MXPA97002787A - Process for the preparation of 3-aminobenzonitrile replace - Google Patents

Abstract

The invention relates to a process for the preparation of substituted 3-aminobenzonitriles of the formula I: (See Formula) wherein: R is hydrogen or alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, COR1, alkoxy 1 to 8 carbon atoms-alkyl, hydroxyalkyl of 1 to 6 carbon atoms, aminoalkyl of 1 to 8 carbon atoms, alkyl of 1 to 8 carbon atoms-NH (alkyl of 1 to 4 carbon atoms), alkyl of 1 to 8 atoms of carbon-N (alkyl of 1 to 4 carbon atoms) 2, substituted or unsubstituted benzyl, and R 1 is alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or phenyl, and which comprises reacting 3- a substituted aminobromobenzene of the formula II: (See Formula), with a cyano donor reagent. The compounds of the formula I are important intermediates in the preparation of benzothiadiazole-7-carboxylic acid, which is obtained by diazotization and hydrolyzation of the compounds of the formula I in any desired sequence.

Description

PROCESS FOR THE PREPARATION OF 3 REPLACED -AMINOBBNZONITRILOS The invention relates to a process for the preparation of substituted 3-aminobenzonitriles of the formula I: wherein: R = s hydrogen or alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, CORlf alkoxy of 1 to 8 carbon atoms-alkyl, hydroxyalkyl of 1 to 6 carbon atoms, aminoalkyl of 1 at 8 carbon atoms, alkyl of 1 to 8 carbon atoms-NH (alkyl of 1 to 4 carbon atoms), alkyl of 1 to 8 carbon atoms-N (alkyl of 1 to 4 carbon atoms) 2 b nyl substituted or unsubstituted, - and Rj is alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or phenyl; which comprises reacting, in a solvent at more than 30 ° C, a substituted 3-aminoclorobenzene of the formula II: Cl 'NH, wherein R is as defined for formula I, with a cyano donor reagent selected from: a; CuCN or cyanoferrate (II) of potassium (= K4 [Fe (CN) 6]) or calcium cyanoferrate (II) (= Ca2 [Fe (CN) 6]), in the presence of a complexing agent; or b] any Cu (I) salt, together with an alkali metal cyanide, in the presence of a complexing agent; or c) alkali metal cyanide, HCN, Ni (CN) 2 or tetramethylsilyl cyanide, or an HCN adduct of ketone or an adduct of Aldehyde HCN, in the presence of an M3 catalyst [Co + (CN) 4] 3", or Pd ° -Ln or preferably [a nickel catalyst] Ni ° -Ln, or a three-way mixture composed of NiL2Hal2, an excess of L, and a reducing agent, M being an alkali metal, L being a ligand, and n being from 2 to 4. The general terms used hereinbefore and hereinafter have the following meanings, unless to be defined otherwise: the alkyl groups are straight or branched chain, depending on the number of carbon atoms, and are, for example, methyl, ethyl, normal propyl, isopropyl, normal butyl, secondary butyl, isobutyl, tertiary butyl , secondary amyl, tertiary amyl, 1-hexyl, or 3-hexyl, depending on the size of the cycloalkyl ring is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl The ligands are phosphine groups PQ3 wherein: Q is alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 a carbon atoms, unsubstituted aryl, or aryl which is substituted by alkyl of 1 to 8 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, di (alkyl of 1 to 4 carbon atoms) ) aminoalkyl (of 1 to 4 carbon atoms), fluorine, S03H or N (alkyl of 1 to 4 carbon atoms) 2; or the ligands are: Q2P-W-PQ2 wherein W is alkyl of 1 to 8 carbon atoms, or unsubstituted ferrocenyl, or ferrocenyl which is substituted by one of the radicals mentioned for "aryl". Preferred ferrocenyl ligands are unsubstituted ferrocenyl and asymmetric monosubstituted representatives, for example 1-hydroxyethyl ferrocene and 1-dimethylaminoethyl ferrocene. Preferred catalysts are those of the formula Ni ° -Ln wherein L is triphenylphosphine and n is from 2 to 4, or those of the formula Ni ° -L2 wherein L is (1,1'-bisdiphenylphosphine-1- (dimethylaminoethyl) ferrocene). The compounds of the formula I are important intermediates in the preparation of the compound of the formula III and its acid derivatives, which have been described as plant immunization agents and plant conditioners (cf. EP-B-313,512) The process according to the invention comprises reacting a substituted 3-aminoclorobenzene of the formula II with a cyanide, to give the compounds of the formula I according to the invention: a) Y b) [for example CuCN / pyridine or -methylpyridine / 200 ° C] c) [for example Ni (PPh3) 4 / KCN / 100 ° C] E .. halogen exchange by the cyano group on the ciromatic compounds by CuCN or by complex metal cyanides for example potassium cyanoferrate (II) (= K4) [Fe (CN) 6]) or calcium cyanoferrate (II) (= Ca2 [Fe (CN) 6]), in the presence of pyridine, is known ("Rosenmund-von Braun synthesis"; for example Houben-Weyl, ethoden der organischen Chemie [Methods of Organic Chemistry], volume VIII, pages 302-3; volume E5, pages 1463-5, 1985). It is also known that the aromatically bound halides can be replaced by the cyano group by means of a cyano donor compound, for example alkali metal cyanide, HCN, Ni (CN) 2, or tetramethylsilyl cyanide, or an HCN adduct of Ketone or an aldehyde HCN adduct in the presence of a Co, Pd, or Ni catalyst (eg "Homogeneous Catalysis II" Adv. Chem. Ser 132 ACS 1974, page 252; Coll. Czechoslovak Chemm. Commun. 