NZ247446A - Nitrosoaniline derivatives and preparation thereof - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £47446 ? 4 7 M 6 Under the provisions of Refutation 23 i'i 'h? Patents Form 5 C^ Specifics'.,j;-: oc.i; to J2.°i » ^C- A<\ Initials f fj .. - | t* ' * f N CA Priority Dst:{ "2" "2_- So Co! i 0v. ~ ~ I ~i c ' \ ^ jf c>,~ .<wr«aw/^. ccrfcztjbki..,, 3fc. Cojouf^/ob rrmm--- 20APRIW3H ~s /3fc) N.Z. No.

UlirttfiftUih NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION NITROSOANILINE DERIVATIVES We, BOEHRINGER MANNHEIM GMBH, a Company of the Federal Republic of Germany of, 6800 Mannheim 31, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - -1 - (Followed by 1A) 247446 - 1A - The present invention provides nitrosoaniline derivatives of the general formula I /-^ r3 m denotes hydrogen, halogen, alkoxy or alkylthio, represents an alkyl residue and represents an hydroxyalJcyl residue or are the same or different and each represents a dialkylaminoalkyl residue, an hydroxy a lkoxya Iky 1 or alkoxyalkyl residue substituted, if desired, by OH in the alkyl moiety or a polyalkoxyalkyl residue which is substituted, if desired, by an hydroxy residue in the alkyl moiety or form an alkylene residue interrupted by sulphur or nitrogen in which nitrogen is substituted by an alkyl, hydroxyalkyl, hydroxy alkoxyalkyl, alkoxyhydroxy alkyl, dioxanylyl-alkyl or polyalkoxyalkyl residue each of which is itself substituted, if desired, in the alkyl moiety by a hydroxy residue or if R1 is in the ortho position to NR2R3, R2 also together with R1 represents an alkylene residue whereby R3 then represents a hydroxyalkyl residue or, if the alkylene residue contains 3 carbon atoms, it also represents, if desired, an alkyl residue or if R1 is not hydrogen, R2 and R3 are the same or different and each represents an hydroxyalkyl residue or a salt of this derivative. in which R1 R2 R3 R2 and R3 R2 and R3 In this connection halogen denotes fluorine, chlorine, bromine or iodine. Fluorine and chlorine are particularly preferred.

Alkyl, alkoxy or alkylthio are residues with 1-6 carbon atoms, those with 1-3 carbon atoms are particularly preferred.

The foregoing definition for alkyl also applies to the alkyl moiety in hydroxyalkyl, dialkylaminoalkyl, hydroxyalkoxy-alky1, alkoxyalkyl, polyalkoxyalkyl, alkoxy-hydroxyalkyl and dioxanylyl-alkyl residues.

A dioxanylyl-alkyl residue is a residue in which a dioxan ring system is bound to an alkyl residue. It is preferably a 1,4-dioxan ring system, i.e.

- Aikyi-<^>.

A polyalkoxyalkyl residue is an -alkyl-(alkoxy)n-alkoxy residue in which n = 1-10. It is preferred that n = 1-4. It is particularly preferred that n = 1-3. An alkylene residue is a straight-chained or branched, - preferably straight-chained-/ saturated or unsaturated, - preferably saturated-/hydrocarbon chain consisting of 2-5, preferably 2-4 C-atoms with two free binding sites. Within the meaning of an alkylene residue of R2 and R3 which is interrupted by sulphur or nitrogen, a thiomorpholine or piperazine residue formed by the inclusion of the nitrogen atom of the general formula III is preferred. The piperazine residue is especially preferred.

Within the meaning of an alkylene residue formed from R1 and R2,. the indoline or 1,2,3,4-tetrahydroquinoline residue formed by the inclusion of the aromatic ring of the general formula III is preferred. 24 7 4 4« As the salt of a nitrosoaniline derivative according to the present invention of the general formula III, those of strong acids, in particular mineral acids such as hydrochloric acid, sulphuric acid, nitric acid and phosphoric acid are preferred. Hydrochlorides are especially preferred, these are salts of hydrochloric acid.

