WO1994008969A1

WO1994008969A1 - Process for producing 4,5-diamino pyrazole derivatives, their use for colouring hair and novel pyrazole derivatives

Info

Publication number: WO1994008969A1
Application number: PCT/EP1993/002644
Authority: WO
Inventors: Hans Neunhoeffer; Stefan Gerstung; Thomas Clausen; Wolfgang R. Balzer
Original assignee: Wella Aktiengesellschaft
Priority date: 1992-10-16
Filing date: 1993-09-29
Publication date: 1994-04-28
Also published as: DE4234885A1; BR9305675A; ES2060574T1; EP0618902A1; JPH07502542A

Abstract

The present invention relates to a process for producing 4,5-diamino pyrazole derivatives of general formula (I) in which R1 and R2 are mutually independently hydrogen, a C1 to C6 alkyl residue or a C2 to C4 hydroxy alkyl residue, which may be used as colorant pre-products, e.g. for hair colorants, and novel pyrzole derivatives. The use of the process of the invention makes it possible to obtain 4,5-diamino pyrazole derivatives of general formula (I) without isomers and with good yields.

Description

description

Process for the preparation of 4,5-diaminopyrazole derivatives, their use for dyeing hair and new pyrazole derivatives

The present invention relates to a process for the preparation of 4,5-diaminopyrazole derivatives of the general formula (I)

Ri

in which R 1 and R 2 independently of one another denote hydrogen, a C 1 -C 4 -alkyl radical or a C 2 -C 4 -hydroxyalkyl radical, and also new pyrazole derivatives, including 4,5-diaminopyrazole derivatives which act as dye precursors, for example for hair dyes.

Several processes for the preparation of 4,5-diaminopyrazole derivatives of the formula (I) are already known in the literature. However, these methods are unsatisfactory in many ways.

For example, according to H. Dorn et al. , Chem. Ber. 98, p. 3368 (1965), starting from ethyl ethoxymethylene-cyanoacetate and methylhydrazine to obtain the 5-amino-l-methylpyrazole-4-carboxylic acid, from which by Decarboxylation, in a total yield of 40 percent, the 5-amino-1-methylpyrazole is formed.

DE-OS 2 141 700 describes a one-step process according to which 5-amino-1-methylpyrazole can be obtained from N, N-dimethylaminoacrylonitrile and methylhydrazine in a yield of 71 percent.

According to M.A. Khan et al. , Can. J. Chem.. 49., P. 3566 (1971), the 5-amino-1-methylpyrazole obtained by the processes described can be obtained in a yield of 23 percent to 5-amino-1-methyl-4-nitropyrazole implement. Catalytic reduction of this product provides according to V.P. Perevalov et al., Khim. Geterotsicl. Soedin. 8__, p. 1090 (1985), l-methyl-4,5-diaminopyrazole-dihydrochloride in a yield of approx. 79 percent. The overall yield over the stages mentioned is 7 to 13 percent.

Overall yields of up to 46 percent are obtained if the 5-amino-l-methylpyrazole according to H. Dorn et al., Liebigs Ann. Chem. 717, p. 118 (1968), with isoamyl nitrite to give 5-amino-1-methyl-4-nitropyrazole and reduced with tin (II) chloride to 4,5-diamino-1-methylpyrazole.

DE-OS 38 43 892 discloses a process for the preparation of 4,5-diamino-1-methylpyrazole in which 2-chloroacrylonitrile with hydrazine (G. Ege, Angew. Chem, 86, p. 237 (1974 )) is cyclized. After acetylation of the amino group, nitration and elimination of the protective group, the tautomeric compounds 3-amino-4-nitropyrazole and 5-amino-4-nitropyrazole are obtained in a total yield of approximately 41 percent. If the tautomeric quantity is alkylated with dimethyl sulfa, an isomer mixture is obtained in 70 percent yield, which is chromatographically divided into the isomeric compounds 5-amino-1-me- thyl-4-nitropyrazole (25 percent) and 3-amino-l-methyl-4-nitropyrazole (45 percent) can be separated. The corresponding diamino compounds can be obtained by reduction. The overall yield of l-methyl-4,5-diaminopyrazole is less than 10 percent.

DE-OS 3 432 983 discloses a process for the preparation of 5-amino-1- (2'-hydroxyethyl) -4-nitropyrazole. Starting from 5-amino-l- (2'-hydroxyethyl) pyrazole-4-carboxylic acid, the compound is obtained in a yield of 59 percent by decarboxylation, subsequent nitrosation and hydrogenation.

In addition to the sometimes low yields, the processes described have further disadvantages. For example, many starting compounds, such as, for example, ethyl ethoxymethylcyanoacetate or N, N-dimethylaminoacrylonitrile, are not commercially available or can only be prepared by in part complex syntheses. In addition, hydrazine derivatives are classified as toxic and in part carcinogenic.

The preparation of 4,5-diaminopyrazole derivatives which are substituted in the 5-position on the nitrogen atom of the amino group is not described.

The object of the present invention was therefore to provide a process for the isomerically pure preparation of differently substituted 4,5-diaminopyrazole derivatives.

It has now been found that the object is achieved by a process for the preparation of 4,5-diaminopyrazole derivatives of the general formula (I)

I.

Ri

in which R 1 and R 2 independently of one another denote hydrogen, a C 1 -C 6 -alkyl radical or a C 2 -C 4 -hydroxyalkyl radical, characterized in that

(A) 3,5-dibromo-4-nitropyrazole with a C] _ to Cδ alkyl, C2 to C4 hydroxyalkyl or benzyl halide or a Ci to Cδ alkyl, C2 to C4 hydroxy alkyl or benzyl sulfate to compounds of the general formula (II)

in which R3 denotes a C 1 -C 6 -alkyl radical, a C 2 -C 4 -hydroxyalkyl radical or a benzyl radical, (B) the compounds of the general formula (II) with Ci- to Cδ-alkyl-, C2- to C4-hydroxyalkyl- or benzylamine to give compounds of the general formula (III)

I.

R ₃

in which R3 and R4 independently of one another denote a Ci to C6 alkyl radical, a C2 to C4 hydroxyalkyl radical or a benzyl radical, substituted in the 5-position and then

(C) the compounds of the general formula (III) are reduced to the compounds of the general formula (I) by catalytic hydrogenation,

can be solved excellently. The above-mentioned method is therefore an object of the invention.