48 (1983) page 1765). The conversion of sulfur-containing chloroanilines to the 1,2,3-specific configuration in the desired nitriles is novel. The surprising aspect is that this reaction proceeds with a good selectivity and a high yield without a substantial dissociation of a carbon-sulfur bond that is observed. Moreover, one could not have expected this reaction to proceed easily in an electron-rich system (both the sulfur and the amino group on the phenyl ring are electron donor substituents). Furthermore, it is surprising that even large groups, for example tertiary thiobutyl, isothiopropyl, and cyclothiohexyl, in the ortho position in relation to the reaction center, do not prevent the reaction to a considerable degree. Reactions a) and b) are carried out in the presence of a complexing agent. This complexing agent causes, on the one hand, an acceleration of the Cl / CN exchange reaction, and on the other hand, it suppresses the dissociation of the S-R bond. The complexing agent is a nitrogen-containing electron donor compound, for example pyridine, quinoline, or isoquinoline, which are unsubstituted or mono- to tri-substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 atoms of carbon, amino, alkyl of 1 to 4 carbon atoms-amino, or (alkyl of 1 to 4 carbon atoms) 2-amino. They are particularly suitable as complexing agents, pyridine which is unsubstituted or mono- to tri-substituted by methyl, and quinoline; very particularly pyridine and 3-methylpyridine. In a particular embodiment, the reaction is carried out with: a) an equimolar amount (based on II) of CuCN or cyanoferrate (II) of potassium (= K4 [Fe (CN) 6]) or calcium cyanoferrate (II) ( = Ca2 [Fe (CN) 6]), in the presence of pyridine, methylpyridine, dimethylpyridine, trimethylpyridine, quinoline, dimethylaniline, acetonitrile, dimethyl sulfoxide, benzonitrile, dimethyl formamide, or tetramethylurea; or b) any Cu (I) salt, together with at least equimolar or greater amounts (based on II) of alkali metal cyanide, in the presence of pyridine, methylpyridine, dimethylpyridine, trimethylpyridine, quinoline, dimethylaniline, acetonitrile, sulfoxide, dimethyl, benzonitrile, dimethyl formamide or tetramethylurea; or c) at least equimolar amounts (based on II) of alkali metal cyanide, HCN, Ni (CN) 2 or tetramethylsilyl cyanide, or an HCN adduct of ketone or an adduct of HCN of aldehyde, in the presence of a M3 catalyst [Co + (CN) 4] 3 ~, or Pd ° -Ln, or preferably, Ni ° -Ln, or a three-way mixture composed of NiL2Hal2, excess L, and a reducing agent, M being a metal alkaline, L a ligand, and n from 2 to 4. The solvents which are conveniently used are polar aprotic solvents, for example dioxane, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, tetramethylurea, hexamethylphosphoric triamide . In a preferred embodiment, at least equimolar amounts of the complexing agent based on Cu or Fe are used directly as the solvent; pyridine and 3-ethylpyridine are particularly preferred, 3-methylpyridine being particularly preferred, because its high boiling point allows the process to be carried out under atmospheric pressure, even at a high temperature. The reaction is carried out at temperatures between 50 ° C and 350 ° C, preferably at temperatures between 150 ° C and 250 ° C. As a rule, the reaction is carried out under atmospheric pressure or at a slightly elevated pressure (20 bar), preferably under atmospheric pressure up to 10 bar. After a reaction time of about 3 to 18 hours, the yield of the compounds of the formula I is up to 75 percent of the theory, while the reaction rate is 80 percent, which corresponds to a yield more than 90 percent, based on the reacted product. Reaction a) is preferred with the use of CuCN. The work is carried out, for example, as follows: Na2S or NaCN, if desired in the form of an aqueous solution, is added to the reaction mixture, then the mixture is diluted with a solvent, for example ethyl acetate or ketone. methylethyl ether (MEK) to facilitate filtration, the salts are filtered, the filtrate is evaporated, and the residue is purified either by distillation or by crystallization. If NaCN is used, the filtration gives CuCN directly reusable. In reaction c), the exchange of chlorine by cyano is carried out in the presence of a catalyst. The reaction can be carried out in nitriles (acetonitrile, benzonitrile), hydrocarbons, in particular aromatics, in addition in ketones, alcohols (ethanol), water, amides (dimethyl formamide = DMF), ethers or mixtures thereof, preferably in dimethyl formamide . The reaction temperatures are between 30 ° C and 150 ° C, preferably between 40 ° C and 100 ° C. The. Catalytic action can be improved by reductive regeneration of the catalyst during the reaction. This regeneration is carried out electrochemically or by the addition of a reducing agent. The yields in this variant are even greater than 90 percent, and the crude mixture can be further reacted directly to obtain the benzothiadiazole-7-carboxylic acid III, without isolating an intermediate. The catalyst is prepared by known methods, for example, European Patent Number EP-384,392, "Homogeneous Catalysis II" Adv. Chem. Ser. 132 ACS 1974 page 252; J. Organomet. Chem. 173 (1979) page 335, J. Organ. Chem. 243 (1983) page 95; Coll. Czechoslovak Chemm. Co mun. Volume 48 (1983) page 1765. The preferred nickel tetrakistriphenylphosphine catalyst is prepared from nickel chloride hydrate, triphenylphosphine, and a reducing agent. The reducing agents used are metals, for example, Mn, Zn, Mg, or Al in the form of turning or powdering; hydrides, for example sodium borohydride, lithium-aluminum hydride, or sodium hydride, or otherwise electrochemical methods. The catalyst can be added to the reaction mixture, but preferably it is prepared on site.