These compounds are useful in the invention described and claimed in New Zealand Patent Specification No. 236931 which concerns a method for the electrochemical determination of an analyte in the presence of .an oxidoreductase and a reducible substance which'transfers electrons which arise during the course of the determination reaction from the oxidoreductase onto an electrode and thus leads to a signal which is a measure for the analyte to be determined, whereby the reducible substance is enzymatically reduced and oxidized at the electrode, or a corresponding process for the electrochemical determination of an oxidoreductase in the presence of an enzyme substrate and a reducible substance as characterized above.

The contents of this specification are incorporated by reference.

The following new nitrosoaniline derivatives are especially preferred according to the present invention: a) 2,2 ' - [(3-fluoro-4-nitrosophenyl)imino]bis-ethanol, b) 2,2'-[(3-chloro-4-nitrosophenyl)imino]bis-ethanol, c) 2,2 1 - [(3-raethoxy-4-nitrosophenyl)imino]bis-ethanol, d) 2,2'-[(3-methylmercapto-4-nitrosophenyl)imino]bis-ethanol, e) 2-[(2-hydroxyethoxy)ethyl-(4-nitrosophenyl) amino]ethanol, f) 2-C(2-methoxyethoxy)ethyl-(4-nitrosophenyl) amino]ethanol, g) l-[N-(2-hydroxyethyl)-(4-nitrosoanilino)]-3-methoxy-2-propanol, 4 7 4 4® h) l-[N-(2-hydroxyethyl) -(4-nitrosoanilino) ]-3-(2-hydroxyethoxy)-2-propanol, i) l-methyl-4-(4-nitrosophenyl) -piperazine, j) 4 - (4-nitrosophenyl) -1-piperazino-ethanol, k) 5-nitroso-l-indoline ethanol, 1) i-methyl-6-nitroso-l ,2,3,4-tetrahydroquinoline, m) 6-nitroso-3,4-dihydro-l(2H)quinoline ethanol-and their salts.

Of these the compounds a), d) , e), f), g) and h) as well as their salts are particularly preferred. Compound e) or its salts, in particular the hydrochloride, is especially preferred.

The compounds of the general formula I can be produced by reacting a compound of the general formula II, J* in which R1, R2 and R3 have the same meaning as in compounds of the general formula T, with nitrite. An analogous process is known from J.J. D'Amico et al., J. Amer. Chem. Soc. 81, 5957 (1959).

Alkali nitrite is preferably used as the nitrite, in which lithium, sodium, potassium, rubidium or caesium are possible as the alkali metal; sodium nitrite and potassium nitrite are preferably used. Sodium nitrite is especially preferred. The reaction preferably takes place in an acid medium at low temperature. It is advantageous when the temperature is below 10°c, preferably between -10 and +5°C.

It is advantageous when the reaction of a compound of the general formula IV with nitrite takes place in an aqueous medium. The pH should be preferably less than 3, particularly preferably less than 2. 24 7 4 4 In a preferred embodiment for the reaction, a compound of the general formula IV or a salt thereof, preferably a salt of a mineral acid such as hydrochloric acid, sulphuric acid, nitric acid or phosphoric acid, is first added to an aqueous acidic medium and cooled.

Then, nitrite, preferably in a dissolved form, is added while maintaining the reaction mixture at a low temperature. It is advantageous when an aqueous medium is also used as the solvent for the nitrite.

After addition of the nitrite the reaction mixture is kept at a low temperature until the reaction is completed. In order to process the reaction mixture it is preferably extracted with an organic solvent and the product is isolated from the extract.

Compounds which can be used as electron carriers can be stored and used in an oxidized form, starting currents are avoided by this means and end-point determinations can be carried out with an excess of electron carriers. Compounds which can be used according to the present invention as electron carriers are stable on storage and can react rapidly with oxidoreductases. Above all they are able to compete with oxygen when using oxidases and can be used in excess over the highest analyte concentration to be determined. It is especially the latter property which is made possible by the good solubility of the electron carriers according to the present invention in an aqueous medium.

