agents to compounds of the formula (I) in which R 1 is hydrogen may be, for example, 0.3 to 5, preferably 0.5 to 3 and more preferably 0.9 to 1.8.
- the reaction temperature in step C) may be, for example, ⁇ 70° C. to 100° C., preferably ⁇ 20 to 60° C. and more preferably 0 to 40° C.
- the reaction time in step C) may be, for example, 10 min to 24 hours, preferably 1 to 8 hours.
- the compounds of the formula (I), (VIII) and (X) are obtained in good yields starting from readily available reactants.
- the compounds of the formula (I), (VII) and (X), and also the compounds of the formula (V), are especially suitable for use in a process for preparing active ingredients in pharmaceuticals and agrochemicals, or intermediates thereof.
- Preferred active ingredients of pharmaceuticals are those which are used to treat chronic bronchitis, and preference is given to those which are described in WO 03/08413 and PCT 03/02154.
- the above freshly prepared diazonium salt solution is added to this solution at such a rate that the internal temperature did not rise above 5° C. During the addition, the pH was monitored regularly. On completion of addition, the mixture was allowed to warm to room temperature, and stirred for a further 60 minutes, and the suspension was then adjusted to pH 4 using 2N HCl. The product was filtered off and washed repeatedly with water. After the drying in a vacuum drying cabinet, 182 g (quantitative yield) of the desired orange-brown azo compound were obtained.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to halogenated 4-aminophenols and to halogenated 4-(phenyldiazenyl)phenols, to a process for their preparation and to the use of the halogenated 4-hydroxyphenols for preparing active ingredients, especially in pharmaceuticals and agrochemicals.
Description
- There is therefore a need to provide a process which enables the preparation of halogenated 4-aminophenols in good yields and in a simple manner.
- The invention relates to a process for preparing a compound of the formula (I):
- wherein
- m is 0, 1, 2 or 3 and
- n is 1, 2, 3 or 4,
- where the sum of
- m+n is a maximum of 4, and
- R1 is hydrogen, C1-C12-alkyl or C5-C15-arylalkyl and
- R2 is in each case independently C1-C12-fluoroalkyl, C1-C12-fluoroalkylthio or C1-C12-fluoroalkoxy and
- Hal is in each case independently bromine, chlorine or fluorine.
- The process involves the steps of A1, converting compounds of the formula (II)
-
- in which
- p is 0, 1, 2 or 3 and
- R3 is in each case independently fluorine, chlorine, bromine, iodine, cyano, thiocyanato, hydroxysulphonyl or alkali metal salts thereof, nitro, C1-C12-alkyl, C1-C12-fluoroalkyl, C1-C12-fluoroalkyoxy, C1-C12-fluoroalkylthio, C1-C12-alkoxy, C1-C12-alkoxycarbonyl, di(C1-C12-alkyl)amino, C4-C14-aryl or C5-C15-arylalkyl
- to diazonium salts of the formula (III)
-
- in which An− is the anion of an acid and
- A2) reacting
- the diazonium salts of the formula (III) with compounds of the formula (IV)
-
- in which
- m, n, Hal and R2 are each as defined under the formula (I)
- in the presence of a base to give compounds of the formula (V)
-
- and
- B) converting the compounds of the formula (V) with a reducing agent to a compound of the formula (I) that has R1 is hydrogen, thereby forming at least one compound of formula (I).
- In one embodiment, the invention relates to a compound of the formula (I):
- wherein
- m is 0, 1, 2 or 3 and
- n is 1, 2, 3 or 4,
- m+n is a maximum of 4, and
- R1 is hydrogen, C1-C12-alkyl or C5-C15-arylalkyl and
- R2 is in each case independently C1-C12-fluoroalkyl, C1-C12-fluoroalkylthio or C1-C12-fluoroalkoxy and
- Hal is in each case independently bromine, chlorine or fluorine,
- wherein the compound of formula (I) excludes a compound selected from the group consisting of 4-amino-3,5-difluorophenol, 4-amino-2,5-difluorophenol, 4-amino-2,6-difluorophenol, 4-amino-2-chloro-6-fluorophenol, 4-amino-2-chloro-3-fluorophenol, 4-amino-2-chloro-5-fluorophenol, 4-amino-2-bromo-5-fluorophenol, 4-amino-2-fluorophenol, 4-amino-3-fluorophenol, 4-amino-2-(trifluoromethyl)phenol, 4-amino-5-chloro-2-(trifluoromethyl)phenol, 4-amino-2-chloro-6-(trifluoromethyl)phenol ot 4-amino-3-(trifluoromethyl)phenol.
- In another embodiment, the invention relates to a composition comprising a compound of the formula (V),
- wherein the compound of formula (V) excludes a compound selected from the group consisting of 3,5-difluoro-4-phenylazophenol, 3-fluoro-4-phenylazophenol, 3-fluoro-4-(4′-nitrophenylazo) phenol, 3-fluoro-4-(3′-nitrophenylazo)phenol, 3-fluoro-4-(4′-thiocyanatophenylazo)phenol, 3-fluoro-4-(4′-sulphophenylazo)phenol, ethyl 4-(2′-fluoro-4′-hydroxyphenylazo)benzoate, 2-fluoro-4-(4′-fluorophenylazo) phenol, 2-fluoro-4-(3′-fluorophenylazo)phenol, 2-fluoro-4-(4′-sulphophenylazo)phenol, ethyl 4-(3′-fluoro-4′-hydroxyphenylazo)benzoate, 2,3-difluoro-4-(4′-iodophenylazo) phenol, 2,3-difluoro-4-(4′-sulphophenylazo) phenol and 2,6-difluoro-4-(2′-bromophenylazo)phenol, 3-(trifluoromethyl)-4-(phenylazo)phenol and 3-(trifluoromethyl)-4-(4′-sodium sulphonate phenylazo)phenol, and combinations thereof.
