GB2138836A

GB2138836A - Process for the preparation of 4-azaphthalide compounds

Info

Publication number: GB2138836A
Application number: GB08315666A
Authority: GB
Inventors: Davor Bedekovic; Ian John Fletcher
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1983-04-07
Filing date: 1983-06-08
Publication date: 1984-10-31
Also published as: FR2543955B1; ES8407492A1; IT1171836B; JPH0316954B2; DE3319978A1; CH652733A5; FI76342C; BE897007A; GB2138836B; ES523098A0; FI831866L; FR2543955A1; FI76342B; JPS59190993A; DE3319978C2; GB8315666D0; FI831866A0; IT8348477A0

Abstract

The invention relates to a novel process for the preparation of 4-azaphthalide compounds of the formula <IMAGE> in which Y is hydrogen, C1-C12 alkyl which is unsubstituted or substituted by halogen, cyano, hydroxyl or lower alkoxy, acyl having 1 to 12 carbon atoms, benzyl or benzyl which is substituted by halogen, nitro, lower alkyl or lower alkoxy, Z is hydrogen, lower alkyl or phenyl, X is -OR1 or, <IMAGE> R1 and R2 independently of each other are hydrogen, C1-C12 alkyl which is unsubstituted or substituted by halogen, cyano, hydroxyl or lower alkoxy, cycloalkyl, phenyl, benzyl or phenyl or benzyl which is substituted by halogen, nitro, cyano, lower alkyl, lower alkoxy or lower alkoxycarbonyl, or R1 and R2 together with the connecting nitrogen atom, are a 5-membered or 6-membered heterocyclic radical and V is hydrogen, halogen hydroxyl, nitro, lower alkyl or lower alkoxy, and in which the ring A is unsubstituted or substituted by halogen, nitro, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, amino, mono-(lower alkyl)-amino or di-(lower alkyl)-amino, which process comprises reacting quinolic anhydride with an indole compound of the formula <IMAGE> in which A, Y and Z are as defined, in the presence of an inorganic or organic metal salt of a polyvalent metal in an organic reaction medium consisting of a lower aliphatic monocarboxylic acid or a nitrile of this acid at a temperature of not more than 65 DEG C, further condensing the resulting reaction product with a compound of the formula <IMAGE> in which X and V are as defined, and adjusting the pH value of the reaction mixture to not less than 6.

Description

SPECIFICATION Process for the preparation of 4-azaphthalide compounds The present invention relates to a novel process for the preparation of azaphthalide compounds, which can be used as colour formers in pressure-sensitive or heat-sensitive recording materials.

In pressure-sensitive, carbon-free copier systems, an oily solution of the chromogenic dye intermediate, for example crystal violet lactone, benzoyl-leucomethylene blue, phthalides or fluoranes, is usually isolated in microcapsules which can be ruptured under pressure and which are present either as a layer on a separate transfer sheet, so that a pair of independent copying sheets are formed, or are on the sensitised side of the copy-receiving sheet, so that a selfreactive sheet of paper is formed.

Crystal violet lactone (3,3-bis-(4'-dimethylamino-phenyl)-6-dimethylaminophthalide) is usually employed as the chromogenic dye intermediate in such pressure-sensitive copier systems. As is known, a print produced with crystal violet lactone fades very rapidly under the influence of light, so that attempts are continually being made to find a suitable substitute.

Azaphthalides which contain an aminophenyl substituent and an indolyl substituent in the 3position are good substitutes which produce a satisfactory blue print with improved stability to light. However, the preparation of this colour-forming agent always results in a mixture of isomers of 4- and 7-azaphthalides. Although an improvement in the light-fastness and at the same time also a decraease in the loss of reactivity (CB decline) can be achieved with these mixtures of isomers, undesirable discolouration (self-colouration) of the micro capsules containing the chromogenic substance usually occurs in the preparation of pressure-sensitive recording materials owing to the presence of the 7-azaphthalide isomer in the mixture of isomers.

It has now been found that an isomer-free 4-azaphthalide compound can be obtained if the reaction of quinolinic anhydride with the indole compound for the preparation of the isomer-free keto-acid required as an intermediate is carried out in a specific organic reaction medium and in the presence of a metal salt of a polyvalent metal.