In the electrochemical determination of analytes in body fluids a particular advantage of the compounds which can be used as electron carriers is their property of not being non- enzymatically reduced, or only to a negligible extent, by substances in body fluids which act reductively. The electron carriers according to the present invention are rapidly oxidized at the electrode surface and are not sensitive to oxygen in their reduced form. With these compounds a low potential can be used for the oxidation at the electrode. 24 7446 The following Examples illustrate the invention: •Ryamnlg 1 Production of 2.21-r f4-nitrosoarvl)iminolbis-ethanols 2 mol N,N-bis-(B-hydroxyethylaniline) (or its aryl-substituted analogues) is added in portions, while stirring vigorously, to a mixture of 200.ml water and 400 ml concentrated hydrochloric acid in a 4 1 three-necked flask with stirrer, thermometer and dropping funnel. The resulting solution is cooled to 0°C with a cold bath and a solution of 148 g (2.1 mol) sodium nitrite in 200 ml water is added dropwise within 20 minutes at 0 to 2°C while stirring. It is then stirred for a further 30 minutes at 0°C, the mostly crystalline nitroso compound which has a yellow to green colour is aspirated and the filter cake is washed twice with 200 ml ice-cold, half-concentrated hydrochloric acid. For purification, the crude product is dissolved in 900 ml water, 400 ml concentrated hydrochloric acid is added while stirring vigorously, it is stirred for 3 0 minutes at room temperature, then for 30 minutes while cooling on ice. The crystallizate obtained is subsequently dissolved in 580 ml water to which 265 ml concentrated hydrochloric acid is added, and stirred for 30 minutes at room temperature and 30 minutes while cooling on ice. The crystals which form are aspirated, washed three times with 150 ml ice-cold acetone each time, twice with 200 ml diethylether each time and dried in a vacuum at room temperature. In this way the following are obtained: a) 2.2'-r f4-nitrosophenvn imidolbis-ethanol-hvdrochloride Yield 32.8 % of theory, green crystals; n.p_. 160°C (decomp.) .

