DE1274584B - Process for the preparation of 3-amino-pyrazole derivatives substituted in the 2-position - Google Patents

Description

Process for the preparation of 3-amino-pyrazole derivatives substituted in the 2-position The invention relates to a process for the preparation of 3-amino-pyrazole derivatives of the general formula (I) in which R1 is an alkyl or cycloalkyl radical and R2 is a hydrogen atom or an arylsulfonyl radical means.

Processes are known which can be used to obtain 2-substituted 3-amino-pyrazoles, but which contain further substituents either in the 4-position or in the 5-position. These processes use a-cyano-carbonyl compounds or their derivatives (II a, II b, III a, III b) or allene cyanide (IV) and monosubstituted hydrazines R'NHNH2 as starting materials. It is known (Austrian patent 575; German patent 1 070 635; J. org. Chem., 21, 1240 [1956J; Helv. Chim. Acta, 39, 986 [1956]; 42, 763 [1959]), Va: R "'= COi2CzH5, R" = H Vd: R "' = H; R" = CH3 Vb: R "'= CN, R" = H Ve: R "' = H, R" = OCH3 Vc: R "'= COOH, R" = H Vf: R "' = H, R" = CH3 2-substituted 3-amino-pyrazoles, which are substituted in the 4-position (Va and Vb), from ethoxymethylene cyanoacetic ester (via) or Ethoxymethylene malonitrile (alb) to produce. The synthesis of 2-phenyl-3-amino-5-methyl-pyrazole (Vd, R '= C6H5) from cyanoacetone (IIIb) and phenylhydrazine (Gaz. Chim. Ital., 80, 303 [1950]) is also known , furthermore the production of 2-phenyl-3-amino-5-methoxy-pyrazole (Ve, R '= CsH5) (German patent specification 1 120 453) as a valuable intermediate which is derived from cyanoacetic acid-phenylhydrazide (according to formula III a ) is obtained in the presence of methanol and acid. A process for the preparation of substituted 3-amino-pyrazoles of type Vf, which are substituted in the 2- and 5-positions and are used as intermediates for the preparation of pharmaceuticals and dyes, is also protected (German Patent 1,093,369). The last-mentioned process is based on allene cyanide (IV) or its homologues and monosubstituted hydrazines R'NHNH2.

All of the above-mentioned, previously known methods have in common that the production of their starting products (via, II b, 111 a, III b or IV) is expensive is and that to convert them into the 3-amino-pyrazole derivatives (V) monosubstituted Hydrazine R'NHNH2 are required. Of the latter, only those with R '= aryl are relative easily accessible without any special technical effort. However, these lead to 2-aryl-substituted 3-amino-pyrazoles, which are not the subject of the present invention are.

It is possible in principle. of substituted in the 4-position 3-Amino-pyrazole derivatives Va or Vb to get to 2-substituted 3-Amino-Pyrazoles. by first converting Va or Vb to Vc and decarboxylating Vc. There are up Only two examples have now become known in which use of this possibility is made, namely the production of 2- (p'-hydroxyethyl) -3-amino-pyrazole by CO. Splitting off from 2- (1; -hydroxyethyl) -3-amino-pyrazolecarboxylic acid- (4) (German Patent specification 1111 640) (Vc. R '= CH2CH2OH) at 160 to 170 C and the production of 3-amino-pyrazole by splitting off CO2 from 3-amino-pyrazole-carboxylic acid- (4) (Vc, R '= H) at 140 to 150 C.

This procedure is very complex, even on a laboratory scale for the industrial production of larger quantities of 2-substituted 3-amino-pyrazoles not usable.

Another process for the preparation of 2-aryl-substituted 3-amino-pyrazoles, which differs greatly from the one listed above, is also known (German patent 1,065,850). According to this, hT-Ar-l-N '- (,; - c-anoethyl) hydrazines (VI) are initially mixed with peracids in the presence of such acids. Hydrogen peroxide or iron (III) salts are oxidized and then cyclized under alkaline conditions to form 2-aryl-3-aminopyrazoles (VII). H2C CH2 a) Oxidation N - C NH b) Cyclization H2N HN7 Aryl aryl (Vl) (VII) This process can only be used for the production of the'-aryl-3-aminopyrazoles but not for the production of the 3-aminopyrazole derivatives of the general formula (I).