- The invention also relates to methods for using the above-mentioned compounds.
- These and other features, aspects, and advantages of the present invention will become better understood with reference to the following description and appended claims.
- Other than in the operating examples or where otherwise indicated, all numbers or expressions referring to quantities of ingredients, reaction conditions, and the like, used in the specification and claims are to be understood as modified in all instances by the term “about.” Various numerical ranges are disclosed in this patent application. Because these ranges are continuous, they include every value between the minimum and maximum values. Unless expressly indicated otherwise, the various numerical ranges specified in this application are approximations.
- A process has now been found for preparing compounds of the formula (I)
- in which
m is 0, 1, 2 or 3 and
n is 1, 2, 3 or 4,
where the sum of
m+n is a maximum of 4, and
R1 is hydrogen, C1-C12-alkyl or C5-C15-arylalkyl and
R2 is in each case independently C1-C12-fluoroalkyl, C1-C12— fluoroalkylthio or C1-C12-fluoroalkoxy and
Hal is in each case independently bromine, chlorine or fluorine, - characterized in that
- in a step A1),
- compounds of the formula (II)
- in which
p is 0, 1, 2 or 3 and
R3 is in each case independently fluorine, chlorine, bromine, iodine, cyano, thiocyanato, hydroxysulphonyl or alkali metal salts thereof, nitro, C1-C12-alkyl, C1-C12-fluoroalkyl, C1-C12-fluoroalkyoxy, C1-C12-fluoroalkylthio, C1-C12-alkoxy, C1-C12-alkoxycarbonyl, di(C1-C12-alkyl)amino, C4-C14-aryl or C5-C15-arylalkyl
are converted to diazonium salts of the formula (III) - in which An− is the anion of an acid and
- in a step A2),
- the diazonium salts of the formula (III) are reacted with compounds of the formula (IV)
- in which
- m, n, Hal and R2 are each as defined under the formula (I)
- in the presence of base to give compounds of the formula (V)
- and
- in a step B),
- the compounds of the formula (V) are converted using a reducing agent to the compounds of the formula (I) in which R1 is hydrogen and
- optionally, in a step C),
- these compounds are converted by O-alkylation to compounds of the formula (I) in which R1 is C1-C12-alkyl.
- This excludes the preparation of 4-amino-3,5-difluorophenol and 4-amino-3-fluorophenol.
- Optionally, in a step D),
- the compounds of the formula (I) can be converted by reacting with compounds of the formulae (VIIa) or (VIIb)
- in which
- R4 is 2,4-difluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl or 4-fluoro-3-chlorophenyl and
- R5 is optionally mono- or poly-chlorine- or -fluorine-substituted phenyl to compounds of the formula (VIII)
- in which
R1, R2, R4, Hal, n and m are each as defined above.
Step D) may be carried out in a manner known per se, for example similar to that described in U.S. Pat. No. 4,851,535.
Optionally, in a step E), - the compounds of the formula (VIII) can be converted by reacting with compounds of the formula (IX)
- in which
- R6 is C1-C12-alkyl, C5-C15-arylalkyl or C4-C14-aryl
- to compounds of the formula (X)
- in which
- R1, R2, R4, R6, Hal, n and m are each as defined above.
- The reaction of the compounds of the formula (VII) with compounds of the formula (IX) to give compounds of the formula (X) may be effected, for example, by heating the two reactants in an organic solvent, preferably an aliphatic alcohol, for example methanol.
- The compounds mentioned as exceptions for steps A) to C) are excluded in the same manner for steps D) and E).
- In the context of the invention, all radical definitions, parameters and illustrations above and listed herein below, in general or specified within areas of preference, i.e. the particular areas and areas of preference, may be combined as desired.
- The term “alkyl” and “alkoxy” are in each case independently a straight-chain, cyclic, branched or unbranched alkyl and alkoxy radical respectively. The same applies to the nonaromatic moiety of an arylalkyl radical.
- C1-C4-Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl, and C1-C12-alkyl is additionally, for example, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 1-ethylpropyl, cyclohexyl, cyclopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and n-dodecyl.
- The term “fluoroalkyl,” “iluoroalkoxy” and “fluoroalkylthio” are in each case independently a straight-chain, cyclic, branched or unbranched alkyl, alkoxy and alkylthio radical respectively, each of which is singly, multiply or fully substituted by fluorine atoms.
- For example, C1-C12-fluoroalkyl is trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, nonafluorobutyl, heptafluoroisopropyl, perfluorooctyl and perfluorododecyl.
- For example, C1-C12-fluoroalkoxy is trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, nonafluorobutoxy, heptafluoroisopropoxy, perfluorooctoxy and perfluorododecoxy.
- For example, C1-C12-fluoroalkylthio is trifluoromethylthio, 2,2,2-tri-fluoroethylthio, pentafluoroethylthio, nonafluorobutylthio, heptafluoroisopropylthio, perfluorooctylthio and perfluorododecylthio.
- “Aryl” is in each case independently a heteroaromatic radical having 5 to 14 skeleton carbon atoms of which nil, one, two or three skeleton carbon atoms per cycle, but at least one skeleton carbon atom in the entire molecule, may be substituted by heteroatoms selected from the group of nitrogen, sulphur and oxygen, and is preferably a carbocyclic aromatic radical having 6 to 14 skeleton carbon atoms.