Using corresponding aryl-substituted analogues the following are obtained analogously: 2 .2 '-r f3-fluoro-4-nitrosophenvl) iminolbis-ethanol- hvdrochloride Yield: 26.5 % of theory, yellow crystals; f.p. 140°C (decomp.). TLC: silica gel 60 (Merck) -mobile phase: ethyl acetate/methanol = 5:1, Rf = 0.59 from 3-fluoro-N, N-bis- [ 2-hydroxyethyl ] aniline (Chem. Abstr. 57, 13922 [1962]) 2 .2 '-r f3-chloro-4-nitrosophenvH iminolbis-ethanol-hvdrochloride Yield: 21 % of theory, yellow crystals; m.p. 154°C (decomp.). TLC: silica gel 60 (Merck) - mobile pnase: methylene chloride/methanol = 5:1, Rf = 0.72 from 3-chloro-N,N-bis-[2 (hydroxyethyl] aniline (M. Freifelder, G. R. Stone, J. Org. Chem. 26,. 1499 (1961)) 2 .2 1 — r f3-methoxv-4-nitrosophenvH iminolbis-ethanol hydrochloride Yield: 32 % of theory, ochre-coloured crystals; m.p. 145 - 146°C (decomp.). TLC: silica gel 60 •(Merck) - mobile phase: methylene chloride/methanol = 5:1, R^ = 0.4 from 3-methoxy-N,N-bis[2-hydroxyethyl]aniline (M. Freifelder et al., J. Org. Chem. .26, 1499 (1961)) 2 4 7 4 2 .2 »-r (3-methvlmer capt o -4-nitrosoohenv 1 ^ iminolbis-ethano 1-hvdrochloride Yield: 59.3 % of theory, red-brown crystals; in.p. 148°C (decomp.). TLC: silica gel 60 (Merck) -mobile phase: ethyl acetate/methanol = 5:1, Rf = 0.53 from 3-methylmercapto-N,N-bis-[2-hydroxyethyl] aniline (obtainable from : dissolve 0.1 mol 3-methylmercaptoaniline in 50 ml 4 N acetic acid and 0.35 mol ethylene oxide and stir for 12 hours at room temperature. Add excess NaHCO^ solution, extract with methylene chloride and purify by column chromatography on silica gel 60 (Merck) - mobile phase toluene / acetone = 5:2, Rf = 0.18, yield 25 %, colourless oil). 2- r methvl (3 -chloro-4 -nitrosophenvl) amino 1 ethanol-hvdrochloride Yield: 15 % of theory, yellow crystals; m.. p. 147°C (decomp.), TLC: silica gel 60 (Merck) - mobile phase: methylene chloride/methanol = 19:1, Rf = . 0.34 from 2-[methyl (3-chlorophenyl) amino ethanol (obtained from 2-[ (3-chlorophenyl) amino] ethanol by boiling for 3 hours with methyliodide in the presence of 10 % NaOH; purified by column chromatography on silica gel 60 (Merck) - mobile phase: toluene/acetone = 5:2, Rg = 0.39, yield 25 %, colourless oil) . 9 14 7 4 4'^ Example 2 2-r f 2-hvdroxYethoxv) -ethvl-f4-nitrosophenvl) amino!ethanol hydrochloride A) 2-r C2-hvdroxvethoxv)ethvl-fphenyl)amino1ethanol 146 g (0.8 mol) 2-(2-anilinoethoxy)ethanol (obtained by reacting aniline with 2-(2-chloroethoxy)ethanol, yield 54 %, colourless oil, b.p.^ 131 - 133°C) is dissolved in 500 ml 4N acetic acid, cooled with a cold bath to 0°c while stirring and 70.5 g, i.e. ca. 79 ml (1.6 mol), ethylenoxide is added dropwise within five minutes at 0""- 10 °C. After leaving it to stand for 12 hours at room temperature, 500 ml water is added, it is neutralised while stirring and carefully adding a total of 200 g NaHCO^ in small portions. Afterwards the liberated base is extracted with 500 ml methylene chloride, shaken again three times with 250 ml methylene chloride each time, the organic phases are combined, dried over sodium sulphate, aspirated and concentrated in a vacuum. 178.2 g product is obtained. TLC silica gel 60 (Merck) -mobile phase: toluene/acetone = 5:2, Rf = 0.18 B) 2-r2-hvdroxvethoxv^ -ethvl- f 4-nitrosophenvl^ amino1ethano1 hydrochloride CHjC HjOH *HCi A mixture of 280 ml concentrated hydrochloric add and 140 ml water is filled into a 2 1 three-necked' flask with stirrer, dropping funnel and thermometer, cooled down to - 5°C with a cooling bath of dry ice, 178 g (0.79 mol) of the substance obtained according to A) is added dropwise within 10 minutes at constant temperature and stirred for a further 15 minutes. A solution of 60 g (0.87 mol) sodium nitrite in 120 ml water is added to this at 0°C whereby the solution becomes a blood-red to brown colour and it is stirred for a further 30 minutes at 0°C. Subsequently it is diluted by adding 500 ml water (pH of the reaction mixture 1.4) and 218 ml concentrated aqueous ammonia solution is added dropwise while cooling on ice at a maximum of 15 °C to pH 9. The liberated nitroso base is extracted five times with 400 ml n-butanol and the solvent is distilled off in a rotary evaporator. 