An additional advantage of the process a, b, or c, is that, after the further reaction of the benzothiadiazole-7-carboxylic acid of the formula III, the unreacted reactant II is converted into the corresponding 7-chlorobenzothiadiazoles. These 7-chlorobenzothiadiazoles can be easily removed from the mixture with the compound of formula III by means of simple phase separation (water / organic solvent). The invention also relates to the use of compounds of the formula I to obtain the compound of the formula III. Accordingly, these compounds can be prepared from 2,3-dichloronitrobenzene, which is known, following Equation 1: Equation 1 III The reaction of 2,3-dichloronitrobenzene of formula IV, with a compound of HS-R, wherein R is as defined above, under basic conditions, results in a specific exchange of the chlorine atom at position 2 by an RS radical to give a compound of the formula V; the reduction of the n-group in the amino group results in a compound of the formula II. The reduction is carried out by methods known per se, for example, by reduction of Béchamp using iron / hydrogen chloride, catalytic hydrogenation [Pd or Raney nickel), or by reduction with Na2S. The resulting compound of formula II is converted into one of the compounds of formula I by exchange of Cl by CN as described above. The diazotization and cyclization compounds of the formula I in the subsequent steps result in the compound of the formula VII from which the compound of the formula III is obtained by hydrolyzing the cyano group in the carboxyl group, or from which the corresponding carboxamide is obtained by partial hydrolysis. Alternatively, if the sequence is reversed, the hydrolysis of the cyano group in the compounds of the formula I will give carboxylic acids, or if desired, carboxamides, of the formula VI, from which the compound III can be obtained by diazotization. The diazotization is carried out by customary methods, for example with nitrous acid (= HONO) or with an inorganic or organic nitrite. Examples that may be mentioned are NaN02 or alkyl nitrite having up to 8 carbon atoms. The acid or alkaline hydrolysis of the nitrile group in compounds I or VII is also carried out by customary methods, for example using concentrated sulfuric acid, hydrochloric acid, or alkali metal oxides, alkali metal hydroxides, alkaline earth metal oxides, or alkaline earth metal hydroxides, for example using NaOH or KOH. Accordingly, the invention also provides the process for the preparation of benzothiadiazole-7-carboxylic acid III from the compounds of the formula II by means of 3-aminobenzonitriles of the formula I, by means of: a) the exchange of Cl by CN to give a 3-aminobenzonitrile of formula I as described above, and in addition any of: bl) hydrolysis of the cyano group to give a compound of formula VI, followed by diazotization of the amino group using nitrous acid or nitrite, with cyclization, to give a compound of formula III; or b2) diazotization of the amino group using nitrous acid or nitrite, with cyclization, to give a compound of the formula VII, followed by hydrolysis of the cyano group to give a compound of the formula III. The process of preference is carried out using compounds wherein R is secondary alkyl of 3 to 6 carbon atoms, tertiary alkyl of 4 to 6 carbon atoms, or cycloalkyl of 5 to 6 carbon atoms, particularly preferably isopropyl, tertiary butyl, or cyclohexyl. The cyclization reaction to obtain benzothiadiazole can be carried out either at the level of the cyanide (I) or at the level of the carboxamide (IA), or at the level of the carboxylic acid (VI), according to equation 2.

Equation 2 VII V? A m The process for the preparation of a compound of formula XI X XI wherein Z is CN, CO-NH2 or COOH comprises diazotizing a compound of formula X, wherein Z and R are as defined above, using nitrous acid or nitrite, and subsequently cyclizing the product, and thus also being provided by the invention. The process of preference is carried out using compounds wherein R is secondary alkyl of 3 to 6 carbon atoms, tertiary alkyl of 4 to 6 carbon atoms, or cycloalkyl of 5 to 6 carbon atoms, particularly preferably isopropyl, butyl tertiary, or cyclohexyl. The conversion of the compound of the formula IV into the compounds of the formula V and its reduction to give a compound of the formula II according to equation 3 is known in principle.