- In addition, the carbocyclic aromatic radical or heteroaromatic radical may be substituted by up to five identical or different substituents per cycle which are selected from the group of fluorine, cyano, nitro, C1-C12-alkyl, C1-C12-fluoroalkyl, C1-C12-fluoroalkoxy, C1-C12-fluoroalkylthio, C1-C12-alkoxy, di(C1-C12-alkyl)amino.
- “Arylalkyl” is in each case independently a straight-chain, cyclic, branched or unbranched alkyl radical as defined above, each of which may be singly, multiply or fully substituted by aryl radicals as defined above.
- The preferred substitution patterns are defined herein below:
- n is preferably 1 or 2,
m is preferably 0 or 1,
R1 is preferably hydrogen or methyl, more preferably hydrogen,
R2 is preferably trifluoromethyl, trifluoromethoxy and trifluoromethylthio,
Hal is preferably bromine, chlorine or fluorine, and at least one Hal radical is more preferably fluorine. - In compounds of the formula (II), p is preferably 0.
- The process according to the invention is especially suitable for preparing 4-amino-2,3-difluorophenol, 4-amino-2,5-difluorophenol, 4-amino-2,6-difluorophenol, 4-amino-2-fluorophenol, 4-amino-3-chloro-5-fluorophenol, 4-amino-3-chloro-2-fluorophenol, 4-amino-5-chloro-2-fluorophenol, 4-amino-3-bromo-5-fluorophenol, 4-amino-2-(trifluoromethoxy)phenol and 4-amino-3-(trifluoromethoxy)phenol.
- Many of the compounds of the formula (I) are novel and likewise encompassed by the invention, although the following are excluded: 4-amino-3,5-difluorophenol, 4-amino-2,5-difluorophenol, 4-amino-2,6-difluorophenol, 4-amino-2-chloro-6-fluorophenol, 4-amino-2-chloro-3-fluorophenol, 4-amino-2-chloro-5-fluorophenol, 4-amino-2-bromo-5-fluorophenol, 4-amino-2-fluorophenol, 4-amino-3-fluorophenol, 4-amino-2-(trifluoromethyl)phenol, 4-amino-5-chloro-2-(trifluoromethyl)phenol, 4-amino-2-chloro-6-(trifluoromethyl)phenol and 4-amino-3-(trifluoromethyl)phenol.
- Particularly preferred individual compounds of the formula (I) include: 4-amino-2,3-difluorophenol, 4-amino-3-chloro-5-fluorophenol, 4-amino-3-chloro-2-fluorophenol, 4-amino-5-chloro-2-fluorophenol, 4-amino-3-bromo-5-fluorophenol, 4-amino-2-(trifluoromethoxy)phenol and 4-amino-3-(trifluoromethoxy)phenol.
- In step A1), the compounds of the formula (III) can be prepared from compounds of the formula (II) in a manner known per se. Advantageously, the compounds of the formula (II) are reacted with a nitrite source in the presence of water and acid.
- The acids used may be, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulphuric acid or tetrafluoroboric acid, or else organic sulphonic acids.
- The nitrite source used may be, for example, the alkali metal nitrites, especially sodium nitrite or potassium nitrite, and also organic nitrites, especially tert-butyl nitrite or methyl nitrite. Preference is given to alkali metal nitrites which are preferably used dissolved in water.
- The molar ratio of protons of the acid used to compounds of the formula (II) may be, for example, 1 to 15, preferably 2 to 10 and more preferably 2.5 to 6.5.
- The molar ratio of compounds of the formula (II) to the nitrite source may be, for example, 0.8 to 4, preferably 1.0 to 2.5 and more preferably 1.05 to 1.5.
- The reaction temperature in step A1) may be, for example, −20° C. to 40° C., preferably −10° C. to 20° C. and more preferably −5° C. to 10° C.; the reaction pressure may be, for example, 0.5 to 100 bar, preferably ambient pressure; the reaction time may be 10 min to 5 hours, preferably 1 hour to 3 hours.
- To convert the compounds of the formula (II), the procedure is, for example, to initially charge the compounds of the formula (II) in water and acid and subsequently add an aqueous solution of the alkali metal nitrite. On completion of the reaction time, an excess of alkali metal nitrite may be destroyed by adding a primary amino compound, for example urea or amidosulphuric acid.
- The starting compounds of the formula (II) required for step A1) are known from the literature or can be synthesized in a similar manner to the literature.
- In step A2), the compounds of the formula (III) obtained in step A1) are reacted with compounds of the formula (IV) in the presence of base to give compounds of the formula (V).
- Suitable bases are in principle all bases which are more basic than the compounds of the formula (IV), preferably by at least 2 pK units.
- Preference is given to using alkali metal or alkaline earth metal hydroxides, carbonates and hydrogen carbonates, of which alkali metal hydroxides, such as sodium hydroxide in particular, are preferred.
- The base may either be initially charged or added in the course of the reaction in such a way that the reaction medium remains alkaline.
- The molar ratio of compounds of the formula (III) to compounds of the formula (IV) may be, for example, 0.3 to 5, preferably 0.5 to 2 and more preferably 0.6 to 0.9.
- The molar ratio of compounds of the formula (III) to base may be, for example, 1 to 15, preferably 3 to 10 and more preferably 4 to 7.
- The reaction temperature in step A2) may be, for example, −20° C. to 50° C., preferably 0° to 40° C. and more preferably 50 to 30° C., the reaction pressure, for example, 0.5 to 100 bar, preferably ambient pressure. In addition, the reaction time may be, for example, 10 min to 15 hours, preferably 3 to 5 hours.