The general reaction scheme is given below.

i

Ri

(I)

The known 3,5-dibromo-4-nitropyrazole (IV) serves as the starting compound for the synthesis of 4,5-diamino-pyrazole derivatives (I), which can be prepared in the following manner:

According to R. Hüttel et al. , Chem. Ber. .88. _/ P. 1577 (1955), the 4-nitropyrazole obtained by nitrating pyrazole with a sulfuric acid / nitric acid mixture, which according to HJ Klebe et al. , Synthesis 1973. p. 294 under milder conditions by nitration of pyrazole to N-nitropyrazole and subsequent rearrangement, with the aid of sulfuric acid (R. Hüttel et al., Chem. Ber. .8J3 _. , P. 1586 (1955)), can be obtained. Subsequent bromination according to JPH Juffermanns et al. , J. Org. Chem. 51, p. 4656 (1986), provides the 3,5-dibromo-4-nitropyrazole (IV). In the process according to the invention, the 3,5-dibromo-4-nitropyrazole (IV) is firstly reacted with C 1 -C 6 -alkyl-, C2- to C4-hydroxyalkyl or benzyl halides in dimethylformamide (DMF) (process I) or alkylated in the 1-position by reaction with Ci to C6 alkyl, C2 to C4 hydroxyalkyl or benzyl sulfate and alkali (method II).

According to method I, an equimolar amount of 3,5-dibromo-4-nitropyrazole, dissolved in absolute DMF, is added dropwise over a period of one hour to an initial charge of sodium hydride in absolute DMF, with stirring at room temperature. After the evolution of gas has ceased, an equimolar amount of C 1 -C 6 -alkyl, C 2 -C 4 -hydroxyalkyl or benzyl halide, preferably chloride or bromide, dissolved in DMF, is added dropwise, and the reaction mixture is heated to 80 ° C. for three hours . The solvent is then distilled off in vacuo and the residue is recrystallized from methylene chloride.

According to process II, the 3,5-dibromo-4-nitropyrazole is dissolved in aqueous alkali, preferably 2N sodium or potassium hydroxide solution, and with a two to five-fold molar amount of C 1 -C 6 -alkyl-, C2- to C4-hydroxyalkyl - or benzyl sulfate added. With vigorous stirring, the mixture is left to react at room temperature for 15 hours, the precipitated product is then filtered off, washed with water until the washing solution is pH-neutral and dried in vacuo.

Both processes give isomerically pure N-substituted, 3,5-dibromo-4-nitropyrazoles of the general formula (II) in good yields. In a subsequent step, the N-substituted 3,5-dibromo-4-nitropyrazoles of the general formula (II) are heated in an aqueous, alcoholic or aqueous-alcoholic solution of C 1 -C 6 -alkyl-, C 2 ~ to C4-hydroxyalkyl or benzylamine or in the corresponding amine itself, as a solvent, to a temperature of 60 to 80 ° C. Methanol and / or ethanol are preferably used as alcohols. After a reaction time of 1 to 20 hours, the cooled reaction mixture is poured into 20 to 150 ml of water and the separated product is filtered off. Then it is washed with water (10 to 20 ml) and dried in vacuo. Isomerically pure 5-amino-3-bromo-4-nitro-pyrazole derivatives of the general formula (III) are obtained in good yields.

The compounds of the general formula (III) are then hydrogenated using hydrogen using a palladium / activated carbon catalyst with a palladium content of 10% by weight. According to the invention, two methods are available for this. According to process (1), two spatula tips, approx. 100 mg, of the catalyst are added to the alcoholic, preferably ethanolic, solution of a compound of general formula (III) and the batch is transferred to an autoclave. In a 50 bar hydrogen atmosphere, the mixture is stirred at room temperature for 1 to 6 hours, preferably 2 to 4 hours. The catalyst is then filtered off through a glass filter crucible and the product is precipitated as a salt with a quantity of sulfuric acid which is equimolar to the pyrazole compound used or a double-molar quantity of hydrochloric acid. According to process (2), 2 spatula tips of the above-described catalyst and an amount of sulfuric acid equimolar to the starting compound are added to the aqueous solution of a compound of the general formula (III) and the batch in a hydrogenation flask shaken at room temperature under a hydrogen atom (normal pressure). As soon as the thin-layer chromatographic analysis of the reaction mixture gives no indication of any educt still present, a glass filter crucible is filtered off over the reaction mixture, the filtrate is concentrated and the product is crystallized out by adding ethanol.

Isomerically pure 4,5-diaminopyrazole derivatives of the general formula (I) are obtained in good yields by both processes.

The compounds of the general formula (I) in which R 1 is hydrogen are present as tautomers. Positions 3 and 5 in the pyrazole ring cannot be distinguished.

In the reduction of compounds of the general formula (III) in which R3 is a benzyl radical or R4 is a benzyl or tert-butyl radical, the N-benzyl and N-tert-butyl radicals are cleaved reductively, so that Compounds of general formula (I) is obtained in which Rl or R2 is hydrogen instead of benzyl or tert-butyl.

The present patent application also relates to new 3,5-dibromo-4-nitropyrazole derivatives of the general formula (II)

I.

R in which R3 is a Ci to C6 alkyl radical, a C2 to C4 hydroxyalkyl radical or a benzyl radical. Examples of compounds of the formula (II) are 3,5-dibromo-l-methyl-4-nitropyrazole, 3,5-dibromo-l-ethyl-4-nitropyrazole, 3,5-dibromo-l -isopropyl-4-nitropyrazole, 3,5-dibromo-l- (2'-hydroxyethyl) -4-nitropyrazole and 1-benzyl-3,5-dibromo-4-nitropyrazole.

Another subject of the invention are 3-bromo-5-amino-4-nitropyrazole derivatives of the general formula (III)

in which R3 and R4 independently of one another denote a Ci to C6 alkyl radical, C2 to C4 hydroxyalkyl radical or a benzyl radical.