Equation 3 IV p It has now been discovered that the compounds of the formula II can be prepared in a particularly high yield and purity, when: a) 2,3-dichloronitrobenzene of the formula IV is reacted, and a compound of HS-R, wherein R is as defined above, in an aqueous base in the presence of a phase transfer catalyst from 30 ° C to 120 ° C, to give a compound of the formula V; after the reaction, the product is extracted by washing with a polar solvent, for example, an alcohol, such as isopropanol or butanol, and subsequently washed with dilute acid, for example hydrochloric acid, at a pH of 5 to 7, and b) the reaction of the nitro group with hydrogen / Raney nickel is carried out in an alcohol or in water, or in a mixture thereof. Using the compound of formula V, which has been prepared and purified as described in a), the reduction of the nitrc group with Raney nickel proceeds in a surprisingly fast manner, and requires only a small amount of catalyst, - this avoids the dangerous accumulation of easily degradable hydroxylamine, which is a considerable improvement from the point of view of safety. Accordingly, the invention also provides the processes described above for the preparation of a compound of the formula V from a compound of the formula IV, the preparation of a compound of the formula II from a compound of the formula V, and the two-step process for the preparation of a compound of formula II from the compound of formula IV by means of a compound of formula V wherein R is as defined above. SW:? novel, and are also provided by the invention, the compounds of the formula I: wherein R is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, COR! , alkoxy of 1 to 8 carbon atoms-alkyl, hydroxyalkyl of 1 to 6 carbon atoms, aminoalkyl of 1 to 8 carbon atoms, alkyl of 1 to 8 carbon atoms-NH (alkyl of 1 to 4 carbon atoms) , alkyl of 1 to 8 carbon atoms-N (alkyl of 1 to 4 carbon atoms) 2, or substituted or unsubstituted benzyl, and R 1 is alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms , or phenyl. Preferred compounds of the formula I are those wherein:? S secondary alkyl of 3 to 6 carbon atoms, alkyl aryl of 4 to 6 carbon atoms, or cycloalkyl of 5 to 6 carbon atoms, in a manner particularly preferable isopropyl, tertiary Rutyl, or cyclohexyl. SOHL novel, and are also provided by the invention compounds of the formula V: wherein R is as defined for formula I, with the exception of hydrogen, methyl, and substituted or unsubstituted benzyl R is preferably secondary alkyl of 3 to 6 carbon atoms, or tertiary alkyl of 4 to 6 carbon atoms carbon, or cycloalkyl of 5 to 6 carbon atoms, particularly preferably isopropyl, or tertiary butyl, or cyclohexyl Soit, and also provided by the invention, are compounds of formula II: wherein R is as defined for formula I, with the exception of hydrogen, methyl, ethyl, and substituted or unsubstituted benzyl; R is preferably secondary alkyl of 3 to 6 carbon atoms, or tertiary alkyl of 4 to 6 carbon atoms, or cycloalkyl of 5 to 6 carbon atoms, particularly preferably isopropyl, or tertiary butyl, or cyclohexyl. The compounds of the formula IA are novel and are also provided by the invention: wherein R is as defined for formula I; R is preferably secondary alkyl of 3 to 6 carbon atoms, or tertiary alkyl of 4 to 6 carbon atoms, or cycloalkyl of to 6 carbon atoms, particularly preferably isopropyl, or tertiary butyl, or cyclohexyl. The compounds of the formula VI are novel and are also provided by the invention: wherein R is as defined for formula I, with the exception of substituted or unsubstituted benzyl; R is preferably secondary alkyl of 3 to 6 carbon atoms, or tertiary alkyl of 4 to 6 carbon atoms, or cycloalkyl of 5 to 6 carbon atoms, particularly preferably isopropyl, or tertiary butyl, or cyclohexyl.

Preparation Examples Example H-1: Process of the prior art Preparation of: Se: 124.4 grams of potassium carbonate and 144 grams of 1,2-dichloro-3-nitrobenzene are introduced into 400 grams of acetic acid, and the mixture is heated to 77 ° C. At this temperature, 72.2 grams of tertiary butyl mercaptan are added dropwise in the course of 1 hour. The mixture is subsequently stirred at 100 ° C for 2 hours. The reaction mixture is concentrated at 75 ° C under a slight vacuum, 500 milliliters of water are added, and the final product is subsequently removed at 60 ° C. This gives 185.5 grams of the product of one p.f. 50 ° C (yield> 95 percent).

Example H-2: Preparation of: Method a): Prior art process The procedure is as described in Example Hl, with the exception that 61 grams of isopropyl mercaptan is used instead of tertiary butyl mercaptan, on which, 175 grams of the product of a pf of 64-67 ° C (yield> 95 percent).

Method b); Process according to the present invention 80.1 grams of isopropyl mercaptan are introduced at 65 ° C-70 ° C, to a mixture of 195.5 grams of 2,3-dichloronitrobenzene, 3.22 grams of tetrabutyl ammonium bromide, 157.3 grams of a solution of 30 percent sodium hydroxide, and 120 grams of water. On this, stirring is continued for 1 hour at 65 ° C-70 ° C, 100 grams of isopropanol are added to the reaction mixture at 70 ° C, and the aqueous phase is separated from the bottom. The organic phase is washed with dilute aqueous hydrochloric acid at a pH of 5 to 7, and cooled to 0 ° C, and the product that is crystallized is filtered and washed with about 40 grams of isopropanol. This gives 225 grams of the product, m.p. 65-67 ° C (95 percent yield of the theory).

Example H-3: Preparation of: 345 grams of sodium sulfide hydrate in 500 milliliters of water are added over the course of 2 hours at 80 ° C-82 ° C, to 401.3 grams of l-chloro-2-cyclothiohexyl-3-nitrobenzene in 560 milliliters of isopropanol . After the mixture is stirred at 82 ° C for 3 hours, it is cooled to 20 ° C-25 ° C, and the aqueous phase is separated. The organic phase is washed using 200 milliliters of a 25 percent sodium chloride solution. Subsequently, the organic phase is concentrated and distilled at 180 ° C / 0.2 tcrr. Yield: 278.4 grams (77 percent) of a yellow oil. • • Example H-4; Preparation of: 355 grams of l-chloro-2-isothiopropyl-3-nitrobenzene (from Example H-2) are hydrogenated in 900 grams of methanol at 35 ° C-40 ° C / 5 bar in the presence of 27.5 grams of Raney nickel ( as an aqueous suspension). After the recovery of hydrogen is complete, the mixture is cooled to room temperature, the Raney nickel is filtered, and the solvent is distilled on a rotary evaporator. The residue (raw product) is used directly for the next step, or distilled at 90 ° C-100 ° C / 0.05 pID, yield: 272 grams (95 percent).

Reaction times; a) with educt which has been prepared according to the prior art: Example H-2, Method a): 3.5 hours, b) with educt which has been prepared by the process according to the invention: Example H-2, method b): 0.5 hours.