- The workup of the compounds of the formula (V) may be effected in a manner known per se by extraction and subsequent distillation, or, in the case of compounds of the formula (V) which are solid at 30° C., by filtration and crystallization.
- The compounds of the formula (V) are likewise encompassed by the invention as important intermediates, although the following are excluded: 3,5-difluoro-4-phenylazophenol, 3-fluoro-4-phenylazophenol, 3-fluoro-4-(4′-nitrophenylazo)phenol, 3-fluoro-4-(3′-nitrophenylazo)phenol, 3-fluoro-4-(4′-thiocyanatophenylazo)phenol, 3-fluoro-4-(4′-sulphophenylazo)phenol, ethyl 4-(2′-fluoro-4′-hydroxyphenylazo)benzoate, 2-fluoro-4-(4′-fluorophenylazo)phenol, 2-fluoro-4-(3′-fluorophenylazo)phenol, 2-fluoro-4-(4′-sulphophenylazo)phenol, ethyl 4-(3′-fluoro-4′-hydroxyphenylazo)benzoate, 2,3-difluoro-4-(4′-iodophenylazo)phenol, 2,3-difluoro-4-(4′-sulphophenylazo)phenol and 2,6-difluoro-4-(2′-bromophenylazo)phenol, 3-(trifluoromethyl)-4-(phenylazo)phenol and 3-(trifluoromethyl)-4-(4′-sodium sulphonate phenylazo)phenol.
- The compounds of the formula (IV) are known from the literature or can be synthesized in a similar manner to the literature.
- In step B), compounds of the formula (V) are converted by reduction to compounds of the formula (I).
- The reduction may be effected, for example, by reducing agents such as sodium bisulphite, titanium(III) chloride or tin and hydrochloric acid. More advantageously, the reduction is carried out in the presence of hydrogen and catalyst.
- Preferred catalysts are, for example, metals or metal compounds, especially salts or complexes of nickel, palladium, platinum, cobalt, rhodium, iridium and ruthenium, and preference is given to metals such as nickel or palladium. Metals are preferably used in finely divided form, for example as Raney metal, or applied to a support material.
- Particular preference is given to carrying out the reduction with hydrogen and palladium on carbon.
- The reduction in step B) may be carried out, for example, at a reaction temperature of 0° C. to 200° C., preferably at 10° C. to 80° C. and more preferably at 20° C. to 40° C.
- The partial hydrogen pressure in the reduction may be, for example, 0.1 to 180 bar, preferably 0.5 to 50 bar and more preferably 1 to 3 bar.
- Optionally and with preference, the reduction may be carried out in the presence of solvents, as long as they are substantially inert under the reaction conditions selected.
- Suitable solvents are, for example, aliphatic, alicyclic or aromatic, optionally halogenated hydrocarbons, for example benzine, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl ether or ethylene glycol diethyl ether; alcohols, for example methanol, ethanol and isopropanol or mixtures of solvents.
- In a particularly preferred embodiment, the reduction is carried out in the presence of palladium on activated carbon and in the presence of methanol or ethanol at a partial hydrogen pressure of 1 to 3 bar.
- The reaction time in the reduction may be 10 min to 100 hours, preferably 2 to 20 hours.
- The workup of the compounds of the formula (I) in which R1 is hydrogen may be effected in a manner known per se by extraction and subsequent distillation or, in the case of compounds of the formula (I) which are solid at 30° C., by recrystallization.
- Optionally, step C), the O-alkylation of compounds of the formula (I) in which R1 is hydrogen, is undertaken.
- Preference is given in this case to carrying out the reaction in the presence of an inorganic base.
- Suitable inorganic bases are in principle all bases which are more basic than the compounds of the formula (I) in which R1 is hydrogen, preferably by at least 3 pK units.
- Preferred inorganic bases are alkali metal or alkaline earth metal carbonates, hydrogencarbonates and hydroxides, and also tetraalkylammonium hydroxides, of which preference is given to alkali metal carbonates and hydroxides.
- Suitable alkylating agents are in particular compounds of the formula (VI)
-
R1-Act (VI) - in which
- R1 is C1-C12-alkyl, C5-C15-arylalkyl and
- Act is iodine, bromine, chlorine or a sulphonate.
- Suitable solvents for carrying out the alkylation are in particular ethers such as methyl tert-butyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl ether or ethylene glycol diethyl ether; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, N-methylcaprolactam or hexamethylphosphoramide; sulphoxides such as dimethyl sulphoxide, sulphones such as tetramethylenesulphone or mixtures of such organic solvents.
- The molar ratio of inorganic base to compounds of the formula (I) in which R1 is hydrogen may be, for example, 0.3 to 5, preferably 0.5 to 3 and more preferably 0.9 to 1.3.
- The molar ratio of alkylating agents to compounds of the formula (I) in which R1 is hydrogen may be, for example, 0.3 to 5, preferably 0.5 to 3 and more preferably 0.9 to 1.8.
- The reaction temperature in step C) may be, for example, −70° C. to 100° C., preferably −20 to 60° C. and more preferably 0 to 40° C.
- The reaction time in step C) may be, for example, 10 min to 24 hours, preferably 1 to 8 hours.
- In the inventive manner, the compounds of the formula (I), (VIII) and (X) are obtained in good yields starting from readily available reactants. The compounds of the formula (I), (VII) and (X), and also the compounds of the formula (V), are especially suitable for use in a process for preparing active ingredients in pharmaceuticals and agrochemicals, or intermediates thereof.
- Preferred active ingredients of pharmaceuticals are those which are used to treat chronic bronchitis, and preference is given to those which are described in WO 03/08413 and PCT 03/02154.