Examples of compounds of the formula (III) are

3-bromo-l-methyl-5-methylamino-4-nitropyrazole,

3-bromo-5- (2'-hydroxyethyl) amino-l-methyl-4-nitropyrazole,

3-bromo-5-tertiary-butylamino-l-methyl-4-nitropyrazole,

5-benzylamino-3-bromo-l-methyl-4-nitropyrazole,

5-benzylamino-3-bromo-l-ethyl-4-nitropyrazole,

5-benzylamino-3-bromo-l-isopropyl-4-nitropyrazole,

3-bromo-1- (2'-hydroxyethyl) -5- (2'-hydroxyethyl) amino-4-nitropyrazole, 3-bromo-1- (2'-hydroxyethyl) -5-methylamino-4-nitropyrazole, 5-benzylamino-3-bromo-1- (2'-hydroxyethyl) -4-nitropyrazole 1-benzyl-3-bromo-5 -methylamino-4-nitropyrazole, l-benzyl-3-bromo-5-ethylamino-4-nitropyrazole, l-benzyl-3-bromo-5- (2'-hydroxyethyl) amino-4-nitropyrazole and l-benzyl-5 -benzylamino-3-bromo-4-nitropyrazole are to be named.

The present invention further relates to new 4,5-diaminopyrazole derivatives of the general formula (V)

I Ra

in which R _a and R are hydrogen, a C 1 -C 6 -alkyl radical or a C 2 -C 4 -hydroxyalkyl radical, with the proviso that when R is hydrogen, R _{a is} not hydrogen, methyl or 2-hydroxyethyl.

As examples of compounds of formula (I)

4-amino-l-methyl-5-methylaminopyrazole,

4-amino-5- (2'-hydroxyethyl) amino-1-methylpyrazole,

4,5-diamino-l-ethylpyrazole,

4,5-diamino-l-isopropylpyrazole,

4-amino-1- (2'-hydroxyethyl) -5- (2'-hydroxyethyl) amino-pyrazole, 4-amino-1- (2'-hydroxyethyl) -5-methylaminopyrazole, 4-amino- (3) 5-methylaminopyrazole, 4-amino- (3) 5-ethylaminopyrazole and 4-amino- (3) 5- (2 '-hydroxyethyl) aminopyrazole,

called.

The compounds of the formula (V) can be used as dye precursors in oxidation hair colorants for dyeing hair (see example of use).

Examples

A) Preparation of N-substituted 3, 5-dibromo-4-nitro-pyrazoles of the general formula (II)

a) General regulation, procedure I:

19.0 g (70 mmol) of 3,5-dibromo-4-nitropyrazole, dissolved in 90 ml of absolute DMF, are added dropwise to 1.75 g (70 mmol) of sodium hydride in 150 ml of absolute DMF (dimethylformamide) over a period of 1 hour , too. After the evolution of gas has ceased, 70 mmol of Ci to C6-alkyl, C2 to C4-hydroxyalkyl or benzyl halide in 30 ml of DMF are added dropwise and the mixture is heated to 80 ° C. for 3 hours. The solvent is then distilled off in vacuo and the residue is recrystallized from methylene chloride.

b) General regulation, procedure II:

92.5 mmol of Ci to C6-alkyl-, C2 to C4-hydroxyalkyl- or benzyl sulfate are added to a solution of 5 g (18.5 mmol) of 3,5-dibromo-4-nitropyrazole in 50 ml of 2N sodium hydroxide solution. is allowed to stir vigorously at room temperature for 15 hours and finally the precipitated product is filtered off, washed with water until the washing solution is pH-neutral and dries in vacuo.

Production Example 1: 3,5-dibromo-1-methyl-4-nitrophyrazole

According to method II, using methyl sulfate, 5.06 g (96 percent of theory) of 3,5-di- bromo-l-methyl-4-nitropyrazole in the form of white crystals with a melting point of 154 ° C.

iH-NMR (60 MHz, DMSO-dδ): = 3.90 ppm (s; 3H; -CH3).

The following applies to this and all the following 1H NMR spectra: The

The chemical shift is given in delta

(ppm), the coupling constant (J) is in Hertz

Standard: tetramethylsilane s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, Ph = phenyl, ring H = proton on the pyrazole ring

MS (70 eV): m / e = 287 (M ⁺ ).

Production Example 2: 3,5-dibromo-1-ethyl-4-nitropyrazole

According to process II, 3.59 g (65 percent of theory) of 3,5-dibromo-1-ethyl-4-nitropyrazole are obtained in the form of white crystals with a melting point of 119 to 121 ° C. using ethyl sulfate.

iH-NMR (60 MHz, DMSO-d6): = 4.26 (q; J = 7.0 Hz; 2H;

-CH2-CH3) and 1.36 ppm (t; J = 7.0 Hz; 3H; -CH2 ~ CH3) ■

MS (70 eV): m / e = 297 (M +).

Production Example 3: 3,5-dibromo-l-isopropyl-4-nitro-pyrazole

Process I gives, using 2-bromopropane, 13.14 g (60 percent of theory) of 3,5-dibromo-l-isopropyl-4-nitropyrazole in the form of brown-yellow crystals with a melting point of 72 to 73 ° C. iH-NMR (60 MHz, DMSO-d6): = 4.84 (dq; J = 6.5 Hz; 1H;

CH) and 1.42 ppm (d; J = 6 Hz; 6H; -CH (CH3) 2)

MS (70 eV): m / e = 311 (M +).

Production Example 4: 3,5-dibromo-1- (2'-hydroxyethyl) -

4-nitropyrazole

According to process I, using l-bromo-2-hydroxyethane, 14.77 g (67 percent of theory) of 3,5-dibromo-l- (2'-hydroxyethyl) -4-nitropyrazole are obtained in the form of pale yellow crystals a melting point of 103 to 105 ° C.

iH-NMR (60 MHz, DMSO-d6): = 4.90 (s; broad; 1H; -OH; exchangeable with D2O), 4.31 (m; 2H; -CH2-) and 4.08-3, 82 ppm (m; 2H; -CH2-; after D2θ exchange: t; 2H; J = 5 Hz).

MS (70 eV): m / e = 317 (M +).

Preparation example 5: 1-benzyl-3,5-dibromo-4-nitro-pyrazole

According to process I, 17.94 g (71 percent of theory) of l-benzyl-3,5-dibromo-4-nitrobenzene are obtained in the form of pale yellow crystals with a melting point of 128 ° C. using benzyl chloride.