Example H-5; Preparation of : H-5 (1): 60.5 grams of 3-chloro-2-isothiopropylaniline (from Example H-4), 26.9 grams of copper cyanide (I), and 26.1 grams of pyridine, heated at 190 ° C for 7 hours . 100 milliliters of acetonitrile are added dropwise with evaporative cooling, and subsequently 7 milliliters of water are added, followed by 21.5 grams of sodium sulfide hydrate, a little at a time. After the mixture is stirred at 80 ° C for 4 hours, it is cooled and filtered, and the filtrate is concentrated. After distillation at 70 ° C-120 ° C / 0.05 torr, 200 milliliters of hexane are added, and the mixture is filtered. Yield: 22.7 grams (40 percent) of 3-amino-2-isothiopropylbenzonitrile of one m.p. of 82 ° C.

H- 5 (2): 202 grams of 3-chloro-2-isothiopropylaniline (from Example H-4), 134 grams of copper (I) cyanide, and 140 grams of 3-methylpyridine, are stirred at 190 ° C for 9 hours. 200 grams of methyl ethyl ketone, 60 grams of sulfide .sodio, and 10 grams of water was then added, the mixture is stirred, the salts are filtered, and the filtrate is concentrated. The residue, which contains pro-uct and educt, is distilled at 70 ° C-120 ° C / 0.05 torr, and the distillate is crystallized from methylcyclohexane. This gives 125 grams of the product (65 percent of the theory); and the educt (20 percent of the theory) remains in the mother liquor and can be recycled.

Example H-6: Preparation of the catalyst Ni (o) (PPh3) 1 47.5 grams of nickel chloride hexahydrate are introduced into 1,000 grams of dimethyl formamide, and the mixture is stirred vigorously. On the same, 209.8 grams of triphenyl osphine are introduced. 150 grams of dimethyl formamide are distilled, and 22 grams of manganese powder are added to an inert atmosphere (nitrogen). The mixture is stirred at 50 ° C for 1.5 hours, during which time the color of the solution changes from deep blue-green, to green, to reddish-brown. The catalyst is now ready to be used without having to be isolated.

Example H-7: Preparation of 3-amino-3-isothiopropylbenzonitrile using Ni (PPh3) 2Cl2 + 2PPh3 prepared separately, as the catalyst 5 milliliters of dimethyl formamide is added to 327 milligrams of nickel (II) bistriphenylphosphine chloride, 82 milligrams of manganese powder, and 262 milligrams of triphenylphosphine under an inert atmosphere, and the mixture is stirred at 50 ° C for 45 minutes. Subsequently one gram of 3-chloro-isothiopropylaniline and 358 milligrams of potassium cyanide are added. I read mixture is stirred at 50 ° C for 17 hours. After 15 milliliters of toluene and 10 milliliters of water have been added, the mixture is clarified by filtration. 100 milliliters of toluene are added, and the mixture is washed using 80 milliliters of water. The organic phase is concentrated, and the residue is chromatographed on silica gel (hexane / ethyl acetate = 4: 1). This gives 0.72 grams of colorless crystals (yield: 76 percent).

Example H-8: Preparation of 3-amino-2-isithiopropylbenzonitrile using the catalyst prepared as described in Example H-6 201.5 grams of 3-chloro-2-isothiopropyl-aniline are added to the catalyst mixture obtained in the Example H-8. 51.5 grams of sodium cyanide are added at 50 ° C with vigorous stirring. The reaction is verified every 3 hours. After a maximum of 24 hours, the reaction ends. The reaction mixture is concentrated in vacuo. The residue is treated with one liter of methylethyl ketone and one liter of water, stirred vigorously, and filtered. The solution is allowed to stand to allow the phases to separate. The organic phase that has separated is concentrated, and the residue is treated with 800 milliliters of cyclohexene at 50 ° C. After the solids dissolve, they are cooled to 0 ° C, and seeded. 117 grams (61 percent) of white crystals are obtained.

Example H-9; Preparation of 3-amino-2-isithiopropylbenzonitrile 6 liters of dimethyl formamide are added to 50 grams of nickel chloride hydrate, 200 grams of BPPFA (1,1'-bisdiphenylphosphine-1- (dimethylaminoethyl) ferrocene), and 49 grams of manganese powder, and the mixture is stirred at 50 ° C for 2 hours under an inert atmosphere. A brown suspension forms. 1,200 grams of 3-chloro-2-isothiopropylaniline and 430 grams of KCN are added to the suspension, and the mixture is stirred for 16 hours at 50 ° C. After work, white crystals of m.p. of 8 ° C in a yield of approximately 90 percent.

Example H-10: Preparation of: 28.8 grams of 3-amino-2-isothiopropylbenzonitrile are added to a mixture of 30.6 grams of 96 percent sulfuric acid and 8.6 grams of water at 120 ° C. After the mixture is heated at 120 ° C for 2 hours, and at 149 ° C for another 2 hours, 3-amino-2-isothiopropyl-phenyl acid is obtained, which is precipitated in the sulfate form, viriually in a quantitative yield. When it is cooled, the suspension is treated with 150 milliliters of water and 80 milliliters of isopropanol. The mixture is cooled to 0 ° C, and a solution of 20.8 grams of sodium nitrite in 48.6 grams of water is added over the course of 4 hours. After an additional hour at 0 ° C, the mixture is treated with 10.6 grams of acetamide in 20 milliliters of water, filtered. Yield: 23.4 grams of white staves (87 percent).