212.8 g dark green oil is obtained. This is mixed with a mixture of 250 ml toluene/acetone = 1:1 in order to remove inorganic products, the insoluble portion is aspirated and washed with 50 ml toluene/acetone = 1:1. 18.4 g inorganic material remains as a residue. The filtrate is purified chromatographically on a silica gel 60 column (7.5 cm in diameter, filling level 90 cm, separating fluid toluene/acetone = 1:1). 155 g nitroso base, dark green oil, is obtained. This is dissolved in 600 ml acetone and reacted dropwise with 250 ml saturated ethereal hydrochloric acid. After stirring for 30 minutes while cooling on ice the crystals which form are aspirated, washed three times with 100 ml acetone and dried in a vacuum at room temperature over diphosphorus pentoxide. 159.9 g (= 69.6 % of the theoretical yield) of the title compound is obtained; m .p. 118°C, TLC: silica gel 60 (Merck) -mobile phase: toluene/acetone = 1:1, Rf = 0.24. 24 7 44 - li - E x a m p 1' e 3 The following compounds are produced in an analogous manner to Example 11: a) 1- TN. NT- (2-hydroxvethy 1) - (4-nitrosoanilino) 1 -3- (1 -hvdroxvethoxv) -2-oropanol hydrochloride 0 *HCi CH^CHCH^OCH^CH^OH OH Yield: 10.5 % of theory, orange coloured crystals, m.p. 104°C. (decomp.) ; TLC - silica gel 60 (Merck) mobile phase: toluene/methanol = 5:1, Rf = 0.13 from 1-[N,N-(2-hydroxyethyl) (anilino) ]-3-(2-hydroxyethcxy)-2-propanol CH^C H C. HjO C H OH (this is from 1-[N-(anilino)]-3-(2-hydroxyethoxy) -2-propanol which is obtained from aniline with l-chloro-3-(2-hydroxyethoxy)-2-propanol - yield: 21.5 % colourless oil, TLC: silica gel 60 (Merck) - mobile E*jase: toluene/acetone = 5:2, R^ = 0.6) by reaction with ethylene oxide in the presence of 4 N acetic acid. 71 % colourless oil, TLC: "silica gel 60 (Merck) - mobile phase: toluene/acetone 5:2, Rf = 0.43 247446 l-rN-f2-hvdroxvethvl^ W 4-nitrosoanilino^ 1-3 methoxv-2-propanol hydrochloride Yield: 44.5 % light yellow crystals, m.p. 122°C (decomp.). TLC: silica gel 60 (Merck) - mobile phase: methylene chloride/methanol = 49:1, Rf = 0.55 from (+) -3- [N- (2-hydroxyethyl) anilino] -l-methoxy-2 propanol (Deutsches Reichspatent 603808 (1933) -Friedlander 21,, 295), (b.p.^ 212 - 214°C) . 2-r(2-methoxvethoxv^ethvl-(4-nitrosophenvl^ amino!ethanol Yield: 25 % of theory, dark brown resin. TLC: silica gel 60 (Merck) - mobile phase: methylene chloride/methanol = 19:1, R^ = 0.49; methylene chloride/methanol = 5:1, R^ = 0.77 (via the amorphous hygroscopic hydrochloride with NH3); from 2-[(2-methoxyethoxy)ethyl-(phenyl)-aminoethanol (A) * HCL OH CH^OCH^OC^ (A) 24 7 4 which was obtained from aniline and 2-methoxy-ethoxy-chloroethane (heat for one hour to 90°C and separate by column chromatography on silica gel. 60 (Merck) with toluene/ethyl acetate = 5:1. The N-(2-methoxyethoxy-ethyl) aniline thus formed (Rf = 0.69, colourless oil) results in (A) as a colourless oil, TLC: silica gel 60 (Merck) - mobile phase: toluene/acetone = 5:1, Rf = 0.31, with ethylene oxide and 4 N acetic acid. d) 2-T2-f2-f2—f2-methoxv) ethoxv) ethoxv) ethvl") -4-fnitroso—phenyl)amino!ethanol Nf CHzCHjOCUzcUzO CHjCW^OCH^CHjO CH3 Yield 63 % of theory, green oil, TLC: silica gel 60 (Merck) - mobile phase: toluene/acetone = 1:5, R^ = 0.64 from 2-[2-(2- (2- (2-methoxy) ethoxy) ethoxy) ethyl) -4-(phenyl) amino J ethanol.