It is also known that pyrazolines are sulfonylated and subsequent cleavage of sulfinate can be converted into pyrazoles. So leads the p-toluenesulfonation of pyrazolines which are unsubstituted or monosubstituted in the 5-position, z. B. of 2-pyrazoline-3, 4-dicarboxylic acid methyl ester, to the corresponding N-p-toluenesulfonylpyrazolines, their treatment with bases in organic solvents to split off p-toluenesulfinic acid Salt and pyrazole formation leads (Tetrahedron Letters, 1963, 25 pp. 1665 and 1666). This manufacturing method is limited to compounds in which the one from the carbon atom 3 hydrogen to be split off by electron-withdrawing substituents, e.g. B. a Phenyl radical or a carbonyl group. is relaxed. whereby the sulfinate cleavage is facilitated. A disadvantage of the method is that working with Bases in organic solvents. z. B. with potassium hydroxide in Glykol.technisch right is expensive.

It is also known. that a sulfonylated 3 (5) -amino-pyrazole, starting from an aminopyrazoline. by sulfonylation and subsequent treatment was made with caustic soda. The sulfonylation of l-phenyl-5-aminopyrazoline gave a reaction product of unknown structure, from which 1-phenyl-5-p-aminobenzenesulfonamido-pyrazole with 7N NaOH originated. This reaction has the disadvantage. that in addition to the reaction with NaOH the said pyrazole derivative 15 to 90f'l "of a sulfamide by a partially Cleavage of the 3 (5) -amino group can be formed. d. h .. it is not unambiguous. but delivers a mixture. Among other things, this means a significant reduction in yield (Helv. Chim. Acta. 41. p. 306 [1958]).

The invention is based on the object. a technically feasible one To find a process for the preparation of 3-amino-pyrazole derivatives. those in 9 position are substituted by alkyl or cycloalkyl radicals.

The starting material used for the preparation of these new 3-amino-pyrazole derivatives is 3-amino-13-pyrazoline (VIII), which is very easily accessible from acrylonitrile and hydrazine in water (cf. British patent specification 679 678). It was found unexpectedly. that under the conditions described below, two of the 4 5 a) + aryl - SO - halog. H2N ß tN H b) + R1X H N'SQ2Aryi HX H MM R1 (IX) (VIII) ¼ - Aryl SO2H | + Aryl - SO - analog. ¼ R '-Ni - ~ Arvl - SO2H j / R2 - ND Aryl-SO Aryl - SO2 - N lx N - SOr - Aryl H R 'Rl (I) (X) A total of four reactive hydrogen atoms of (VIII) located on the nitrogen atoms can be selectively substituted, namely the hydrogen atom on the 1-ring nitrogen atom of (VIII) by an arylsulfonyl radical and the hydrogen atom on the 2-ring nitrogen atom of (VIII) by an alkyl or cycloalkyl radical. The conversion of a molar amount of 3-amino-13-pyrazoline (VIII) and an aryl sulfochloride, aryl - SO2Cl, in water with the addition of a hydrogen halide binding agent. preferably of an alkali hydrogen carbonate, monoarylsulfonylation product of (VIII) obtained in excellent yield on the action of alkylating agents gives R1X, preferably of esters of sulfuric acid or p-toluenesulfonic acid, in which R 'has the same meaning as in the general formula (I), in excellent Yield the previously unknown crystalline salts of 2-alkyl or. cycloalkyl-substituted 1-mononrylsulfonylated 3-amino-pyrazoline.

To obtain the salts (IX) it is expedient to proceed in this way. that he the monoarylsulfonylation product of (VIII) in a solvent such as e.g. B.

Acetone. Methyl ethyl ketone. Dioxane. Acetonitrile, preferably in dimethylformamide or dimethyl sulfoxide. with the molar amount of the alkylating agent R'X to react brings. The formation of (IX) already takes place at room temperature, but is through Warmed up to 60 to 90 - C significantly accelerated so that they then already. dependent on of Rl, after 30 minutes to 3 hours has ended. The salts (IX) precipitate or are made from solvents. in which they are soluble at room temperature, e.g. B. off Dimethylformamide, with a solvent. in which they are difficult to dissolve. preferably with a hydrocarbon or ether. failed.

The surprising finding was also made. that the Salts (IX) with alkalis in excellent yield to give 2-substituted 3-amino-pyr- azoles of the general formula (I) (R1 = alkyl or cycloalkyl, R2 = H) and sulfinate can be split are.