Example H-ll Preparation of: 9.6 grams of 3-amino-2-isothiopropyl-enzyme-nitrile are added dropwise in 20 milliliters of butanol at 15 ° C over the course of 3 hours, to 7 grams of pentyl nitrite, 40 milliliters < jie butanol, and 1.1 grams of concentrated hydrochloric acid. After the mixture is stirred for another three hours, 0.6 grams of acetamide and 100 milliliters of water are added. You. The organic phase is separated and concentrated in vacuo. This gives 8.3 grams of 7-cyanobenzothiadiazole in the form of white crystals (yield:> 97 percent); p.f. 114-117 ° C, Example H-12: Preparation of: COOH 8. 1 grams of 7-cyanobenzothiadiazole in 80 grams of butanol are treated with 16.8 grams of a 5 percent potassium hydroxide solution, and the mixture is heated at 195 ° C for 3 hours. During these 3 hours, 7-carboxamide-benzothiadiazole is precipitated, and subsequently it is redissolved as the acid salt. After the mixture is cooled to 40 ° C-50 ° C, 200 milliliters of water are added, and the phases are separated. The aqueous phase is acidified using hydrochloric acid, and filtered. Yield: 8 grams of benzothiadiazole-7-carboxylic acid of one m.p. of approximately 230 ° C (88 percent).

Example H-13: Preparation of: 9. 6 grams of 3-amino-2-isothiopropylbenzonitrile in the form of a suspension in 80 milliliters of water and 14.3 grams of 32 percent hydrochloric acid are treated at 15 ° C in the course of 2 hours, with a solution of 3.45 grams of sodium nitrite in 20 milliliters of water. After the stirring is continued for 2 hours at 15 ° C, 1.5 grams of acetamide are added, and the product that is precipitated is filtered with suction, washed with water, and dried. Yield: 7.7 grams (93 percent) of white crystals of one p.f. from 116-119 ° C.

Example H-14: Preparation of: . 2 grams of 3-chloro-2-isothiopropylaniline, 10.8 grams of copper cyanide (I), 0.7 grams of copper (II) chloride, and 3.2 grams of pyridine, are heated at 160 ° C for 22 hours. After this time, 50 milliliters of butanol and 11.2 grams of KOH are added, and the mixture is heated at 110 ° C for 6 hours. Subsequently, 4 milliliters of water are added, and the mixture is stirred for another 18 hours at 110 ° C. When it is cooled, the mixture is treated with 100 milliliters of water, filtered, and the liquid phases are washed using 50 milliliters of methyl isobutyl ketone and 50 milliliters of water, and acidified using 20 grams of concentrated hydrochloric acid. After phase separation, the aqueous phase is made alkaline using a 30 percent sodium hydroxide solution, and the precipitate is extracted using methyl isobutyl ketone. The filtration and concentration of the methylisobutyl ketone phase yields 4.2 grams (20 percent) of a brown oil, which subsequently solidifies; p.f. 93-97 ° C.

Example 15: Preparation of: 2. 1 grams of 3-cymino-2-isothiopropylbenzamide (from Example H-ll), 20 milliliters of water, and 5.7 grams of concentrated hydrochloric acid, are treated with 0.7 grams of sodium nitrite in 4 milliliters of water at 10 ° C in the course of 45 minutes. After 1 hour at 10 ° C, 1 gram of sulfamic acid is added, and the mixture is subsequently made alkaline using a sodium hydroxide solution. After filtration and washing with water, the mixture is dried. Yield: 1.2 grams of crystals (67 percent) of p. f. > Example H-16: Preparation of: An aqueous solution of 140 grams of sodium nitrite at 0-5 ° C is introduced into a suspension of 192 grams of 3-amino-2-isot: Lopropylbenzonitrile in 110 grams of sulfuric acid and 500 grams of water. After the reaction, the mixture is extracted using toluene, and the organic phase together with 360 grams of a 30 percent sodium hydroxide solution is stirred at 60 ° C for 4 hours. The toluene phase (containing the by-products) is separated, the aqueous phase is acidified using hydrochloric acid, and the product that is crystallized during this process is filtered. Yield: 171 grams (95 percent of the theory).

Claims (40)

NOVELTY OF THE INVENTION By describing the above invention, it is considered as a novelty, and therefore, the content of the following is claimed as property: CLAIMS

1. A process for the preparation of substituted 3-aminobenzonitriles of formula I: wherein: R is hydrogen or alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, COR ,, alkoxy of 1 to 8 carbon atoms-alkyl, hydroxyalkyl of 1 to 6 carbon atoms, amir. o-alkyl of 1 to 8 carbon atoms, alkyl of 1 to 8 carbon atoms-NH (alkyl of 1 to 4 carbon atoms), alkyl of 1 to 8 carbon atoms-N (alkyl of 1 to 4 carbon atoms) 2, substituted or unsubstituted benzyl; and Rj? alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or phenyl; which comprises reacting, in a solvent at more than 30 ° C, a substituted 3-aminoclorobenzene of the formula II Cl wherein R is as defined for formula I, with a cyano donor reagent selected from: a) CuCN or cyanoferrate (II) potassium (= K4 [Fe (CN) 6]) or cyanoferra: or (II) of calcium (= Ca2 [Fe (CN) 6]), in the presence of a complexing agent; or b) any Cu (I) salt, together with an alkali metal cyanide, in the presence of a complexing agent; or c) alkali metal cyanide, HCN, Ni (CN) 2 or tetramethylsilyl cyanide, or an HCN adduct of ketone or an aldehyde HCN adduct, in the presence of a catalyst M [Co + (CN) 4] 3" , or Pd ° -Ln or preferably [a nickel catalyst] Ni ° -Ln, or a three-way mixture composed of NiL2Hal2 an excess of L, and a reducing agent, M being an alkali metal, where L is a ligand, and n being from 2 to 4.