The present invention accordingly relates to a process for the preparation of 4-azaphthalide compounds of the formula

in which Y is hydrogen, C1-C,2 alkyl which is unsubstituted or substituted by halogen, cyano, hydroxyl or lower alkoxy, acyl having 1 to 1 2 carbon atoms, benzyl or benzyl which is substituted by halogen, nitro, lower alkyl or lower alkoxy, Z is hydrogen, lower alkyl or phenyl, X is -OR, or, preferably

wherein R, and R2 independently of each other are hydrogen, C,-C,2 alkyl which is unsubstituted or substituted by halogen, cyano hydroxyl or lower alkoxy, cycloalkyl, phenyl, benzyl or phenyl or benzyl which is substituted by halogen, nitro, cyano, lower alkyl, lower alkoxy or lower alkoxycarbonyl, or R1 and R2, together with the connecting nitrogen atom, are a 5membered or 6-membered, preferably saturated heterocyclic radical and V is hydrogen, halogen, hydroxyl, nitro, lower alkyl or lower alkoxy, and in which the ring A is unsubstituted or substituted by halogen, nitro, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, amino, mono-(lower alkyl)-amino or di-(lower alkyl)-amino.

The process comprises reacting quinolinic anhydride with an indole compound of the formula

in which A, Y and Z are as defined, in the presence of an inorganic or organic metal salt of a polyvalent metal in an organic reaction medium consisting of a lower aliphatic monocarboxylic acid or a nitrile of this acid at a temperature of not more than 65"C, further condensing the resulting reaction product with a compound of the formula

in which X and V are as defined, and adjusting the pH value of the reaction mixture to not less than 6.

In the definition of the radicals of the 4-azaphthalide, lower alkyl and lower alkoxy are as a rule groups or moieties of groups having 1 to 5, in particular 1 to 3 carbon atoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl or alkyl; and examples of lower alkoxy groups are methoxy, ethoxy or isopropoxy.

Acyl is, in particular, formyl, lower alkylcarbonyl, for example acetyl or propionyl, or benzoyl.

Other acyl radicals can be lower alkylsulfonyl, for example methyl-sulfonyl or ethylsulfonyl, and phenylsulfonyl. Benzoyl and phenylsulfonyl can be substituted by halogen, methyl, methoxy or ethoxy.

An alkyl group Rt, R2 or Y can be a straight-chain or branched alkyl radical. Examples of such alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, amyl, n-hexyl, 2ethylhexyl, n-heptyl, n-octyl, iso-octyl, n-nonyl, isononyl and n-dodecyl.

A substituted alkyl radical R1, R2 or Y is, in particular, cyanoalkyl, halogenoalkyl, hydroxyalkyl or alkoxyalkyl, in each case preferably having a total of 2 to 4 carbon atoms, for example ss cyanoethyl, ss-chloroethyl, ss-hydroxyethyl, ssmethoxyethyl or ssethoxyethyl.

Examples of cycloalkyl R, or R2 are cyclopentyl and, preferably, cyclohexyl.

Examples of preferred substituents on a benzyl group R1, R2 or Y or a phenyl group R1 or R2 are halogens, nitro, methyl and methoxy. Examples of such araliphatic or aromatic radicals are p-methylbenzyl, o- and p-chlorobenzyl, o- and p-nitrobenzyl, o- and p-tolyl, xylyl o-, m- or pchlorophenyl, o- and p-nitrophenyl and o- and p-methoxyphenyl.

Examples of heterocyclic radicals formed by the substituents R1 and R2 together with the common nitrogen atom are pyrrolidino, piperidino, pipecolino, morpholino, thiomorpholino and piperazino, for example N-methylpiperazino. Preferred heterocyclic radicals are pyrrolidino, piperidino and morpholino.

X is preferably the amino group of the formula -NR1R2.

V is preferably in the m-position relative to the substituent X.

The substituents R1 and R2 can be different, but are preferably identical. Preferably, R1 and R2 are benzyl or lower alkyl, especially methyl or ethyl.

V is preferably hydrogen, methyl, methoxy or, in particular, ethoxy.