1 H-NMR (60 MHz, DMSO-d6): = 7.26-7.41 (m; 5H; Ph-H) and

5.51 ppm (s; 2H; -CH2-). MS (70 eV): m / e = 363 (M +). B) Preparation of 5-amino-3-bromo-4-nitropyrazole derivatives of the general formula (III)

Production Example 6: 3-bromo-l-methyl-5-methylamino-4-nitropyrazole

2 g (7.02 mmol) of 3,5-dibromo-l-methyl-4-nitropyrazole are heated to boiling temperature in 50 ml of a 40 percent solution of methylamine in ethanol for 4 hours. After cooling, 100 ml of water are added to the reaction mixture, the separated product is filtered off and washed with a little water (20 ml). After drying in vacuo, 1.45 g (88 percent of theory) of 3-bromo-l-methyl-5-methylamino-4-nitropyrazole are obtained in the form of yellow crystals with a melting point of 185 ° C.

iH-NMR (60 MHz, DMSO-d6): = 7.50 (s; broad; 1H; -NH; exchangeable with D2O), 3.88 (s; 3H; N-CH3) and 3.16 ppm (i.e. ; 3H; J = 6 Hz; -NH-CH3; after D2O exchange s).

MS (70 eV): m / e = 236 (M ⁺ ).

Production Example 7: 3-bromo-5- (2'-hydroxyethylamino) - 1-methyl-4-nitropyrazole

3 g (10.5 mmol) of 3,5-dibromo-l-methyl-4-nitropyrazole are heated to boiling temperature in a solution of 30 ml of ethanolamine in 30 ml of ethanol for 15 hours. The reaction mixture is then poured onto 200 ml of water, the separated product is filtered off, washed with water (20 ml) and dried in vacuo. Further product crystallized out of the filtrate in the cold (5 ° C). 2.25 g (81 percent of theory) of 3-bromo-5- (2 'hydroxyethyl) amino-1-methyl-4-nitropyrazole are obtained in the form of white crystals with a melting point of 150 ° C.

iH-NMR (60 MHz, DMS0-d6): = 7.38 (s; broad; 1H; -NH; exchangeable with D2O), 4.98 (s; broad; 1H; -OH; exchangeable with D2O), 3 , 82 (s; 3H; N-CH3) and 3.60 ppm (m; 4H; -NH-CH2-CH2) •

MS (70eV): m / e = 266 (M ⁺ )

Production Example 8: 3-bromo-5-tert-butylamino-1-methyl-4-nitropyrazole

1.5 g (5.26 mmol) of 3,5-dibromo-l-methyl-4-nitropyrazole are heated to boiling temperature in a solution of 20 ml of tert-butylamine in 30 ml of ethanol for 20 hours. After cooling, the mixture is poured Reaction mixture on 150 ml of water, the separated product is filtered off and washed with 100 ml of water. After drying in vacuo, 1.14 g (78 percent of theory) of 3-bromo-5-tert-butylamino-l-methyl-4-nitropyrazole are obtained in the form of pale yellow leaves with a melting point of 75 to 77 ° C.

1 H-NMR (60 MHz, DMSO-d6): = 5.35 (s; 1H; -NH; exchanges with D2O), 3.75 (s; 3H; N-CH3) and 1.20 ppm (s; 9H; -C (CH ₃ ) ₃ ).

MS (70 eV): m / e = 277 (M ⁺ ). Production Example 9: 5-Benzylamino-3-bromo-1-methyl

4-nitropyrazole

2 g (7.02 mmol) of 3,5-dibromo-l-methyl-4-nitropyrazole are heated to boiling temperature in a solution of 11 g (0.1 mol) of benzylamine in 50 ml of ethanol for 10 hours. After cooling, the reaction mixture is poured onto 100 ml of water, the separated product is filtered off and washed with water (20 ml). After drying in vacuo, 1.76 g (81 percent of theory) of 5-benzylamino-3-bromo-1-methyl-4-nitropyrazole are obtained in the form of yellow needles with a melting point of 133 ° C.

iH-NMR (60 MHz, DMSO-d6): = 7.88 (t; 1H; J = 6Hz; -NH; exchangeable with D2O), 7.32 (m; 5H; Ph-H), 4.73 ( d; 2H; J = 6 Hz; -NH-CH2-; after D2θ exchange s) and 3.68 ppm (s; 3H; N-CH3).

MS (70 eV): m / e = 312 (M ⁺ ).

Production Example 10: 5-Benzylamino-3-bromo-1-ethyl

4-nitropyrazole

6.3 g (21 mmol) of 3,5-dibromo-1-ethyl-4-nitropyrazole are heated to 80 ° C. in 10 ml of benzylamine for 1 hour. The reaction mixture is then poured onto 50 ml of water and the separated oil is separated off, from which, after addition of 20 to 30 ml of ethyl acetate, the product crystallizes out. After one Umkristalli¬ Sieren from methanol obtained 5.2 g (76 percent of theory) of 5-benzylamino-3-bromo-l-ethyl-4-nitropyrazole in the form of light yellow needles having a melting point of 92 ^C C. iH-NMR (300 MHz, DMSO-d6): = 7.90 (t; J = 6.7Hz; 1H; -NH; exchanges with D2O), 7.26- 7.40 (m; 5H; Ph- H), 4.68 (d; J = 6.7 Hz, 2H; NH-CH? -; after D2θ exchange s), 4.00 (q; J = 7.3 Hz; 2H; -CH2-CH3) , and 1.18 ppm (t; J = 7.2Hz; 3H; -CH2-CH3).

MS (70 eV): m / e = 324 (M ⁺ )

Production Example 11: 5-Benzylamino-3-bromo-1-isopropyl-4-nitropyrazole

3.13 g (10 mmol) of 3,5-dibromo-l-isopropyl-4-nitropyrazole are heated in 80 ml of benzylamine at 80 ° C. for 1 hour. The reaction mixture is then poured onto 50 ml of water and the separated product is filtered off. After recrystallization once from a toluene / petroleum ether mixture (1: 1), 2.3 g (68 percent of theory) of 5-benzylamino-3-bromo-l-isopropyl-4-nitro-pyrazole in the form of light yellow crystals with a Melting point of 120 and 122 ° C.

iH-NMR (300 MHz, DMSO-d6): = 7.78 (t; J = 6.6Hz; 1H; -NH; after D2θ exchange s), 7.25-7.39 (m; 5H; Ph -H); 4.66 (d; J = 6.6Hz; 2H, -NH-CH2-; after D2θ exchange s); 4.57 (dq; J = 6.4Hz; 1H; -CH (CH3) 2) and 1.19 ppm (d; J = 6.4Hz; 6H: -CH (CH3) 2).