The starting compound was produced as follows: .5 % of the theoretical yield of a yellow oil, R^ = 0.5 ^^CH.CHjOGH.CH^OCH.C H<0 CHjCKJCI \=r nh is obtained from aniline and diethylglycol-bis-(2-chloroethylether) (Perry, Hibbert -Can. J. Res. 14/ 81 (1936) by heating to 140°C for four hours and subsequent separation by column chromatography on silica gel 60 (Merck) with toluene/ethyl acetate = 2:1. 247446 14 Its reaction with ethylene oxide in 4 N acetic acid yields almost quantitatively as a beige coloured oil, TLC: silica gel 60 (Merck) -mobile phase: methylene chloride/methanol = 19:1, R^ = 0.61.

Using NaOCH3 in methanol (heat for 24 hours under reflux, evaporate, add water, take up in ethyl acetate and subsequently purify the crude product by column chromatography on silica gel 60 (Merck) with toluene/acetone = 5:2), 51.3 % of the theoretical yield of product is obtained as a colourless oil, Rf = 0.21.

Example 4 N-(4-nitrosophenvl) -N-f (2-diethvlamino) -ethvll-N.N1-diethvl-1.2-ethane-diamine-tris-hvdrochloride m.p. 125°C (decomp.), TLC: silica gel 60 (Merck) -mobile phase: isopropanol/n-butyl- acetate/water/concentrated aqueous NH3 = 50:30:15:5, Rf = 0.56 Q-« NCH4CHi0H from N-[di- (2-diethylamino) ethyl]aniline. 247 Example 5 Production of 1-N-substituted 4-(4-nitrosophenvl) pjperazines a) l-methvl-4- (4-nitrosophenvl) -piperazine— dihvdrochloride 17.62 g (0.1 mol) l-methyl-4-phenyl-piperazine (40.1 % of the. theoretical yield, b.p.g Q5 82 -84°C, Rf = 0.31, is obtained as a colourless liquid from 0.3 mol 1-phenylpiperazine by heating to 150°C for four hours with 0.2 mol tri-methyl phosphate, isolation by adding NaOH and extracting with diethylether and purifying by column chromatography on silica gel 60 (Merck) with methylene chloride/methanol = 5:1, (according to Stewart et al., J. Org. Chem. .13, 134 (1948)) is dissolved in a mixture of 20 ml concentrated hydrochloric acid and 10 ml water, then a solution of 8 g (0.12 mol) sodium nitrite in 16 ml water is added dropwise at 0 - 2°C within 15 minutes and it is stirred for a further 30 minutes at 10°c. 60 ml concentrated aqueous ammonia is added at the same temperature while cooling further, it is diluted by addition of 100 ml water and the red-brown solution (pH 9) is extracted three times by shaking with 100 ml methylene chloride each time, the organic phase is dried over Na2S04, aspirated and evaporated. The residue (20.6 g moss-green crystals) is taken up in 40 ml methanol and reacted with 20 ml saturated ethereal hydrochloric acid while cooling. 15.8 g = 56.8 % of the theoretical yield of moss-green crystals of the title compound is obtained after aspirating and washing twice with 20 ml ether.m .p. 187 - 189°C (decomp.), TLC: silica gel 60 (Merck) -mobile phase: methylene chloride/methanol = 5:1, Rf = 0.72.