This is very surprising insofar as it is the case with the previously known Sulfinate cleavages from pyrazolines are compounds whose cleavable Hydrogen is loosened by electron-attracting substituents or by a phenyl substituent in the 1-position shows considerable differences in reactivity demonstrate. The simplest procedure is to use the aqueous solution of the salts (IX) a short time with a small excess of alkali or alkaline earth metal hydroxide or Heated alkali carbonate and the 2-substituted 3-amino-pyrazoles obtained in this way Distilling off the water extracted with an organic solvent, such as. B. with methylene chloride, preferably with tetrahydrofuran or isopropanol.

Another surprisingly simple embodiment of the cleavage the salts (IX) consists in that their aqueous solution with a basic exchanger heated, and after a short time an aqueous solution of the 2-substituted 3-amino-pyrazoles and the sulfinic acid is bound to the exchanger.

The cleavage of the salts (IX) described in the previous section can also be applied to their derivatives. So deliver z. B. the in surprising easily accessible from the salts (IX) and aryl sulfohalides, so far unknown bisarylsulfonylated compounds (X) with alkalis with cleavage from 1 mole of sulfinate in excellent yield the new 3-amino-pyrazole derivatives of the general formula (I) (R '= alkyl or cycloalkyl, R- = arylsulfonyl).

Those which are technically easily accessible by means of the method according to the invention 3-Amino-pyrazole derivatives are valuable intermediates for pharmaceuticals and dyes. The following examples illustrate the invention.

Example 1 a) I- (p-Toluenesulfonyl) -2-methyl-3-amino-13-pyrazoline tosylate 26.4 g of sodium bicarbonate are added to a solution of 15.8 g of 3-amino-13-pyrazoline dihydrochloride in 200 ml of water and 20.9 g of p-toluenesulfochloride in 50 ml of benzene and the mixture is stirred rapidly at room temperature for 2 hours. The precipitated monosulfonylation product is then filtered off with suction and washed with water and ether or benzene or methylene chloride. The monosulfonylation product obtained (23.5 g = 98.4 "" of theory, melting point 186 to 187 ° C.) is heated to 85 ° C. in 50 ml of dimethylformamide or dimethyl sulfoxide and 18.6 g of methyl p-toluenesulfonate are slowly added with stirring and the mixture is stirred at 85 ° C. for 1 hour. After cooling, 200 ml of benzene are added. The precipitated UI crystallizes spontaneously after rubbing. It is filtered off with suction and washed with a little acetone. about 80 "" yield. M.p. (n-propanol) 906.5 to 207.5 C. b) 2-methyl-3-aminopyrazole 0.2 mol of the salt obtained according to a) are heated to 90 to 100 ° C. with 16 g of sodium hydroxide (0.4 mol) in 50 ml of water for 5 minutes. From the clear solution obtained, the 0.2 mol of 2-methyl-3-aminopyrazole. 0.2 mol of the sodium salt of p-toluenesulfinic acid and 0.2 mol of the sodium salt of p-toluenesulfonic acid, the water is distilled off under reduced pressure. The 2-methyl-3-aminopyrazole is made from the residue with an alcohol or ether. preferably washed out with isopropanol or tetrahydrofuran. The 2-methyl-3-amino-pyrazole solution can optionally be lightened with activated charcoal. After distilling off the solvent, the 2-methyl-3-aminopyrazole is obtained as a viscous, yellowish U1, which still contains traces of sodium p-toluenesulfinate and sodium p-toluenesulfonate, which can be obtained by redissolving, preferably in isopropanol, suctioning off and concentrating of the filtrate can be easily removed. In this way, an already very pure 2-methyl-3-aminopyrazole is obtained in quantitative yield, which crystallizes after inoculation. It can be purified again by distillation: bp 72 to 73 ° C.

Example 2 a) 1- (p-Toluenesulfonyl) -2-methyl-3-aminod 3-pyrazoline methyl sulfate 35.3 g of triethylamine are added dropwise to 15.8 g of 3-amino-III-pyrazoline dihydrochloride and 28.5 g of p-toluenesulphochloride in 150 ml of methylene chloride with stirring at 5 to 10 ° C. and the mixture is stirred at room temperature for 20 hours. The precipitated monosulfonylation product (19.5 g = 81.5010 of theory) is filtered off with suction, washed with water and methylene chloride, mixed with 10.3 g of dimethyl sulfate in 60 ml of dimethylformamide and left to stand for 6 days at room temperature. It is then diluted with benzene and the precipitated oil is made to crystallize by grinding. Yield about 500/0 of theory, after recrystallization from ethanol, mp.