The N-substituent Y is preferably benzyl, acetyl, propionyl or, in particular, alkyl having 1 to 8 carbon atoms, for example n-octyl, n-butyl, methyl or ethyl. A particularly preferred Nsubstitutent y is ethyl or n-octyl. Z is preferably phenyl or, in particular, methyl.

The benzene ring A is preferably not further substituted or is substituted by halogen.

Examples of halogen are fluorine, bromine and, preferably, chlorine.

In carrying out the process according to the invention, the substances participating in the reaction are preferably each employed in molar amounts.

The azaphthalide compounds of the formula (1) are prepared continuously in two steps without isolation of the intermediate formed as reaction product.

The first step, in which quinolinic anhydride is reacted with the indole compound of the formula (2) in organic solvents of the type defined and in the presence of an organic or inorganic metal salt, is advantageously carried out at a temperature of O to 50"C, preferably at room temperature (17 to 30"C).

The reaction time depends on the temperature, the metal salt used as the catalyst and the solvent, and is generally between > and 10 hours, preferably 2 and 6 hours.

The lower aliphatic monocarboxylic acid used as the reaction medium in the process according to the invention is advantageously a carboxylic acid which is liquid under the reaction conditions, and can have 1 to 5 carbon atoms.

Suitable aliphatic monocarboxylic acids which form the reaction medium are formic acid, acetic acid, dichloroacetic acid, propionic acid, butyric acid, isobutyric acid and valeric acid, and mixtures of these acids.

Examples of corresponding nitriles which can likewise be used as the reaction medium in the process according to the invention are acetonitrile, propionitrile and butyronitrile.

However, preferred solvents are aliphatic monocarboxylic acids having 2 to 4 carbon atoms, for example butyric acid, isobutyric acid, propionic acid and, in particular, acetic acid, and mixtures of these carboxylic acids.

The metal salts used according to the invention are advantageously derived from polyvalent metals of atomic weight 24 to 210, preferably 26 to 140 and in particular 26 to 1 20.

Examples of such metals are aluminium, barium, lead, cadmium, calcium, chromium, iron, gallium, cobalt, copper, magnesium, manganese, molybdenum, nickel, mercury, strontium, tantalum, titanium, vanadium, tungsten, zinc, tin and zirconium. Aluminium, calcium, cadmium, iron, chromium, cobalt, copper, nickel, manganese, strontium, tin and zinc are preferred. The anionic component of these metal salts is advantageously derived from mineral acids or from organic acids, and is, for example, a sulfate, halide, nitrate, formiate, acetate, propionate, citrate or stearate.

A halide can be a fluoride, iodide, bromide or, preferably, chloride, as well as a pseudohalide, such as a thiocyanate.

The metal salts can be used individually or as mixtures.

Preferred metal salts are sulfates or, in particular, halides of metals from the group comprising aluminium, calcium, iron, cadmium, cobalt, copper, manganese, nickel, tin and zinc, for example aluminium chloride, calcium chloride, nickel chloride, cobalt chloride, iron chloride, copper chloride, zinc chloride, tin chioride, tin bromide, manganese chloride, nickel bromide, calcium fluoride and cadmium iodide and mixtures thereof. In general, the best results are achieved in the presence of chlorides of aluminium, calcium, cobalt, iron, copper or zinc. Zinc chloride and aluminium chloride are of particular interest. A mixture of calcium chloride and zinc chloride, preferably in a ratio of 1:9 to 2:1, is also preferred.

The amount of metal salt in the first reaction stage is advantageously 10 to 100 mol%, preferably 1 2 to 50 mol%, based on the quinolinic anhydride used.

When the first reaction stage had ended, the reaction product (keto-acid, which is not isolated) is further condensed directly with the compound of the formula (3). This second reaction stage is preferably carried out by reacting the components in the presence of an acid dehydrating agent at a temperature of 20" to 80"C. Examples of such condensing agents are sulfuric acid, phosphoric acid, phosphorus oxychloride and, in particular, acetic anhydride. If acetic anhydride is used, temperatures between 20 and 60"C are preferred. The reaction time of the second step is generally 1 to 4 hours, preferably 1+ to 3 hours.