MS (70 eV): m / e = 338 (M +) Production Example 12: 3-bromo-1- (2'-hydroxyethyl) -5-

(2'-Hydroxyethyl) amino-4-nitropyrazole

1.5 g (4.8 mmol) of 3,5-dibromo-l- (2 '-hydroxyethyl) -4-nitro-pyrazole are dissolved in a solution of 0.58 g (9.6 mmol) of ethanolamine in 30 ml of ethanol Heated to 80 ° C for 15 hours. After cooling, 50 ml of water are added to the reaction mixture and extracted three times with 70 ml of ethyl acetate each time. 200 ml of n-hexane are added to the combined extraction solutions and the solvent mixture is distilled off in vacuo to a third of the original amount. Then add n-hexane again until the solution becomes cloudy. The product which has crystallized out is then filtered off and washed with n-hexane (10 to 20 ml). 1.04 g (74 percent of theory) of 3-bromo, l- (2 '-hydroxyethyl) -5- (2' -hydroxyethyl) amino-4-nitropyrazole are obtained in the form of pale yellow crystals with a melting point of 132 up to 134 ° C.

iH-NMR (60 MHz, DMSO-dß): = 7.42 (s; broad; 1H; -NH; exchangeable with D2O), 5.23-5.02 (m; 2H; -OH; exchangeable with D2O) , 4.18 (m; 2H; N-CH2-) and 3.93-3.45 ppm (; 6H; -CH2-).

MS (70 eV): m / e = 296 (M +)

Production Example 13: 3-bromo-1- (2'-hydroxyethyl) -5-methylamino-4-nitropyrazole

3.15 g (10 mmol) of 3,5-dibromo-l- (2 '-hydroxyethyl) -4-nitro-pyrazole are heated to 60 ° C. for 1 hour in 70 ml of a 30 percent solution of methylamine in water. After cooling, the product precipitates in the form of light yellow crystals with a melting point of 158 to 160 ° C. 2.4 g (91 percent of theory) of 3-bromo-1- (2 'hydroxyethyl) -5-methylamino-4-nitropyrazole are obtained.

iH-NMR (300 MHz DMSO-d6): = 7.67 (s; 1H; -NH; exchanges with D2O); 5.06 (s; 1H; -OH; exchanges with D2O), 4.18 (t; 2H; N-CH2-), 3.68 (t; 2H; -CH2-OH) and 3.15 ppm ( d; J = 4.5 Hz; 3H; -NH-CH3; after D2θ exchange s).

MS (70 eV): m / e = 266 (M ⁺ ).

Preparation example 14: 5-benzylamino-3-bromo-1- (2'-hydroxyethyl) -4-nitropyrazole

6.3 g (20 mmol) of 3,5-dibromo-l- (2'-hydroxyethyl) -4-nitro-pyrazole are heated in 60 ml of benzylamine at 60 ° C for 2 hours. After cooling, the mixture is poured onto 50 ml of water, the separated product is filtered off and recrystallized once from toluene / ligroin (1: 1). 4 g (59 percent of theory) of 5-benzylamino-3-bromo-l- (2'-hydroxyethyl) -4-nitropyrazole are obtained in the form of yellow crystals with a melting point of 133 to 135 ° C. iH-NMR (300 MHz, DMSO-d6): = 7.89 (t; J = 6.6Hz; 1H; -NH; exchanges with D2O), 7.22- 7.44 (m; 5H; Ph- H); 5.15 (s; 1H; -0H; exchanges with D2O), 4.77 (d; J = 6.6Hz; 2H; -NH-CH2-; after D2O exchange s), 3.99 ( t; J = 4.9H; 2H; -CH2-) and 3.96 ppm (t; J = 5Hz; 2H; -CH2 ~).

MS (70 eV): m / e = 340 (M ⁺ )

Production Example 15: 1-Benzyl-3-bromo-5-methylaπtino

4-nitropyrazole

3.61 g (10 mmol) of l-benzyl-3,5-dibromo-4-nitropyrazole are heated in 100 ml of a 35 percent solution of methylamine in water at 60 ° C. for 4 hours. After cooling, the deposited precipitate is filtered off and recrystallized once from ethanol. 2.7 g (87 percent of theory) of 1-benzyl-3-bromo-5-methylamino-4-nitropyrazole are obtained in the form of colorless crystals with a melting point of 116 ° C.

iH-NMR (300 MHz, DMSO-dß): = 7.71 (s; 1H; -NH; exchanges with D2O), 7.15-7.40 (m;

5H, Ph-H), 5.45 (s; 2H;

-CH2-) and 3.02 ppm (s; 3H;

-CH ₃ ). MS (70 eV): m / e = 312 (M ⁺ ). Production Example 16: 1-Benzyl-3-bromo-5-ethylamino

4-nitropyrazole

3.61 (10 mmol) l-benzyl-3,5-dibromo-4-nitropyrazole are heated in 120 ml of a 30 percent aqueous ethylamine solution at 60 ° C. for 1 hour. After cooling, the product separates in the form of colorless crystals with a melting point of 122 ° C. 2.88 g (89 percent of theory) of l-benzyl-3-bromo-5-ethylamino-4-nitropyrazole are obtained.

iH-NMR (300 MHz, DMS0-d6): = 7.15-7.41 (m; 6H; -NH and

Ph-H; 1H exchanges with D2O), 5.37 (s; 1H; -CH2-), 3.32-3.39 (m; 2H; -CH2-CH3) and 1.07-1.12 ppm (t; 3H ; - CH2-CH3).

MS (70 eV): m / e = 326 (M ⁺ )

Production Example 17: 1-Benzyl-3-bromo-5- (2'-hydroxyethyl) amino-4-nitropyrazole

3.61 g (10 mmol) of l-benzyl-3,5-dibromo-4-nitropyrazole are heated to 80 ° C. in 15 ml of ethanolamine for 2 hours. After cooling, the reaction mixture is poured onto 30 ml of water and the deposited precipitate is filtered off. After recrystallization from toluene once, 2.5 g (74 percent of theory) of l-benzyl-3-bromo-5- (2'-hydroxyethyl) amino-4-nitropyrazole are obtained in the form of pale yellow crystals with a melting point of 110 to 112 ° C. iH-NMR (300 MHz, DMSO-d6): = 7.54 (t; 1H; -NH; exchanges with D20), 7.15-7.40 (m; 5H; Ph-H), 5.44 (s; 2H; -CH2-Ph), 5.05 (t; 1H; -0H; exchanges with D2O) and 3.32-3.53 ppm (m; 4H; -CH2 ~ CH ₂ -).