151 to 152 "C. b) 2-methyl-3-aminopyrazole 0.1 mol of that obtained according to a) Salt, 100 ml of water or 100 ml of an alcohol, e.g. B. n-propanol, and 300ml of one basic exchanger are heated to boiling for 3 hours, then the exchanger sucked off, washed out with water or alcohol and the resulting aqueous or alcoholic Solution of 2-methyl-3-aminopyrazole concentrated under reduced pressure. You get 2-methyl-3-aminopyrazole in quantitative yield. The split creates pro Mole of 2-methyl-3-aminopyrazole, 1 mole of p-toluenesulfinic acid and 1 mole of methylsulfuric acid (HSO30CH3), which are bound to the exchanger and from this with z. B. 2 N sodium hydroxide solution can be eluted.

Example 3 a) 1 - (p-Chlorobenzenesulfonyl) -2-methyl-3-amino-3-pyrazoline tosylate 15.8 g of 3-amino-23-pyrazoline dihydrochloride are, as described in Example 1 a), reacted with 23.2 g of p-chlorobenzenesulphonyl chloride. The monosulfonylation product obtained (23.6 g = 910/0 of theory, melting point 171 to 172 "C) is left to stand with 17 g of ethyl p-toluenesulfonate in 70 ml of dimethylformamide for 6 days at room temperature or 1 hour at 70 to 90" C. It is then diluted with ether, the precipitated U1 crystallized, filtered off with suction and washed with acetone, yield 70 to 800/0 of theory, melting point (n-propanol) 200 to 201 "C. b) 2-methyl-3-amino pyrazole The tosylate obtained according to 3 a) is converted into 2-methyl-3-aminopyrazole analogously to Example 1 b) a) 1-benzenesulfonyl-2-methyl-3-aminoa 13-pyrazoline tosylate 15.8 g of 3-amino-S3-pyrazoline dihydrochloride are, as described in Example 1 a), - reacted with 18.6 g of benzenesulphonyl chloride. The monosulfonylation product obtained (19.1 g = 850/0 of theory, melting point 167 to 168 "C) is, as described in Example 3a), reacted with methyl p-toluenesulfonate and precipitated. Yield 70 to 800/0 of theory, Melting point (n-propanol) 188.5 to 1900 ° C. b) The tosylate obtained in accordance with 4 a) is converted into 2-methyl-3-aminopyrazole analogously to Example 1 b).

Example 5 a) 1- (p-Toluenesulfonyl) -2-ethyl-3-amino-13-pyrazoline tosylate 23.9 g of 1- (p-toluenesulfonyl) -3-amino- 13-pyrazoline (obtained by reacting 3-amino-13-pyrazoline dihydrochloride with p-toluenesulfonyl chloride as described in Examples 1 a) and 2 a)) are brought to 85 ° C. in 50 ml of dimethylformamide, 20.1 g of ethyl p-toluenesulfonate are slowly added with stirring, the mixture is stirred for 3 hours at 85 ° C. and, after cooling, diluted with ether. The precipitated Ul crystallizes after standing for a short time. It is filtered off with suction and washed with a little acetone. Yield 60 to 70% of theory, after recrystallization from ethanol, melting point 176 to 177 "C. b) 2-ethyl-3-aminopyrazole 87.8 g (0 'mol) of the tosylate obtained according to a) are heated with 16 g (0.4 mol) of sodium hydroxide and 50 ml of water at 90 to 100 ° C. for 5 minutes and the clear solution obtained is as in Example 1 b ) described, worked up further. The crude, already very pure -ethyl-3-amino-pyrazole is obtained as a yellowish, viscous UI in quantitative yield. It can be distilled for renewed purification. Bp 0.01 92 to 94 "C.

One can also proceed in such a way that 43.9 g of that obtained according to a) are obtained Tosylates, 100 ml water or

100 ml of an alcohol, e.g. B. n-propanol, and 300 ml of a basic Heat exchanger to 90 to 100 C for 3 hours. It will continue as in the example 2 b) described, proceed. It becomes very pure 2-ethyl-3-aminopyrazole in quantitative terms Yield obtained.