Finally, the pH value of the reaction mixture is adjusted to not less than 6. For this purpose it is convenient to use alkalis such as alkali metal hydroxides, for example sodium or potassium hydroxide, ammonia or an alkali metal carbonate or bicarbonate, as well as mixtures of these compounds. The pH value is preferably adjusted to 7 to 11.

The final product of the formula (1) is isolated in generally known manner by removal of the precipitate washing and drying, or by treatment with suitable organic solvents, for example methanol, ethanol or isopropanol, and if necessary recrystallisation of the product.

If GIR, and/or V in the reaction product of the formula (1) are hydroxyl, the hydroxyl group can be subsequently alkylated or aralkylated as defined for R, and V.

Alkylation or aralkylation of the reaction products in which V and/or OR, are hydroxyl is generally carried out by known processes. For example, the reaction is carried out in the presence of an acid acceptor, for example an alkali metal carbonate or a tertiary nitrogen base, such as triethylamine, if necessary in the presence of an inert organic solvent, for example acetone, isopropyl alcohol, chlorobenzene or nitrobenzene.

Suitable alkylating agents are alkyl halides, for example methyl or ethyl iodide or chloride, and dialkyl sulfates, for example dimethyl or diethyl sulfate. Particularly suitable aralkylating agents are benzyl chloride and the corresponding substitution products, for example p-chlorobenzylchloride or 2,4-dimethylbenzyl chloride, which are preferably used in a non-polar, organic solvent, for example, benzene, toluene or xylene.

A particularly advantageous embodiment of the novel process comprises dissolving or suspending quinolinic anhydride in a saturated aliphatic C2-C4-monocarboxylic acid, in particular acetic acid, or also in acetonitrile, adding an indole compound of the formula (2) and stirring the mixutre at room temperature in the presence of an inorganic metal salt, in particular a metal halide, of a polyvalent metal of atomic weight 26 to 66, for example zinc chloride, calcium chloride, aluminium chloride, iron chloride, cobalt chloride or copper dichloride, preferably for 2 to 6 hours. The compound of the formula (3) is then added and, after addition of acetic anhydride, the reaction mixture is heated at 30 to 60"C, preferably for 1 to 3 hours.The pH is then adjusted to 7.5 to 9 for example with an alkali metal hydroxide or aqueous ammonia. The precipitated 4-azaphthalide compound of the formula (1) is isolated and, if necessary, recrystallised.

The preferred 4-azaphthalide compounds of the formula (1), which are prepared continuously by the continuous process of to the invention, are those in which V is hydrogen, methyl, hydroxyl, methoxy or, in particular, ethoxy and X is a group of the formula -NR1R2, in which R, and R2 are methyl or ethyl, or -NR1R2 is pyrrolidino or piperidino. Y is preferably alkyl having 1 to 8 carbon atoms, Z is, in particular, methyl and the ring A is preferably unsubstituted. The most preferred azaphthalide compounds of the formula (1) are those in which the group

is 2-ethoxy-4-dimethylaminophenyl or 2-ethoxy-4-diethylamino-phenyl, Y is ethyl or octyl and Z is methyl, and the ring A is unsubstituted.

A material advantage of the process of the present invention is that it can easily be applied industrially, and that it gives pure final products in very good yields without isolation of the keto-acids formed as intermediates. In particular, 4-azaphthalide compounds which are completely free from the corresponding 7-azaphthalide isomers of the formula

are obtained.

The 4-azaphthalide compounds of the formula (1) prepared by the process according to rhe invention are usually colourless or at most faintly coloured. They are particularly suitable as rapidly developing colour-forrning agents for use in a heat-sensitive or, in particular, pressuresensitive recording material, which can also be a copying material. When these colour formers are brought into contact with a developer, which is preferably acid, i.e. an electron acceptor, there result intense green-blue, blue or violet-blue colour shades which are fast to sublimation and light both on clays and, in particular, on phenolic substances.

Compared with the mixture of isomers of 4- and 7-azaphthalides known hitherto from German Offenlegungsschrift 2,842,263 or German Offenlegungschrift 3,116,815, according to which lather publication the troublesome 7-azaphthalide compound is reduced to a content of 2%, the isomer-free 4-azaphthalides prepared according to the invention have the advantage that they do not cause undesirable premature discolouration (self-colouration) during preparation or storage of the recording materials.