2. A process according to claim 1, wherein the reaction is carried out with: a) an equimolar amount (based on II) of CuCN or cyanoferrate (II) potassium (= K4 [Fe (CN) 6]) or calcium cyanoferrate (II) (= Ca2 [Fe (CN) 6]), in the presence of pyridine, methylpyridine, dimethylpyridine, trimethylpyridine, quinoline, dimethylaniline, acetonitrile, dimethyl sulfoxide, benzonitrile, dimethyl formamide, or tetramethylurea; or b) any Cu (I) salt, together with at least equimolar or greater amounts (based on II) of alkali metal cyanide, in the presence of pyridine, methylpyridine, dimethylpyridine, trimethylpyridine, quinoline, dimethylaniline, acetonitrile, sulfoxide, dimethyl, benzonitrile, dimethyl formamide or tetramethylurea; or c) at least equimolar amounts (based on II) of alkali metal cyanide, HCN, Ni (CN) 2 or tetramethylsilyl cyanide, or an HCN adduct of ketone or an aldehyde HCN adduct, in the presence of a M3 catalyst [Co + (CN) 4] 3", or Pd ° -Ln, or preferably, Ni ° -Ln, or a three-way mixture composed of Ni2Hal2, excess L, and a reducing agent, M being a alkali metal, L a ligand, and n from 2 to 4.

3. A process according to claim 1, wherein the complexing agent of reaction a) or b) is a nitrogen-containing electron donor compound.

A process according to claim 3, wherein the complexing agent is pyridine, quinoline, or isoquinoline, which are unsubstituted or mono- to tri-substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, amino, alkyl of 1 to 4 carbon atoms-amino, or (alkyl of 1 to 4 carbon atoms) 2amino.

5. A process according to claim 4, wherein the complexing agent is pyridine which is unsubstituted or mono- to tri-substituted by methyl, or is quinoline.

6. A process according to claim 5, wherein the eigendant complex-forming is pyridine or 3-methylpyridine.

7. A process according to claim 1, wherein the reaction a) is carried out using CuCN.

8. A process according to claim 1, wherein the reaction b) is carried out using alkali metal cyanide.

9. A process according to claim 1, wherein reaction c) is carried out using a catalyst of the formula Ni ° -Ln wherein L is triphenylphosphine, and n is 2 to 4, or a catalyst of the formula Ni ° -L2, wherein L2 is (1.1 '-bisdiphenylphosphine-1- (dimethylaminoethyl) ferrocene).

10. A process according to claim 1, wherein the reaction catalyst c) is prepared on site.

11. A process according to claim 1, wherein the reaction is carried out at 50 ° C to 350 ° C.

12. A process according to claim 1, wherein the reaction a) or b) is carried out from 150 ° C to 250 ° C.

13. A process according to claim 1, wherein the reaction c) is carried out from 30 ° C to 150 ° C.

A process according to claim 1, wherein, in reaction a), at least equimolar amounts of the complexing agent are used, based on Cu or Fe, as the solvent.

A process according to claim 14, wherein pyridine is used which is unsubstituted or mono- to tri-substituted by methyl, or quinoline, as the solvent.

16. A process according to claim 15, wherein pyridine or 3-methylpyridine is used as the solvent.

17. A process for the preparation of benzothiadiazole-7-carboxylic acid, of formula III, from a compound of formula II wherein R is as defined above, III which comprises: a) exchanging the chlorine atom in a substituted 3-aminoclorobenzene of the formula II, by the cyano group, to give a 3-aminobenzonitrile of the formula I according to claim 1, and in addition any of: bl) hydrolysis of the cyano group to give a compound of the formula VI, followed by diazotization of the amino group using nitrous acid or nitrite, with cyclization, to give a compound of; Formula III; or b2) diazotization of the amino group using nitrous acid or nitrite, with cyclization, to give a compound of the formula VII, followed by hydrolysis of the cyano group to give a compound of the formula III.

18. A process according to claim 17, wherein: R is secondary alkyl of 3 to 6 carbon atoms, or tertiary alkyl of 4 to 6 carbon atoms, or cycloalkyl of 5 to 6 carbon atoms. 1S.

A process according to claim 18, wherein: R is isopropyl, tertiary butyl, or cyclohexyl. 2 C .

A process for the preparation of a compound of the formula XI: XI wherein Z is CN, CO-NH2 or COOH, which comprises diazotizing a compound of the formula X wherein Z and R are as defined above, with a nitrous acid or with nitrite, and the product is subsequently cycled.

21. A process according to claim 20, wherein: R is secondary alkyl of 3 to 6 carbon atoms, or tertiary alkyl of 4 to 6 carbon atoms, or cycloalkyl of 5 to 6 carbon atoms.

22. A process according to claim 21, wherein: R is isopropyl, tertiary butyl, or cyclohexyl.

23. A process for the preparation of a compound of formula II from a compound of formula IV: IV V II which comprises: a) reacting 2, 3-dichloronitrobenzene, of formula IV, with a compound of HS-R, wherein R is as defined above, in an aqueous base in the presence of a catalyst phase transfer, - from 30 ° C to 120 ° C, to give a compound of formula V; after the reaction, extract the product by washing with an alcohol, and subsequently wash the product with diluted acid at a pH of 5 to 7; b) reducing the resulting compound of formula V using hydrogen / Raney nickel in an alcohol or water, or in a mixture thereof, to give a compound of formula II.

24. A process for the preparation of a compound of the formula V from a compound of the formula IV: IV V which comprises reacting 2, 3-dichloronitrobenzene, of formula IV, with a compound of HS-R wherein R is as defined above, in an aqueous base, in the presence of a phase transfer catalyst, of 30 ° C at 120 ° C, to give a compound of the formula V; after the reaction, extract the product by washing with an alcohol, and subsequently wash the product with dilute acid at a pH of 5 to 7.