- The invention is further illustrated but is not intended to be limited by the following examples in which all parts and percentages are by weight unless otherwise specified.
- At 0° C., 108.2 g (1.16 mol) of aniline were dissolved with vigorous stirring in 500 g of 27% hydrochloric acid. Afterwards, at 5°-0° C., 95.2 g (1.38 mol) of sodium nitrite (dissolved in 283 ml of water) were added dropwise and the solution was stirred for another 60 minutes on completion of addition. Excess sodium nitrite was destroyed with amidosulphuric acid. In a further flask, 101.2 g (0.77 mol) of 3,5-difluorophenol were dissolved in a solution of 182.8 g (4.57 mol) of sodium hydroxide in 2281 ml of water, and precooled to 5° C. The above freshly prepared diazonium salt solution is added to this solution at such a rate that the internal temperature did not rise above 5° C. During the addition, the pH was monitored regularly. On completion of addition, the mixture was allowed to warm to room temperature, and stirred for a further 60 minutes, and the suspension was then adjusted to pH 4 using 2N HCl. The product was filtered off and washed repeatedly with water. After the drying in a vacuum drying cabinet, 182 g (quantitative yield) of the desired orange-brown azo compound were obtained.
- EI-MS: m/z 234 [M]+
- 20.4 g (0.09 mol) of 3,5-difluoro-4-(phenyldiazenyl)phenol from Example 1 and 0.5 g of Pd/C (10%) were initially charged in 120 ml of methanol. The solution was degassed and aerated with hydrogen. The mixture was stirred at room temperature under a 1 bar hydrogen atmosphere for 16 hours. On completion of hydrogen uptake, the catalyst was filtered off and the filtrate concentrated on a rotary evaporator. The residue was chromatographed on silica gel (n-hexane/ethyl acetate, 3:1). The resulting solid was stirred with n-hexane and dried. 7.6 g (60%) of 4-amino-3,5-difluorophenol were obtained as a yellow-brown solid.
- 1H NMR (400 MHz, CDCl3): δ=3.40 (s, 2H, NH2); 4.55 (s, 1H, OH); 6.39 (m, 2H, Ar—H)
- 19F NMR (376.3 MHz, CDCl3): δ=−130.5
- EI-MS: m/z 145 [M]+
- m.p.: 150-151° C.
- At 0° C., 27.3 ml (0.3 mol) of aniline were added dropwise with vigorous stirring to 140 ml of HCl (semiconc.). Afterwards, at 5°-0° C., 21.7 g (0.315 mol) of NaNO2 (dissolved in 100 ml of water) were added dropwise and, on completion of addition, the solution was stirred for another 20 minutes.
- In a further flask, 39 g (0.3 mol) of 2,3-difluorophenol were dissolved in 300 ml of 2N NaOH and precooled to 0° C. The above freshly prepared diazo solution was added to this solution at such a rate that the internal temperature does not rise above 5° C. During the addition, the pH was monitored regularly and, if necessary, made alkaline again by means of Na2CO3. On completion of addition, the mixture was allowed to warm to room temperature, stirred for a further 30 minutes and then the suspension was adjusted to pH 3-4 using 2N HCl. The product was filtered off and washed repeatedly with water. After the drying in the vacuum drying cabinet, 61 g (87%) of the desired bright yellow azo compound were obtained.
- EI-MS: m/z 234 [M]+
- 61 g (0.26 mol) of 2,3-difluoro-4-(phenyldiazenyl)phenol from Example 3 and 1 g of Pd/C (10%) are initially charged in 800 ml of ethanol. The solution was degassed and aerated with hydrogen. The mixture was stirred at room temperature under a 1 bar hydrogen atmosphere for 18 hours. On completion of hydrogen uptake, the catalyst was filtered off and the filtrate was concentrated on a rotary evaporator, in the course of which the product already crystallized out. The resulting solid was filtered off, washed with a little cold ethanol and dried under high vacuum for 4 hours. 28 g (74%) of the desired compound were obtained as a light brown powder.
- 1H NMR (400 MHz, DMSO-d6) δ=4.72 (s, 2H, NH2), 6.39 (t, 1H, Ar—H), 6.51 (t, 1H, Ar—H), 9.13 (s, 1H, OH);
- EI-MS: m/z 145 [M]+
- At 0° C., 17.5 ml (0.19 mol) of aniline were added dropwise with vigorous stirring to 185 ml of HCl (semiconc.). Afterwards, at 50-0° C., 13.9 g (0.2 mol) of NaNO2 (dissolved in 50 ml of water) were added dropwise and, on completion of addition, the solution was stirred for another 20 minutes.
- In a further flask, 25 g (0.19 mol) of 2,5-difluorophenol were dissolved in 190 ml of 2N NaOH and precooled to 0° C. The above freshly prepared diazo solution was added to this solution at such a rate that the internal temperature did not rise above 5° C. During the addition, the pH was monitored regularly and, if necessary, made alkaline again by means of Na2CO3. On completion of addition, the mixture was allowed to warm to room temperature, stirred for a further 30 minutes, and the suspension was then adjusted to pH 3-4 using 2N HCl. The product was filtered off and washed repeatedly with water. After drying in a vacuum drying cabinet at 50° C., 42 g (93%) of the desired orange-coloured azo compound were obtained.