The following are prepared analogously: b) 4-(4-nitrosophenvl)-l-pjperazine-ethanol-dihvdrochloride from 2-(4-phenyl-piperazino) -ethanol (Kremer, J. Amer. Chem. Soc. 58, 379 (1963)) as light grey crystals; purified by recrystallization from methanol/water = 7:1, ra.p. 170 - 173°C (decomp.), TLC: silica gel 60 (Merck) - mobile phase: methylene chloride/methanol = 5:1, Rf = 0.67 c) 3-r4-f4-nitrosophenvl1-1-pjperazinvll-1.2-oropane-dio1-dihvdrochloride 0 a O-cn*hch^OH * 4 HCL OH from l-phenyl-4-(2,3-dihydroxypropyl)-piperazine (H. Howell et al., J. Org. Chem. 27, 1711 (1962)) as green crystals, m.p. 163°C (decomp.)- TLC: silica gel 60 (Merck), mobile phase: ethyl acetate/methanol = 2:1, Rf = 0.41. 4—(4—nitrosophenvl)-a-fmethoxvmethvl)-pjperazine-1-ethanol-dihvdrochloride O«n-(^VN^-CH.CHCH.0CH, *J. HCl from l-phenyl-4-(2-hydroxy-3-methoxypropyl)-piperazine (H. Howell et al., J. Org. Chem. 27, 1711 (1962)) as yellow crystals, m.p. 162°C (decomp.) - TLC: silica gel 60 (Merck), mobile phase: methylene chloride/methanol = 19:1, Rf = 0.51 2-r 2-r 4(4-nitrosophenvl)-l-piperazinvl1ethoxvl-ethano1-dihvdrochloride 0-MCH^OGHjGHjOCH3 * Z HCl from 2-[2-[4-(phenyl)-i-piperazinyl]ethoxy-ethanol (obtained from 2 mol 1-phenylpiperazine and l-[2-chloroethoxy]-2-methoxyethane (the latter according to US-Patent 2,837,574) as green crystals, m.p. 134°C (decomp.) - TLC: silica gel 60 (Merck) -mobile phase: ethyl acetate/methanol = 5:1, Rf = 0.31. 24 7 4 4 6 f) 1-f1.4-dioxanvlvl)methvl-4-f 4-nitrosophenvl)-pjperazine-dihvdrochloride HCt from 1- (1,4-dioxanyly1)methy1-4-(phenyl)-piperazine (obtained by heating l-chloro-3-(6-hydroxyethoxy)-2-propanol (M.S. Kharash, W. Nudenberg, J. Org. Chem. 8., 189 (1943) for five, hours .with 1-phenylpiperazine to 130°C, extracting with ethyl acetate and evaporating. Purification by column chromatography on silica gel 60 (Merck) - mobile phase: toluene/acetone =5:2) as green yellow-crystals, m.p. 166°C (decomp.), TLC: silica gel 60 (Merck) - mobile phase: toluene/methanol = 5:1, Rf = 0.69.

Example 6 Nitrosoheterocvcles a) 5-nitroso-l-indolinoethanol hydrochloride CH^CRjOH The nitroso compound is obtained from 1-indolinoethanol (obtained by heating 1 mol indoline with 1 mol 2-chloroethanol in the presence of 1 mol finely powdered K2C03 under reflux yielding 63.8 % of the theoretical yield of a /• I. 24 7 4 4 6 colourless oil, b.p-0.i 128 ~ 130°C, TLC: silica gel 60 (Merck) - mobile phase: toluene/acetone = 5:2, Rf = 0.42) and is isolated as a base after addition of ammonia with methylene chloride. It is converted into the hydrochloride with ethereal hydrochloric acid. Light brown crystals are obtained, m.p. 180°C, TLC: silica gel 60 (Merck) -mobile phase: methylene chloride/methanol = 5:1, Rf = 0.51 b) l-methvl-6-nitroso-1,2,3.4-tetrahvdr ocruino'line hydrochloride C"""T 1 "HCl •IS/* CH3 The title compound is prepared from 1-methyl-1,2,3,4-tetrahydroquinoline (obtained from- 1,2,3,4' tetrahydroquinoline by heating with., trimethylphosphate (according to Huisgen et al., Chem. Ber. 92. 203 (1959)). The crude product is produced in the usual manner analogous to Examples 10 and 11 and purified on silica gel 60 (Merck) with isopropanol/n-butylacetate/water = 5:3:2. The title compound is obtained by dissolving this in acetone after addition of ethereal hydrochloric acid, m.p. 123 - 124°C (decomp.), TLC: silica gel 60, mobile phase: isopropanol/n-butyl-acetate/water = 5:3:2, Rf = 0.7.