Example 6 a) 1 - (p-Tol 3 ol sulfon yl-zmethyl-3- (p-tol uolsulfonamido) - 13-pyrazoline 21.2 g of the 1- (p-toluenesulfonyl) -2-methyl-3-amino-13-pyrazoline tosylate obtained according to Example 1 a) are mixed with 10.4 g of p-toluenesulfonyl chloride and 9 g of pyridine in 100 ml of methylene chloride 8 Reacted for hours at room temperature with stirring, the methylene chloride is distilled off, the residue is mixed with methanol and the disulfonyl compound which crystallizes out after a short time is filtered off with suction. You can also proceed in such a way that '1.2 g of the 1 - (p-toluenesullonyl) -2-methyl-3-amino-1³-pyrazoline tosylate obtained according to Example 1 a) in 100 ml of water with 10.4 g p-toluenesulfochloride and 55 ml of 2N sodium hydroxide solution for 3 hours at room temperature while stirring. The 2N sodium hydroxide solution is added dropwise in this way. that a pH of 7 to 7.5 is always maintained. The crystalline 1- (p-toluene sulphonyl) -2-1lietllvl-3- 1} l-toluenesulfotlamido) - I: s-pyl azole obtained in this way is filtered off with suction and washed with water and ether or benzene or gasoline. Bulging 90 to 96% of theory, after recrystallization from n-propanol, melting point 189 to 190.degree.

The following were prepared analogously: 1- (p-Toluenesulfonyl) -2-methyl-3-benzenesulfonamido- 13-pyrazoline (m.p. 138-140 "C).

1- (p-Toluenesulfonyl) -2-methyl- (p-chlorobenzenesulfonamido) - 13-pyrazoline (melting point 200 to 701 "C), 1 - (p-toluenesulfonyl) -2-methyl-3- (p- acetylaminobenzenesulfonamido) - 13-pyrazoline (mp. 108 to 1103C 1 - (p-toluenesulfonyl) -2-ethyl-3- (p-acetylaminobenzenesulfonamido) - 13-pyrazoline (mp. 163 to 165'C). b) 2-methyl -3- (p-toluenesulfonamido) pyrazole 10.2 g of the 1- (p-toluenesulfonyl) -2-methyl-3- (p-toluenesulfonamido) - 13-pyrazoline obtained in accordance with a) are refluxed for a few minutes with 30 ml of 2N sodium hydroxide solution. 15 ml of 4N hydrochloric acid are then added, and the precipitated 2-methyl-3- (p-toluenesulfonamido) pyrazole is filtered off with suction and washed with water, yield about 85 to 95% of theory, after recrystallization from ethanol, melting point 151. 5 to 152.5-C.

The following are prepared in the same way: 2-methyl-3-benzenesulfonamido-pyrazole (melting point. 165 to 1665C), 2-methyl-3- (p-amino-benzenesulfonamido) -pyrazole (melting point 172 to 173 ° C), 2-methyl-3- (p-chlorobenzenesulfonamido) pyrazole (melting point 167 to 168 ° C.), 2-ethyl-3- (p-aminobenzenesulfonamido) pyrazole (M.p. 196 to 198GC).

Claims (1)

Claim: Process for the preparation of 3-amino-pyrazole derivatives of the general formula (I) substituted in the 2-position where Rl is an alkyl or cycloalkyl radical and RS is a hydrogen atom or an optionally substituted arylsulfonyl radical, characterized in that 3-amino-13-pyrazoline is mixed in an organic solvent and / or water with an optionally substituted arylsulfohalide with the addition of a hydrogen halide-hindering component , preferably an alkali metal hydrogen carbonate, is converted into the corresponding Nl-arylsulfonyl derivative, this with an alkylating agent providing the radical R 'in a solvent, preferably in dimethylformamide or dimethylsulfoxide, to a salt of a 2-alkyl- or cycloalkyl-substituted-1-arylsulfonylated 3-amino -13-pyrazoline can react and - if R2 denotes a hydrogen atom - this salt as such or - if R2 denotes an optionally substituted arylsulfonyl radical - according to its with the molar amount of an optionally substituted arylsulfohalide with the addition of a hydrogen halide bond the means, preferably in water at pH 7, arylsulfonylation on the exocyclic nitrogen atom with a slight excess of alkali or alkaline earth metal hydroxide or of alkali metal carbonate or with a basic exchanger by heating in a 3-aminopyrazole derivative of the general Formula (I) and 1 mole of sulfinate splits. ~~~~~~~~ Considered publications: Angew. Chem., 73: 560-570 (1961); Tetrahedron Letters, 1963, 25, pp. 1665 and 1666; Helv. Chim. Acta, 41 (1958), pp. 306-309.