MS (70 eV): m / e = 342 (M ⁺ ).

Production Example 18: 1-Benzyl-5-benzylamino-3-bromo

4-nitropyrazole

3.61 g (10 mmol) of l-benzyl-3,5-dibromo-4-nitropyrazole are heated in a solution of 3.6 g of benzylamine at 60 ° C. for 2 hours. After cooling, the reaction mixture is poured onto 20 ml of water and the deposited precipitate is filtered off. After single recrystallization from a ligroin / toluene mixture (1: 1), 2.6 g (68 percent of theory) of l-benzyl-5-benzylamino-3-bromo-4-nitropyrazole are obtained in the form of pale yellow crystals with a melting point of 103 ° C.

iH-NMR (300 MHz, DMSO-dß): = 8.04 (t; J = 6.1Hz; 1H; -NH; exchanges with D2O), 7.08- 7.47 (m; 10H; Ph- H), 5.24 (s; 2H; -CH2_-Ph) and 4.55 ppm (d; J = 6.1Hz; 2H; -NH-CH2-Ph; after D2θ exchange s).

MS (70 eV): m / e = 388 (M +) C) Preparation of 4,5-diaminopyrazole derivatives of the general formula (I)

a) General regulation, procedure (1):

An amount of a compound of the general formula given in the following preparation examples

(II) is dissolved in 130 ml of ethanol and transferred to an autoclave (250 ml). After the addition of 2 spatula tips (approx. 100 mg) of a palladium / activated carbon catalyst with a polladium content of 10 percent by weight, the mixture is stirred at room temperature at 50 bar hydrogen atmosphere for the period specified in the following production examples. The reaction mixture is then transferred into a glass flask by means of a water jet pump and the catalyst is immediately filtered off through a glass filter crucible. Then one adds to the filtrate an equimolar amount of sulfuric acid (97 percent) to the starting compound or the double molar amount of hydrochloric acid (36 percent).

b) General regulation, procedure (2):

(III) is in a hydrogenation flask with an equimolar amount of 97 percent sulfuric acid, 2 spatula tips palladium / activated carbon catalyst (10 percent by weight palladium) and the amount of water indicated at room temperature under hydrogen atmosphere (normal pressure) over the in the period specified in the following production examples. The course of the reaction is checked by means of thin layer chromatography. After the starting material has been completely converted, the react tion mixture filtered through a glass filter crucible. After the solvent has been distilled off, the product is crystallized from ethanol.

Production Example 19: 4-Amino-1-methyl-5-methylamino-pyrazole

0.5 g (2.13 mmol) of 3-bromo-l-methyl-5-methylamino-4-nitro-pyrazole are in a solution of 220 mg (2.13 mmol) of sulfuric acid in 20 ml of water, after adding the catalyst ¬ tors, hydrogenated for 14 hours as described in process (2). After filtering off the catalyst, the filtrate is concentrated to dryness and the residue is recrystallized from ethanol. 370 mg (78 percent of theory) of 4-amino-1-methyl-5-methylaminopyrazole hydrosulfate are obtained in the form of colorless crystals with a melting point of 185 to 188 ° C.

iH-NMR (60 MHz, DMSO-d6): = 8.53 (s; broad; 5H, -NH2;

-NH; H2SO4; exchangeable with D2O), 7.30 (s; 1H; Ring-H 3.58 (s; 3H; N-CH3) and 2.80 ppm (s; 3H; -NH-CH3).

MS (70 eV): m / e = 126 (M ⁺ ).

Preparation example 20: 4-amino-5- (2'-hydroxyethyl) amino-1-methylpyrazole

1 g (3.77 mmol) of 3-bromo-5- (2'-hydroxyethyl) amino-1-methyl-4-nitropyrazole are dissolved in a solution of 380 mg (3.77 mmol) of sulfuric acid in 50 ml of water 2 Hydrogenated for hours according to method (2). 720 mg (75 percent of theory) of 4-amino-5- (2'-hydroxyethyl) amino-l-me- thylpyrazole hydrosulfate in the form of colorless crystals with a melting point of 94 to 97 ° C.

iH-NMR (60 MHz, DMS0-d6): = 8.00 (s; broad; 6H; -NH2;

-NH, -0H, H2SO4, exchange

D2O off), 7.45 (s; 1H;

Ring-H), 3.60 (s; 3H;

-CH3) and 3.50-3.10 (m; 4H;

-CH2-CH2-) • MS (70 eV): m / e = 156 (M +).

Preparation 21: 4,5-diamino-l-methylpyrazole

a) 0.5 g (1.81 mmol) of 3-bromo-5-tert-butylamino-1-methyl-4-nitropyrazole are dissolved in a solution of 1.84 mg (1.81 mmol) of sulfuric acid in 20 ml Water, after addition of the catalyst, is hydrogenated for 48 hours after process (2). After distilling off the solvent to half the original amount and adding an equivalent amount of ethanol, 360 mg (87 percent of theory) of 4,5-diamino-l-methylpyrazole hydrosulfate hydrate are obtained in the form of white crystals with a Melting point from 200 to

201 ° C.

b) 0.5 g (1.61 mmol) of 5-benzylamino-3-bromo-l-methyl4-nitropyrazole are dissolved in a solution of 165 mg (161 mmol) of sulfuric acid in 20 ml of water, after adding the catalyst, 48 Hydrogenated for hours as described in process (2). The catalyst is then filtered off and the filtrate is concentrated to about 2 ml. After adding a little ethanol (approx. 2 ml), the product separates out in the form of white crystals. 330 mg (90 percent of theory) of 4,5-slide mino-1-methylpyrazole hydrosulfate hydrate in the form of white crystals with a melting point of 200 to 201 ° C.

Preparation 22: 4,5-diamino-l-ethylpyrazole

1.62 g (5.6 mmol) of 3-benzylamino-3-bromo-1-ethyl-4-nitrophyrazole are hydrogenated over a period of 2 hours according to procedure (1). After filtering off the catalyst, the product is precipitated as dihydrochloride by adding 1 ml (11.6 mmol) of concentrated hydrochloric acid (36 percent). 0.8 g (72 percent of theory) of 4,5-diamino-1-ethylpyrazole dihydrochloride are obtained in the form of colorless crystals with a melting point of 184 to 186 ° C.

iH-NMR (300 MHz, DMSO-d6): = 8.01 (s; broad; 6H; -NH2;

HC1; exchanges with D2O), 7.63 (s; 1H; Ring-H; 4.03 (q; J = 6.4 Hz; 2H; -CH2_- CH3) and 1.25 ppm (t; J = 6, 5 Hz; 3H; -CH2-CH3).