- EI-MS: m/z 234 [M]+
- 42 g (0.18 mol) of 2,5-difluoro-4-(phenyldiazenyl)phenol from Example 5 and 1 g of Pd/C (10%) were initially charged in 650 ml of ethanol. The solution was degassed and aerated with hydrogen. The mixture was stirred at room temperature under a 1 bar hydrogen atmosphere for 18 hours. On completion of hydrogen uptake, the catalyst was filtered off and the filtrate distilled under reduced pressure, and dried under high vacuum at 70° C. for 4 hours. The residue (24 g) was recrystallized from ethanol and dried. 15 g (60%) of 4-amino-2,5-difluorophenol are obtained as orange-brown powder.
- 1H NMR (400 MHz, DMSO-d6) δ=4.68 (s, 2H, NH2), 6.58 (m, 2H, Ar—H), 9.05 (s, 1H, OH);
- EI-MS: m/z 145 [M]+
- At 0° C., 10.23 ml (0.11 mmol) of aniline were added dropwise with vigorous stirring to 50 ml of HCl (semiconc.). Afterwards, at 5°-0° C., 8.1 g (0.117 mol) of NaNO2 (dissolved in 30 ml of water) were added dropwise and, on completion of addition, the solution was stirred for a further 20 minutes.
- In a further flask, 20.0 g (0.12 mol) of 2-trifluoromethoxyphenol were dissolved in 140 ml of 2N NaOH and precooled to 0° C. The above freshly prepared diazo solution was added to this solution at such a rate that the internal temperature did not rise above 5° C. During the addition, the pH was monitored regularly and, if necessary, made alkaline again by means of Na2CO3. On completion of addition, the mixture was allowed to warm to room temperature and stirred for a further 30 minutes, and the suspension was then adjusted to pH 3-4 using 2N HCl. The product was filtered off with suction and washed repeatedly with water. After drying in a vacuum drying cabinet, 26 g (81%) of the desired light brown azo compound were obtained.
- 25 g (0.09 mol) of 2-trifluoromethoxy-4-(phenyldiazenyl)phenol from Example 7 and 1 g of Pd/C (10%) were initially charged in 350 ml of ethanol. The solution was degassed and aerated with hydrogen. The mixture was stirred at room temperature under a 1 bar hydrogen atmosphere for 72 hours. On completion of hydrogen uptake, the catalyst was filtered off and the filtrate concentrated on a rotary evaporator, in the course of which the product already crystallizes out. The resulting solid was filtered off with suction, washed with a little cold ethanol and dried under high vacuum for 4 hours. 8.5 g (50%) of the desired compound were obtained as a light brown powder.
- 1H NMR (400 MHz, DMSO-d6) δ=4.72 (s, 2H, NH2), 6.42 (d, 1H, J=8.6 Hz, Ar—H), 6.5 (s, 1H, Ar—H), 6.72 (d, 1H, J=8.6 Hz, Ar—H), 8.9 (s, 1H, OH);
- EI-MS: m/z 193 [M]+
- Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.
Claims (2)
1. A compound of the formula (I):
wherein
m is 0, 1, 2 or 3 and
n is 1, 2, 3 or 4,
m+n is a maximum of 4, and
R1 is hydrogen, C1-C12-alkyl or C5-C15-arylalkyl and
R2 is in each case independently C1-C12-fluoroalkyl, C1-C12-fluoroalkylthio or C1-C12-fluoroalkoxy and
Hal is in each case independently bromine, chlorine or fluorine;
wherein the compound excludes a compound selected from the group consisting of 4-amino-3,5-difluorophenol, 4-amino-2,5-difluorophenol, 4-amino-2,6-difluorophenol, 4-amino-2-chloro-6-fluorophenol, 4-amino-2-chloro-3-fluorophenol, 4-amino-2-chloro-5-fluorophenol, 4-amino-2-bromo-5-fluorophenol, 4-amino-2-fluorophenol, 4-amino-3-fluorophenol, 4-amino-2-(trifluoromethyl)phenol, 4-amino-5-chloro-2-(trifluoromethyl)phenol, 4-amino-2-chloro-6-(trifluoromethyl)phenol ot 4-amino-3-(trifluoromethyl)phenol, and combinations thereof.
2. A compound of the formula (V),
wherein
R2 is in each case independently C1-C12-fluoroalkyl, C1-C12-fluoroalkylthio or C1-C12-fluoroalkoxy,
R3 is in each case independently fluorine, chlorine, bromine, iodine, cyano, thiocyanato, hydroxysulphonyl or alkali metal salts thereof, nitro, C1-C12-alkyl, C1-C12-fluoroalkyl, C1-C12-fluoroalkyoxy, C1-C12-fluoroalkylthio, C1-C12-alkoxy, C1-C12-alkoxycarbonyl, di(C1-C12-alkyl)amino, C4-C14-aryl or C5-C15-arylalkyl, and
Hal is in each case independently bromine, chlorine or fluorine,
m is 0, 1, 2 or 3 and
n is 1, 2, 3 or 4,
where the sum of
m+n is a maximum of 4; and