25. A process for the preparation of a compound of the formula II, from a compound of the formula V: V II which comprises reducing a compound of the formula V using hydrogen / Raney nickel in an alcohol or in water, or in a mixture thereof, to give a compound of the formula II.

26. A compound of the formula I: wherein: R is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, COR ,, alkoxy of 1 to 8 carbon atoms-alkyl, hydroxyalkyl of 1 to 6 carbon atoms, aminoalkyl of 1 to 8 carbon atoms, alkyl of 1 8 carbon atoms-NH (alkyl of 1 to 4 carbon atoms), alkyl of 1 to 8 carbon atoms-N (alkyl of 1 to 4 carbon atoms) 2, or a substituted or unsubstituted benzyl radical; and Rj is alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or phenyl.

27. A compound of the formula I according to claim 26, wherein R is secondary alkyl of 3 to 6 carbon atoms, or tertiary alkyl of 4 to 6 carbon atoms, or cycloalkyl of 5 to 6 carbon atoms.

28. A compound of the formula I according to claim 27, wherein R is isopropyl, tertiary butyl, or cyclohexyl.

29. A compound of the formula V: Cl wherein: R is alkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, CORj, alkoxy of 1 to 8 carbon atoms-alkyl, hydroxyalkyl of 1 to 6 carbon atoms, aminoalkyl of 1 to 8 carbon atoms, alkyl of 1 to 8 carbon atoms-NH (alkyl of 1 to 4 carbon atoms) or alkyl of 1 to 8 carbon atoms-N (alkyl of 1 to 4 carbon atoms) 2; Y Rj is alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or phenyl.

30. A compound of the formula V according to claim 29, wherein R is secondary alkyl of 3 to 6 carbon atoms, or tertiary alkyl of 4 to 6 carbon atoms, or cycloalkyl of 5 to 6 carbon atoms .

31. A compound of the formula V according to claim 30, wherein R is isopropyl, tertiary butyl, or cyclohexyl.

32. A compound of formula II: wherein: R is alkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, COR ^ alkoxy of 1 to 8 carbon atoms-alkanoyl, hydroxyalkyl of 1 to 6 carbon atoms, aminoalkyl of 1 to 8 carbon atoms, alkyl of 1 to 8 carbon atoms-NS (alkyl of 1 to 4 carbon atoms), or alkyl of 1 to 8 carbon atoms-N (alkyl of 1 to 4 carbon atoms) 2; and Ri is alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or phenyl.

33. A compound of formula II according to claim 32, wherein R is secondary alkyl of 3 to 6 carbon atoms, or tertiary alkyl of 4 to 6 carbon atoms, or cycloalkyl of 5 to 6 carbon atoms.

34. A compound of the formula II according to claim 33, wherein R is isopropyl, tertiary butyl, or cyclohexyl.

35. A compound of the formula IA: wherein: R is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, COR1; C 1 -C 8 alkoxy-alkyl, hydroxyalkyl of 1 to 6 carbon atoms, aminoalkyl of 1 to 8 carbon atoms, alkyl of 1 8 carbon atoms-NH (alkyl of 1 to 4 carbon atoms), alkyl from 1 to 8 carbon atoms-N (alkyl of 1 to 4 carbon atoms) 2, or substituted or unsubstituted benzyl, and R 1 is alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or phenyl.

36. A compound of the formula IA according to claim 35, wherein: R is secondary alkyl of 3 to 6 carbon atoms, or tertiary alkyl of 4 to 6 carbon atoms, or cycloalkyl of 5 to 6 carbon atoms .

37, A compound of formula IA according to claim 36, wherein: R is isopropyl, tertiary butyl, or cyclohexyl.

38. A compound of formula VI: wherein R is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, COR1 (alkoxy of 1 to 8 carbon atoms-alkyl, hydroxyalkyl of 1 to 6 carbon atoms, aminoalkyl of 1 to 8 carbon atoms, alkyl of 1 8 carbon atoms-NH (alkyl of 1 to 4 carbon atoms), alkyl of 1 to 8 carbon atoms-N (alkyl of 1 to 4 carbon atoms) 2, and Rj is alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or phenyl

39. A compound of formula VI according to claim 38, wherein: R is secondary alkyl of 3 to 6 carbon atoms or tertiary alkyl of 4 to 6 carbon atoms, or cycloalkyl of 5 to 6 carbon atoms

40. A compound of formula VI according to claim 39, wherein: R is isopropyl, tertiary butyl, or cyclohexyl. SUMMARY OF THE INVENTION The invention relates to a process for the preparation of substituted 3-aminobenzonitriles of the formula I: wherein: R is hydrogen or alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, CORj, alkoxy of 1 to 8 carbon atoms-alkyl, hydroxyalkyl of 1 to 6 carbon atoms, aminoalkyl of 1 at 8 carbon atoms, alkyl of 1 to 8 carbon atoms-NH (alkyl of 1 to 4 carbon atoms), alkyl of 1 to 8 carbon atoms-N (alkyl of 1 to 4 carbon atoms) 2, benzyl replaced or unsubstituted; and Rj is alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or phenyl; and which comprises reacting a substituted 3-aminoclorobenzene of the formula II: with a cyano donor reagent. The compounds of the formula I are important intermediates in the preparation of benzothiadiazole-7-carboxylic acid, which is obtained by diazotization and hydrolyzation of the compounds of the formula I in any desired sequence. * * * * *