Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
1999-12-21
2002-06-04
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
Reexamination Certificate
active
06399807
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The invention relates to a process for preparing 2,4,5-trifluoro-benzonitrile which is used as starting material for active compounds in the fields of medicine and agriculture.
BACKGROUND OF THE INVENTION
It is known that 2,4,5-trifluoro-benzonitrile is obtained when 1-bromo-2,4,5-trifluorobenzene is heated with copper(I) cyanide and N-methyl-pyrrolidone in a closed reaction vessel at temperatures between 170° C. and 190° C. for several hours (see EP-A-191 185). However, this synthesis process affords a highly contaminated product which can be isolated in a satisfactory purity only after column chromatography.
According to a somewhat modified process, 1-bromo-2,4,5-trifluoro-benzene can also be converted with copper(I) cyanide into 2,4,5-trifluoro-benzonitrile using N,N-dimethyl-formamide as solvent and prolonged heating under reflux (see J. Med. Chem. 31 (1988), 983-991). However, this application does not describe the isolation of pure 2,4,5-trifluoro-benzonitrile.
Also known is the reaction of 2,4-dichloro-5-fluoro-benzonitrile with potassium fluoride, if appropriate in the presence of reaction auxiliaries, such as, for example, caesium fluoride and octadecyl-trimethylammonium chloride, in the presence of diluents, such as, for example, dimethyl sulphoxide, tetramethylene sulphone (sulpholane) and toluene, at temperatures above 150° C. (see EP-A-431 373, EP-A-433 124, EP-A-497 239, EP-A-635 486). However, here 2,4,5-trifluoro-benzonitrile is in most cases obtained in addition to other products, and only in low or moderate yields. Only if relatively large amounts of phase-transfer catalysts, in particular tetraalkylphosphonium halides, are employed, 2,4,5-trifluoro-benzonitrile is said to be obtained in relatively high yields (see EP-A-557 949).
It is furthermore known that 2,4,5-trifluoro-benzonitrile can be obtained in a mixture with other fluorination products by reaction of 2,4-difluoro-benzonitrile with elemental fluorine at low temperatures (see EP-A-566 268).
The synthesis of some trihalogenobenzonitriles—however, not that of 2,4,5-trifluoro-benzonitrile—has also been described starting from the corresponding trihalogenoanilines via the diazonium salts and their reaction with metal cyanides (for this “Sandmeyer process”, see GB-A-951 770, Coll. Czech. Chem. Com. 42 (1977), 2001-2017). However, quality and/or yield of the resulting products are unsatisfactory.
DETAILED DESCRIPTION OF THE INVENTION
It is an object of the present invention to provide a process which permits the preparation of 2,4,5-trifluoro-benzonitrile in high purity and large yields starting from 2,4,5-trifluoro-aniline.
This object is achieved by a process for preparing 2,4,5-trifluoro-benzonitrile of the formula (I)
in which 2,4,5-trifluoro-aniline of the formula (II)
is, in a first step A), reacted with a nitrosating agent in the presence of a diluent and in which, in a second step B), the reaction product obtained in step A) is reacted with an alkali metal cyanide in the presence of a transition metal compound, an acid acceptor and a diluent.
Surprisingly, 2,4,5-trifluoro-benzonitrile can be obtained by the process according to the invention in a large yield and in high purity.
When carrying out the process according to the invention, the reaction temperatures can be varied within a relatively wide range. In general, the first step is carried out at temperatures between −20° C. and +30° C., preferably between −10° C and +20° C., and the second step is generally carried out at temperatures between −10° C. and +40° C., preferably between 0° C. and +30° C.
The two steps of the process according to the invention are generally carried out under atmospheric pressure. However, it is also possible to carry out the process according to the invention under elevated or reduced pressure—generally between 0.1 bar and 10 bar.
The starting material 2,4,5-trifluoro-aniline is known and can be prepared in a simple manner (see GB-A-11 31 501, EP-A-415 585).
The first step of the process according to the invention is carried out using a nitrosating agent. Suitable nitrosating agents are the nitrosating agents which are conventionally used for preparing diazonium salts. Examples of these are: Alkali metal nitrites, such as, for example, sodium nitrite and potassium nitrite (in the presence of an acid, such as, for example, sulphuric acid, methanesulphonic acid, formic acid or acetic acid), alkyl nitrites, such as, for example, methyl, ethyl, n- or i-propyl, n-, i-, s- or t-butyl, n-, i-, s- or t-pentyl nitrite, and furthermore also nitrosylsulphuric acid.
A particularly preferred nitrosating agent for carrying out the first step of the process according to the invention is nitrosylsulphuric acid.
The second step of the process according to the invention is carried out using an alkali metal cyanide. Preferred alkali metal cyanides are sodium cyanide or potassium cyanide. In addition, a transition metal compound, preferably a copper compound, such as, for example, copper cyanide or copper sulphate is used. Surprisingly, the transition metal compound can be employed in amounts which are far below the stoichiometric amount, i.e. in catalytic amounts.
The second step of the process according to the invention is furthermore carried out in the presence of an acid acceptor. Suitable acid acceptors are, in general, the customary inorganic or organic bases or acid binders. These preferably include alkali metal or alkaline earth metal acetates, amides, carbonates, bicarbonates, hydrides, hydroxides or alkoxides, such as, for example, sodium acetate, potassium acetate or calcium acetate, lithium amide, sodium amide, potassium amide or calcium amide, sodium carbonate, potassium carbonate or calcium carbonate, sodium bicarbonate, potassium bicarbonate or calcium bicarbonate, lithium hydride, sodium hydride, potassium hydride or calcium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, sodium methoxide, ethoxide, n- or i-propoxide, n-, i-, s- or t-butoxide or potassium methoxide, ethoxide, n- or i-propoxide, n-, i-, s- or t-butoxide; furthermore also basic organic nitrogen compounds, such as, for example, trimethylamine, triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, N,N-dimethylcyclohexylamine, dicyclohexylamine, ethyl-dicyclohexylamine, N,N-dimethyl-aniline, N,N-dimethyl-benzylamine, pyridine, 2-methyl-, 3-methyl-, 4-methyl-, 2,4-dimethyl-, 2,6-dimethyl-, 3,4-dimethyl- and 3,5-dimethyl-pyridine, 5-ethyl-2-methyl-pyridine, 4-dimethylamino-pyridine, N-methyl-piperidine, 1,4-diazabicyclo[2.2.2]-octane (DABCO), 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN), or 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU).
Preference is given to using alkali metal carbonates or bicarbonates or alkaline earth metal carbonates or bicarbonates, such as, for example, sodium (bi)carbonate or potassium (bi)carbonate.
The process according to the invention is carried out in the presence of a diluent. Suitable diluents for carrying out the process according to the invention are especially inert organic solvents. These include, in particular, aliphatic, alicyclic or aromatic, optionally halogenated hydrocarbons, such as, for example, benzine, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl ether or ethylene glycol diethyl ether; ketones, such as acetone, butanone or methyl isobutyl ketone; carboxylic acid, such as, for example, formic acid, acetic acid or propionic acid; nitriles, such as acetonitrile, propionitrile or butyronitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide, N-methyl-pyrrolidone or hexamethylphosphoric triamide; esters, such as methyl acetate or ethyl acetate, sulphoxides, such as dimethyl sulphoxide, alcohols, such as methanol, ethanol, n- or i-propan
Hupperts Achim
Lantzsch Reinhard
Bayer Aktiegesellschaft
Franks James R.
Gil Joseph C.
Stockton Laura L.
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