Unless otherwise indicated, in the following examples, the percentages are by weight.

Example 1: 20.0 g of quinolinic anhydride, 80 ml of acetic acid, 20.3 g of N-ethyl-2 methylindole and 2.74 g of zinc chloride are stirred at 20"C for 5 hours. 23.6 g of 3-(N,Ndiethylamino)-phenetole and 30 ml of acetic an hydroxide are then added, after which the reaction mixture is warmed to 50 to 60"C and stirred at this temperature for 2 hours. After addition of 1 70 ml of 30% aqueous ammonia and 100 ml of water, the product precipitates as a paste and is isolated. 160 ml of isopropanol are added to the paste and the mixture is refluxed for 1 hour.

After cooling, the recrystallised product is filtered off, washed with isopropanol and dried, affording 46.9 9 of the isomer-free 4-azaphthalide compound of the formula

of melting point 1 56' to 1 58 C.

Example 2: 6.0 g of quinolinic anhydride, 9.5 g of N-octyl-2-methylindole and 0.56 g of zinc chloride are stirred in 30 ml of glacial acetic acid at 20"C for 5 hours. 6.6 g of 3diethylaminophenetole and 8 ml of acetic anhydride are then added, after which the mixture is stirred at 50"C for 2+ hours. The product is precipitated with 30% aqueous ammonia, separated from the aqueous phase and recrystallised from isopropanol, affording 1 6.5 g of the isomer-free 4-azaphthalide compound of the formula

of melting point 11 3-11 8'C.

The procedure described in the example is repeated, using 0.30 g of copper-ll dichloride or 0.53 g of aluminium trichloride instead of 0.56 of zinc chloride. Yield: 1 5.9 g or 16.8 g of the 4-azaphthalide compound of the formula (12) of melting point 113-1 16"C or 1 15-11 9 C.

Example 3:1.5 g of quinolinic anhydride, 2.3 g of N-octyl-2-methylindole, 10 ml of glacial acetic acid and a mixture of 0.11 g of calcium chloride and 0.14 g of zinc chloride are stirred at 90 G for 5 hours. 1.6 g of 3-diethylaminophenetole and 2 ml of acetic anhydride are then added, after which the reaction mixture is stirred at 50"C for 2+ hours. The product is precipitated with 30% aqueous ammonia, separated from the aqueous phase and recrystallised from isopropanol, affording 3.8 g of the isomer-free 4-azaphthalide compound of the formula (12) of melting point 114-11 7'C.

The procedure described in this Example is repeated, using 0.1 9 g of iron trichloride or 0.14 g of cobalt dichloride instead of the indicated metal salt mixture. Yield: 3.3 g or 3.8 g of the 4azaphthalide compound of the formula (12) of melting point 113-11 7 C or 113-11 6 C.

Example 4: 8 g of quinolinic anhydride, 1.1 9 of zinc chloride, 40 ml of acetic acid and 9.95 g of N-butyl-2-methylindole are stirred at 20-23 (: for 5 hours. Then 9.3 g of 3-(N,Ndiethylamino)-phenetole and 7.5 ml of acetic anhydride are added, and the reaction mixture is stirred at 50-60"C for 2 hours. When the reaction is complete, the acetic acid solution is neutralised with 30% aqueous ammonia, whereupon the product precipitates. After separation from the aqueous phase, the crude product is dissolved in glacial acetic acid, again precipitated with 30% aqueous ammonia and recrystallised from ethanol, affording 16.8 g of the isomer-free 4-azaphthalide compound of the formula

of melting point 152-154"C.

Example 5: A solution of 3 9 of the 4-azaphthalide compound of the formula (11) in 80 9 of diisopropylnaphthalene and 1 7 g of kerosene is microencapsulated by coacervation in a manner which is known per se with gelatin and gum arabic, after which no discolouration of the microcapsules occurs. The microcapsules are mixed with starch solution and brushed onto a sheet of paper. A second sheet of paper is coated on the face with phenolic resin as colour developer. The first sheet containing the microcapsules and the paper coated with colour developer are placed on top of one another with the coated sides face to face. A pressuresensitive copying paper which does not discolour even on storage is obtained. Pressure is exerted on the first sheet by writing by hand or with a typwriter, and an intense blue copy of excellent light fastness develops immediately on the sheet coated with the developer.