MS (70 eV): m / e = 126 (M ⁺ )

Preparation 23: 4,5-diamino-l-isopropylpyrazole

0.5 g (1.6 mmol) of 1-benzylamino-3-bromo-1-isopropyl-4-nitropyrazole are hydrogenated for 2 hours according to procedure (1). After filtering off the catalyst, the product is precipitated with 0.3 ml (3.5 mmol) of concentrated hydrochloric acid as dihydrochloride. 0.25 g (73 percent of theory) of 4,5-diamino-l-isopropylpyrazole dihydrochloride are obtained in the form of colorless crystals with a melting point of 164 ° C. iH-NMR (300 MHz, DMSO-d6): = 7.90 (s; broad; 6H; -NH2;

HC1; exchanges with D2O),

7.51 (s; 1H; Ring-H), 4.54 (; 1H; -CH (CH3) 2) and 1.30 ppm (d; 6H-CH (CH3) 2) •

MS (70 eV): m / e = 140 (M ⁺ )

Production Example 24: 4-amino-1- (2'-hydroxyethyl) -5-

(2'-hydroxyethyl) aminopyrazole

0.8 g (2.7 mmol) of 3-bromo-1- (2'-hydroxyethyl) -5- (2'-hydroxyethyl) amino-4-nitropyrazole are hydrogenated for 4 hours according to procedure (1). After filtering off the catalyst, 0.27 g (2.7 mmol) of sulfuric acid (97 percent) is added. After cooling to - 30 ^C C to obtain 630 mg (82 percent of theory) of 4-amino-l- (2'-hydroxyethyl) -5- (2'-hydroxyethyl) aminopyrazole hydrosulfate farb¬ in the form of a white crystal having a melting point from 140 to 142 ° C.

iH-NMR (60 MHz, DMSO-d6): = 10.18 (s; broad; 7H; -NH;

-NH2; -OH; H2SO4; interchangeable with D2O), 7.37 (s; 1H; Ring-H), 4.00 (m; 2H; -CH2-), 3.53

(m; broad; 4H; -CH2-) and 3.13 ppm (m; 2H; -CH2-).

MS (70 eV): m / e = 186 (M ⁺ ). Preparation 25: 4-amino-1- (2'-hydroxyethyl) -5-methylaminopyrazole

2.65 g (10 mmol) of 3-bromo-1- (2'-hydroxyethyl) -5-methylamino-4-nitropyrazole are hydrogenated for 4 hours according to procedure (1). After adding 1 g (10 mmol) of sulfuric acid and 10 ml of isopropanol, the product separates. 1 g (40 percent of theory) of 4-amino-l- (2'-hydroxyethyl) -5-methylaminopyrazole hydrosulfate are obtained in the form of colorless crystals with a melting point of 138 to 140 ° C.

iH-NMR (300 MHz, DMSO-d6): = 9.6 (s; 2H; -NH2, exchanges with D2θ), 7.38 (s; 1H; Ring-H), 6.35 (s; 2H ; -NH and -OH; exchanges with D2O), 3.96 (t; J = 5.8 Hz; 2H; -CH2-CH2), 3.65 (t; J = 5.7 Hz; 2H; - CH2-CH2-) and

2.80 ppm (s; 3H; -NH-CH3)

MS (70 eV): m / e = 156 (M ⁺ )

Preparation Example 26: 4,5-diamino-1- (2'-hydroxyethyl) pyrazole

1.7 g (5 mmol) of 5-benzylamino-3-bromo-1- (2'-hydroxyethyl) -4-nitropyrazole are hydrogenated for 4 hours according to procedure (1). After addition of 0.5 g (5 mmol) of sulfuric acid, 0.8 g (62 percent of theory) of 4,5-diamino-l- (2'-hydroxyethyl) pyrazole hydrosulfate hydrate are obtained in the form of colorless crystals with a melting point from 158 to 160 ° C. Preparation 27: 4-amino- (3) 5-methylaminopyrazole

1 g (2.9 mmol) of l-benzyl-3-bromo-5-methylamino-4-nitrophyrazole are dissolved in a solution of 0.29 g (2.9 mmol) of sulfuric acid in 50 ml of water according to regulation (2) hydrogenated over a period of 8 hours. After filtering off the catalyst and adding 50 ml of ethanol, the filtrate is concentrated to 30 ml and cooled to -30 ° C. 244 mg (40% of theory) of 4-amino- (3) 5-methylaminopyrazole hydrosulfate are obtained in the form of colorless crystals with a melting point of 182 ° C.

iH-NMR (60 MHz, DMS0-d6): = 10.10-9.20 (m; 6H; NH; -NH2;

H2SO4; interchangeable with D2θ); 7.95 (s; 1H; Ring-H) and

2.85 ppm (s; 3H; -CH3). MS (70 eV): m / e = 112 (M +).

Preparation 28: 4-amino- (3) 5-ethylaminopyrazole

0.5 g (1.31 mmol) of l-benzyl-3-bromo-5-ethylamino-4-nitrophyrazole are dissolved in a solution of 130 mg (1.31 mmol) of sulfuric acid in 50 ml of water according to regulation (2) hydrogenated over a period of 8 hours. After filtering

of the catalyst, the filtrate is concentrated to 10 ml. Then 10 ml of ethanol are added, whereupon the product crystallizes out in the form of colorless crystals with a melting point of 188 ° C. 0.1 g (34 percent of theory) of 4-amino- (3) 5-ethylaminopyrazole hydrosulfate is obtained.

iH-NMR (300 MHz, DMSO-d6): = 8.53 (s; broad; 6H; -NH;

-NH2; H2SO4; exchanges with D2O), 7.78 (s; 1H; Ring-H); 3.21 (q; J = 7.1 Hz; 2H; -CH2-CH3) and 1.18 ppm (t; J = 7.1 Hz; 3H; -CH2-CH3).

MS (70 eV): m / e = 126 (M +).