Claims (1)

1. - 20 - 6-nitroso-3 .4-dihvdro-l C2H) -cruinoline-ethanol hydrochloride 'HCl The title compound is obtained from 2-(3,4 dihydro-2H-quinolin-l-yl)ethanol (Zaheer et al., Indian J. Chem. 1, 479 (1963), b.p.g 140 - 144°C) . The crude product is purified by column chromatography on silica gel 60 (Merck), mobile phase: methylene chloride/methanol = 19:1. 10.5 % of the theoretical yield of ochre-coloured crystals of the title compound are obtained by precipitation of the hydrochloride from isopropanol with ethereal hydrochloric acid and recrystallizing from ethanol, m.p. 193 - 195°C (decomp.), TLC: silica gel 60 (Merck) - mobile phase: methylene chloride/methanol = 19:1, Rf = 0.36. - 21 - 2^7446 what we claim is: l. Nitrosoaniline derivative of the general formula X' 3 /—i "R <-iT R1 in which [* 17JANJ994-; R1 denotes hydrogen, halogen, alkoxy or " ^ alkylthio, Jv *V R2 represents an alkyl residue and R3 represents an hydroxyalkyl residue or R2 and R3 are the. same or different and represent a dialkylaminoalkyl residue, an hydroxyalkoxyalkyl or alkoxyalkyl residue substituted, if desired, by OH in the alkyl moiety or a polyalkoxyalkyl residue which is substituted, if desired, by an hydroxy residue in the alkyl. moiety or R2 and R3 form an alkylene residue interrupted by sulphur or nitrogen which is substituted by an alkyl, hydroxyalkyl, hydroxyalkoxyalkyl, alkoxyhydroxyalkyl, dioxanylyl-alkyl or polyalkoxyalkyl residue each of which is itself substituted, if desired, in the alkyl moiety by an hydroxy residue or 1 2 5 if R is in the ortho position to np r , R2 also together with R1 represents an alkylene residue, whereby R3 then represents a hydroxyalkyl residue or, if the alkylene residue contains 3 carbon atoms, it also represents, if desired, an alkyl residue or if R1 is not hydrogen, R2 and R3 are the same or different and each represents an hydroxyalkyl residue or a salt of this derivative. - 22 - 24 7 A A 6 A nitrosoaniline derivative according to claim 1 chosen from the following group a) 2,21-[(3-fluoro-4-nitrosophenyl)imino]bis-ethanol, b) 2,2'(3-chloro-4-nitrosophenyl)imino]bis-ethanol, c) 2,2'-[(3-methoxy-4-nitrosophenyl)imino]bis-ethanol, d) 2,2'-[(3-methylitiercapto-4-nitrosophenyl)imino]bis-ethanol, e) 2-[(2-hydroxyethoxy)ethyl-(4-nitrosophenyl) amino]ethano1, f) 2-[(2-methoxyethoxy)ethyl-(4-nitrosophenvl) amino]ethanol, g) l-[N-(2-hydroxyethvl)-(4-nitrosoanilino)]-3-methoxy-2-propanol, h) l-[N-(2-hydroxyethyl)-(4-nitrosoanilino)] -3- (2-hydroxyethoxy)-2-propanol, i) l-methyl-4-(4-nitrosophenyl)-piperazine, j) 4-(4-nitrosophenyl)-1-piperazino-ethanol, k) 5-nitroso-l-indoline ethanol, 1) l-methyl-6-nitroso-l,2,3,4-tetrahydroquinoline, m) 6-nitroso-3,4-dihydro-l(2H)quinoline ethanol-and their salts. A nitrosoaniline derivative according to claim 1 substantially as herein described or exemplified. Process for the production of a compound as claimed in claim 1, wherein a compound of the general formula IV 2 (IV) in which R*^, R^ and R3 have the meaning given i claim 12, is reacted with, a nitrite. \ 17 JAN 1994 24 7 4 4 6 - 23 - 5. A process according to claim 4 substantially as herein described or exemplified. BOEHRINGER MANNHEIM GMBH By \ • °'X f V x' \ jf %§j c