Corresponding non-discoloured pressure-sensitive copying paper and intense, light-fast blue copies produced by writing are also obtained using any of the other colour formers obtained in Examples 2, 3 and 4.

Claims

1. A process for the preparation of a 4-azaphthalide compound of the formula

in wpich Y is hydrogen, C1-C,2 alkyl which is unsubstituted or substituted by halogen, cyano, hydroxyl or lower alkoxy, acyl having 1 to 1 2 carbon atoms, benzyl or benzyl which is substituted by halogen, nitro, lower alkyl ar lower alkoxy, Z is hydrogen, lower alkyl or phenyl, X is -OR1 or,

R1 and R2 independently of each other are hydrogen, C1 -C12 alkyl which is unsubstituted or substituted by halogen, cyano, hydroxyl or lower alkoxy, cycloalkyl, phenyl, benzyl or phenyl or benzyl which is substituted by halogen, nitro, cyano, lower alkyl, lower alkoxy or lower alkoxycarbonyl, or R1 and R2 together with the connecting nitrogen atom, are a 5-membered or 6-membered heterocyclic radical and V is hydrogen, halogen, hydroxyl, nitro, lower alkyl or lower alkoxy, and in which the ring A is unsubstituted or substituted by halogen, nitro, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, amino, mono-(lower alkyl)-amino or di-(lower alkyl)-amino, which process comprises reacting quinolinic anhydride with an indole compound of the formula

2. A process according to claim 1, wherein X is the amino group of the formula -NR,R2.

3. A process according to either of claims 1 or 2, wherein R1 and R2 independently of each other are lower alkyl or benzyl, or R1 and R2, together with the connecting nitrogen atom, are pyrrolidino, piperidino or morpholino.

4. A process according to any one of claims 1 to 3, wherein V is hydrogen, methyl, methoxy or ethoxy.

5. A process according to any one of claims 1 to 4, wherein Y is alkyl having 1 to 8 carbon atoms, acetyl, propionyl or benzyl.

6. A process according to any one of claims 1 to 5, wherein Z is methyl or phenyl.

7. A process according to any one of claims 1 to 6, wherein the ring A is unsubstituted.

8. A process according to any one of claims 1 to 7, wherein the reaction of quinolinic anhydride with the indole compound of the formula (2) is carried out at a temperature of O to 50"C.

9. A process according to any one of claims 1 to 7, wherein the reaction of quinolinic anhydride with the indole compound of the formula (2) is carried out at room temperature.

10. A process according to any one of claims 1 to 8, wherein an aliphatic monocarboxylic acid having 2 to 4 carbon atoms is used as the organic reaction medium.

11. A process according to claim 10, wherein the aliphatic monocarboxylic acid is acetic acid.

1 2. A process according to any one of claims 1 to 11, wherein the metal salt is derived from a polyvalent metal of atomic weight 24 to 210.

1 3. A process according to claim 1 2, wherein the polyvalent metal has an atomic weight of 26 to 140.

14. A process according to any one of claims 1 to 13, wherein the metal salt is a halide of the metals aluminium, calcium, iron, cadmium, cobalt, copper manganese, nickel, tin or zinc.

1 5. A process according to any one of claims 1 to 14, wherein the condensation of the reaction product obtained from quinolinic anhydride and the indole compound of the formula (2) with the compound of the formula (3) is carried out in the presence of an acid dehydrating agent at a temperature of 20 to 80"C.

t6. A process according to any one of claims 1 to 15, wherein the pH value of the reaction mixture is finally brought to 7 to 11.

17. A process according to claim 1, which comprises dissolving or suspending quinolinic anhydride in a saturated aliphatic C2-C4-monocarboxylic acid, adding the indole compound of the formula (2), and stirring the mixture at room temperature in the presence of an inorganic metal salt of a polyvalent metal of atomic weight 26 to 66, then adding the compound of the formula (3) and acetic anhydride and heating the mixture at 30 to 60 C and finally adjusting the pH value of the reaction mixture to 7.5 to 9.

18. A 4-azaphthalide compound of the formula (1), which has been prepared by a process according to any one of claims 1 to 17.