Preparation 29: 4-amino- (3) 5- (2'-hydroxyethyl) aminopyrazole

1 g (2.9 mmol) of l-benzyl-3-bromo-5- (2 '-hydroxyethyl) amino-4-nitropyrazole are dissolved in a solution of 0.29 g (2.9 mmol) of sulfuric acid and 50 ml of water hydrogenated for a period of 3 hours according to regulation (2). After filtering off the catalyst, the solvent is distilled off in vacuo. The product which crystallizes out is washed with a little (20 ml) of ethanol and then dried. 240 mg (35 percent of theory) of 4-amino- (3) 5- (2'-hydroxyethyl) aminopyrazole hydrosulfate are obtained in the form of colorless crystals with a melting point of 185 ° C. iH-NMR (60 MHz, DMSO-d6): = 8.35 (s; broad; 6H; -NH;

-NH2; -OH; H2SO4, exchangeable with D2O), 7.58 (s; 1H; Ring-H); 3.55 (m, 2H; -CH2-OH) and 3.15 ppm (m; 2H; -NH-CH2-).

MS (70 eV): m / e = 142 (M ⁺ )

Preparation 30: 4, (3) 5-diaminopyrazole

1 g (2.4 mmol) of l-benzyl-5-benzylamino-3-bromo-4-nitrophyrazole are dissolved in a solution of 0.25 g (2.4 mmol) of sulfuric acid and 50 ml of water over a period of 4 Hours hydrogenated according to regulation (2). After filtering off the catalyst, 50 ml of ethanol are added to the filtrate and the mixture is cooled to −30 ° C. 184 mg (39 percent of theory) of 4, (3) 5-diaminopyrazole hydrosulfate are obtained in the form of colorless crystals with a melting point of 240 ° C. (decomposition).

Example of use:

6.35 g of 4-amino-1- (2'-hydroxyethyl) -5-methylamino-pyrazole 2.73 g of 3-aminophenol 10.00 g of lauryl alcohol diglycol ether sulfate sodium salt

(28 percent aqueous solution) 10.00 g ammonia (22 percent aqueous solution)

100.00 g 50 g of the above hair dye are mixed with 50 g of hydrogen peroxide solution (6 percent) immediately before use. The mixture is then applied to blonde natural hair and left to act at a temperature of 40 ° C for 30 minutes. The hair is then rinsed with water and dried. The hair is colored in a fashionable purple tone.

Claims

1) Process for the preparation of 4,5-diaminopyrazole derivatives of the general formula (I)

i

(A) 3,5-dibromo-4-nitropyrazole with a Ci to Cβ-alkyl, C2 to C4-hydroxyalkyl or benzyl halide or a Cid ~ to Cß-alkyl, C2 to C4-hydroxyalkyl or benzyl sulfate to compounds of the general formula (II)

in which R3 is a Ci to C6 alkyl radical, a C2 to C4 hydroxyalkyl radical or a benzyl radical,

(B) the compounds of the general formula (II) with Ci- to Cö-alkyl-, C2- to C4-hydroxyalkyl- or benzylamine to give compounds of the general formula (III)

I

R ₃

in which R3 and R4 independently of one another are a C 1 -C 6 -alkyl radical, a C 2 -C 4 -hydroxyalkyl radical or a benzyl radical, substituted in the 5-position and then

(C) the compounds of the general formula (III) are reduced to the compounds of the general formula (I) by catalytic hydrogenation.

2) compounds of the general formula (II)

in which R3 is a Ci- to Cδ-alkyl radical, a C2- to C4-hydroxyalkyl radical or a benzyl radical.

3) 3,5-dibromo-l-methyl-4-nitropyrazole.

4) 3,5-dibromo-1-ethyl-4-nitropyrazole.

5) 3,5-dibromo-l-isopropyl-4-nitropyrazole.

6) 3,5-dibromo-1- (2'-hydroxyethyl) -4-nitropyrazole.

7) l-Benzyl-3,5-dibromo-4-nitropyrazole.

8) Compounds of the general formula (III)

I

R ₃ in which R3 and R4 independently of one another are a C 1 -C 6 -alkyl radical, C2- to C4-hydroxyalkyl radical or a benzyl radical.

) 3-bromo-l-methyl-5-methylamino-4-nitropyrazole.

3-bromo-5- (2'-hydroxyethyl) amino-l-methyl-4-nitrophyrazole.

1 3-bromo-5-tertiarybutylamino-l-methyl-4-nitropyrazole.

5-benzylamino-3-bromo-1-methyl-4-nitropyrazole.

5-benzylamino-3-bromo-1-ethyl-4-nitropyrazole.

5-benzylamino-3-bromo-l-isopropyl-4-nitropyrazole.

3-bromo-1- (2'-hydroxyethyl) -5- (2'-hydroxyethyl) amino-4-nitropyrazole.

3-bromo-1- (2'-hydroxyethyl) -5-methylamino-4-nitro-pyrazole.

5-benzylamino-3-bromo-1- (2'-hydroxyethyl) -4-nitro-pyrazole

l-benzyl-3-bromo-5-methylamino-4-nitropyrazole.

l-benzyl-3-bromo-5-ethylamino-4-nitropyrazole.

l-benzyl-3-bromo-5- (2'-hydroxyethyl) amino-4-nitro-pyrazole.

l-benzyl-5-benzylamino-3-bromo-4-nitropyrazole. 22) Compounds of the general formula (V)

in which R _a and Rb denote hydrogen, a C 1 -C 6 -alkyl radical or a C 2 -C 4 -hydroxyalkyl radical, with the proviso that when R _{b is} hydrogen, R _{a is} not hydrogen, methyl or 2-hydroxy- is ethyl.

23) 4-Amino-1-methyl-5-methylaminopyrazole.

24) 4-Amino-5- (2'-hydroxyethyl) amino-1-methylpyrazole.

25) 4,5-diamino-1-ethylpyrazole.

26) 4,5-diamino-l-isopropylpyrazole.

27) 4-Amino-1- (2'-hydroxyethyl) -5- (2'-hydroxyethyl) aminopyrazole.

28) 4-Amino-1- (2'-hydroxyethyl) -5-methylaminopyrazole.

29) 4-Amino- (3) 5-methylaminopyrazole. 30) 4-Amino- (3) 5-ethylaminopyrazole.

31) 4-amino- (3) 5- (2'-hydroxyethyl) aminopyrazole.

32) Use of a compound of the general formula (V) as a dye precursor in oxidation hair dye.