wherein the compound of formula (V) excludes a compound selected from the group consisting of 3,5-difluoro-4-phenylazophenol, 3-fluoro-4-phenylazophenol, 3-fluoro-4-(4′-nitrophenylazo) phenol, 3-fluoro-4-(3′-nitrophenylazo)phenol, 3-fluoro-4-(4′-thiocyanatophenylazo)phenol, 3-fluoro-4-(4′-sulphophenylazo)phenol, ethyl 4-(2′-fluoro-4′-hydroxyphenylazo)benzoate, 2-fluoro-4-(4′-fluorophenylazo) phenol, 2-fluoro-4-(3′-fluorophenylazo)phenol, 2-fluoro-4-(4′-sulphophenylazo)phenol, ethyl 4-(3′-fluoro-4′-hydroxyphenylazo)benzoate, 2,3-difluoro-4-(4′-iodophenylazo) phenol, 2,3-difluoro-4-(4′-sulphophenylazo) phenol and 2,6-difluoro-4-(2′-bromophenylazo)phenol, 3-(trifluoromethyl)-4-(phenylazo)phenol and 3-(trifluoromethyl)-4-(4′-sodium sulphonate phenylazo)phenol, and combinations thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/011,550 US20080139795A1 (en) | 2003-09-09 | 2008-01-28 | Preparation of halogenated 4-aminophenols |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10341533A DE10341533A1 (en) | 2003-09-09 | 2003-09-09 | Process for the preparation of halogenated 4-aminophenols |
DE10341533.5 | 2003-09-09 | ||
US10/934,919 US7358397B2 (en) | 2003-09-09 | 2004-09-03 | Preparation of halogenated 4-aminophenols |
US12/011,550 US20080139795A1 (en) | 2003-09-09 | 2008-01-28 | Preparation of halogenated 4-aminophenols |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/934,919 Division US7358397B2 (en) | 2003-09-09 | 2004-09-03 | Preparation of halogenated 4-aminophenols |
Publications (1)
Publication Number | Publication Date |
---|---|
US20080139795A1 true US20080139795A1 (en) | 2008-06-12 |
Family
ID=34129715
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/934,919 Expired - Fee Related US7358397B2 (en) | 2003-09-09 | 2004-09-03 | Preparation of halogenated 4-aminophenols |
US12/011,550 Abandoned US20080139795A1 (en) | 2003-09-09 | 2008-01-28 | Preparation of halogenated 4-aminophenols |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/934,919 Expired - Fee Related US7358397B2 (en) | 2003-09-09 | 2004-09-03 | Preparation of halogenated 4-aminophenols |
Country Status (4)
Country | Link |
---|---|
US (2) | US7358397B2 (en) |
EP (1) | EP1514865A1 (en) |
CN (1) | CN1616412A (en) |
DE (1) | DE10341533A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008538581A (en) * | 2005-04-22 | 2008-10-30 | ワイス | Crystal form of {[(2R) -7- (2,6-dichlorophenyl) -5-fluoro-2,3-dihydro-1-benzofuran-2-yl] methyl} amine hydrochloride |
CN102030616A (en) * | 2010-09-17 | 2011-04-27 | 上海赫腾精细化工有限公司 | Preparation method for 2,3,5,6-tetrafluorohydroquinone |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3238223A (en) * | 1962-01-09 | 1966-03-01 | Rohm & Haas | N-chloro or methyl-alkyl, alkoxy, alkylthio, cyclopentoxy or cyclohexoxy-phenyl-3, or 5, or 3 or 6 methyl-2-pyrrolidinones and -2-piperidones |
US3794734A (en) * | 1971-03-03 | 1974-02-26 | Merck & Co Inc | Methods of treating edema and hypertension using certain 2-aminoethylphenols |
US4939170A (en) * | 1987-06-03 | 1990-07-03 | Bayer Aktiengesellschaft | Substituted aminophenyl carbamates |
US5068436A (en) * | 1989-03-10 | 1991-11-26 | E. I. Du Pont De Nemours And Company | Hydrogenation of halonitrobenzenes without dehalogenation |
US5132325A (en) * | 1986-02-28 | 1992-07-21 | Ciba-Geigy Corporation | Benzoylphenylureas the preparation thereof and the use thereof in pest control |
US5176914A (en) * | 1989-09-02 | 1993-01-05 | Bayer Aktiengesellschaft | Fungicidal carbocyclic anilide carbamates |
US5622967A (en) * | 1993-04-26 | 1997-04-22 | Sterling Winthrop, Inc. | Quinolone carboxamide Calpain inhibitors |
US6124504A (en) * | 1996-07-08 | 2000-09-26 | Bayer Aktiengesellschaft | Process for preparing 4-hydroxyanilines |
US7208559B2 (en) * | 2002-12-27 | 2007-04-24 | Mitsui Chemicals, Inc. | Ethylened polymer and molded object obtained therefrom |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS503372B1 (en) * | 1963-05-04 | 1975-02-04 | ||
JPS61126055A (en) * | 1984-11-24 | 1986-06-13 | Nippon Soda Co Ltd | 4-aminophenol bearing trifluoromethyl group and its preparation |
US4851535A (en) | 1985-01-23 | 1989-07-25 | Toyama Chemical Co., Ltd. | Nicotinic acid derivatives |
JPH0713045B2 (en) | 1987-06-10 | 1995-02-15 | 財団法人相模中央化学研究所 | 2.5-difluorophenol derivative |
DE3827133A1 (en) * | 1987-08-13 | 1989-02-23 | Ciba Geigy Ag | N-benzoyl-N'-2,3,5-trihalo-4-haloalkoxyphenylureas, their preparation, and their use in pest control |
DE4119919A1 (en) * | 1990-06-20 | 1992-01-02 | Ciba Geigy Ag | New n-benzoyl-n'-(pyridin-2-yloxy)-phenyl-urea derivs. - useful as insecticides with good ovicidal and larvicidal properties, and low warm-blooded toxicity |
JPH05125030A (en) * | 1991-11-06 | 1993-05-21 | Seiko Epson Corp | Azobenzene compound |
ES2184623B1 (en) | 2001-06-29 | 2004-09-16 | Centro De Investigaciones Energeticas, Medioambientales Y Tecnologicas (C.I.E.M.A.T.) | ARTIFICIAL SKIN AUTOLOGA SECRETORA DE LEPTINA AND METHOD OF OBTAINING. |
GB0117506D0 (en) * | 2001-07-18 | 2001-09-12 | Bayer Ag | Imidazopyridinones |
US20060046999A1 (en) * | 2002-03-14 | 2006-03-02 | Cristina Alonso-Alija | Monocyclic aroylpyridinones as antiinflammatory agents |
-
2003
- 2003-09-09 DE DE10341533A patent/DE10341533A1/en not_active Withdrawn
-
2004
- 2004-08-28 EP EP04020500A patent/EP1514865A1/en not_active Withdrawn
- 2004-09-03 US US10/934,919 patent/US7358397B2/en not_active Expired - Fee Related
- 2004-09-09 CN CNA2004100771833A patent/CN1616412A/en active Pending
-
2008
- 2008-01-28 US US12/011,550 patent/US20080139795A1/en not_active Abandoned
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3238223A (en) * | 1962-01-09 | 1966-03-01 | Rohm & Haas | N-chloro or methyl-alkyl, alkoxy, alkylthio, cyclopentoxy or cyclohexoxy-phenyl-3, or 5, or 3 or 6 methyl-2-pyrrolidinones and -2-piperidones |
US3794734A (en) * | 1971-03-03 | 1974-02-26 | Merck & Co Inc | Methods of treating edema and hypertension using certain 2-aminoethylphenols |
US5132325A (en) * | 1986-02-28 | 1992-07-21 | Ciba-Geigy Corporation | Benzoylphenylureas the preparation thereof and the use thereof in pest control |
US4939170A (en) * | 1987-06-03 | 1990-07-03 | Bayer Aktiengesellschaft | Substituted aminophenyl carbamates |
US5068436A (en) * | 1989-03-10 | 1991-11-26 | E. I. Du Pont De Nemours And Company | Hydrogenation of halonitrobenzenes without dehalogenation |
US5176914A (en) * | 1989-09-02 | 1993-01-05 | Bayer Aktiengesellschaft | Fungicidal carbocyclic anilide carbamates |
US5622967A (en) * | 1993-04-26 | 1997-04-22 | Sterling Winthrop, Inc. | Quinolone carboxamide Calpain inhibitors |
US6124504A (en) * | 1996-07-08 | 2000-09-26 | Bayer Aktiengesellschaft | Process for preparing 4-hydroxyanilines |
US7208559B2 (en) * | 2002-12-27 | 2007-04-24 | Mitsui Chemicals, Inc. | Ethylened polymer and molded object obtained therefrom |
Also Published As
Publication number | Publication date |
---|---|
US20050143425A1 (en) | 2005-06-30 |
EP1514865A1 (en) | 2005-03-16 |
CN1616412A (en) | 2005-05-18 |
DE10341533A1 (en) | 2005-03-31 |
US7358397B2 (en) | 2008-04-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10500577B2 (en) | Oxalic amide ligands, and uses thereof in copper-catalyzed coupling reaction of aryl halides | |
JP4353633B2 (en) | Process for producing (hetero) aromatic hydroxylamine | |
US8053572B2 (en) | Alkyl-analide producing method | |
MX2007009457A (en) | Method for producing substituted biphenyls. | |
CA2418040C (en) | Process for the preparation of substituted phenylacetonitriles | |
US8124786B2 (en) | Mental-catalyzed process for preparation of substituted pyrazolecarboxamides | |
US20080139795A1 (en) | Preparation of halogenated 4-aminophenols | |
JP4949590B2 (en) | Method for producing aniline compound | |
US6124504A (en) | Process for preparing 4-hydroxyanilines | |
EP1902015A1 (en) | Process for the preparation of 1-[cyano (4-hydroxyphenyl)methyl]cyclohexanol compounds | |
US7919632B2 (en) | Method for producing carboxamides | |
JP2012246275A (en) | Method for producing phenylhydrazines | |
JP2006131568A (en) | Hydroxynaphthoic acid hydrazide, derivative thereof and method for producing the same | |
EP0415595A1 (en) | Fluorobenzene derivatives | |
US5453542A (en) | Preparation of 4,6-diaminoresorcinol through a bisazoarylresorcinol intermediate | |
WO2013127441A1 (en) | Process for the preparation of substituted phenylpropanones | |
JPH07149741A (en) | Azo coupling of 2-nitroaniline with 2,4-di-substituted phenol | |
CA2208734C (en) | Process for preparing 4,6-bis(difluoro-methoxy)pyrimidine derivatives | |
TW202417408A (en) | Process for preparation of 2-chloro-3-fluoro-4-alkoxy-anilines and 2-fluoro-3-chlorophenol | |
JP2003171359A (en) | Method for producing 2-nitrophenylacetonitrile derivative, and its synthetic intermediate | |
WO2024023012A1 (en) | Process for preparation of 2-chloro-3-fluoro-4-alkoxy-anilines and 2-fluoro-3-chlorophenol | |
Jin et al. | One-pot method to synthesize 4, 6-bis (isopropylamino) resorcinol through hydrodechlorination and catalytically reductive mono-N-alkylation | |
CN110740987A (en) | Process for mono-N-alkylation of aminophenols | |
MXPA97005092A (en) | Process for preparing 4-hydroxanylin | |
JP2003238499A (en) | Method for producing benzylamines |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: LANXESS DEUTSCHLAND GMBH, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BAYER CHEMICALS AG;REEL/FRAME:021756/0509 Effective date: 20061025 Owner name: BAYER CHEMICALS AG, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PEILSTOCKER, KAREN;MARHOLD, ALBRECHT;JOSCHEK, JENS-PETER;REEL/FRAME:021756/0442;SIGNING DATES FROM 20040816 TO 20040820 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |