DD228248A1 - PROCESS FOR SYNTHESIS OF PYRAZOLES - Google Patents

Abstract

The invention relates to a process for the preparation of substituted pyrazoles. The title compounds can be used as drugs with spasmolytic activity and can be used as organic intermediates. According to the invention, they can be prepared in good yields from 1,3,4-thiadiazines or 1,3,4-seleno-diazines substituted in the 6-position by heating in organic solvents in the presence of triphenylphosphine or triethylphosphite.

Description

-Λ-

a) Title of the invention

Process for the synthesis of pyrazoles

b) Field of application of the invention

The invention relates to a process for the preparation of substituted pyrazoles which are of interest with regard to spasmolytic properties and as organic intermediates.

c) Characteristics: known technical solutions It is known that 3-amino-pyrazoles are obtained from acylacetonitriles and hydrazines (0 · Seidel, J. prakt. Chem. [2] 5§, (1898) 129, C. Alberti, Gazz Chim. Ital. 82, (1959) 1017). 3-Alkylamino- or 3-aryl-amino-5-phenyl-pyrazoles are obtained from .beta.-morpholinothiozimic acid-1-alkyl (aryl) -amides and hydrazines (H. Beyer, H. Honeck and R. Reichelt, Liebigs Ann. Chem · 741 (1970) 45 »S. Hünig and K. Huebner, Chem. Ber. 95 (1962) 937) · H. Beyer et al. and J. Sandström independently observed a ring narrowing of 6H-1,3> 4-thiadiazines to pyrazoles proceeding under the deposition of elemental sulfur (H. Beyer and G. Wolter, Chem. Ber. 82 (1956) 1652; J. Sandström, Ark. Eemi 8 (1956) 523). These desulfurization reactions of 1,3, .4-thiadiazines can be carried out in the presence of acids, such. B. by heating in glacial acetic acid in ethanolic hydrochloric acid or conc. Hydrochloric acid or hydrobromic acid (see H. Beyer, Z. Chem., 9 (1969) 361; WD Pfeiffer,

E. DiIk and E. Bulka, Wiss. Journal of Serious

Moritz-Arndt University XXVII (1978) 135 and literature cited therein). But also with bases such as sodium ethanolate (WD Pfeiffer, E, DiIk and E. Bulka, Synthesis 1977 196), sodium hydroxide (WD-Pfeiffer and E. Bulka, DDE patent WP 0 07 D / 244 624/7)> Butyllithium (ER Schmidt and E. Hutht Tetrahedron Letters London 1975 "33; WD Pfeiffer, K. Geisler, H. Rossberg and E. Bulks, Z. Chem. 22 (1982) 137) converted 1,3,4-thiadiazines into pyrazoles. The action of thiophilic phosphorus compounds on unsubstituted in 6-i position 1,3,4-thiadiazines to obtain a reaction mixture of S-free pyrazoles and 3-mercaptopyrazoles, which partially or completely to Dipyrazolyl- (4,4 ») - < 3isalfides are oxidized (WiD Pfeiffer and E. Bulka, Synthesis 1977 485). In this synthesis method, however, the isolation of the S-free pyrazoles by the lifting products formed is made difficult ·

d) Object of the invention

The invention has the goal of a new process for the preparation of 3-amino, 3-hydrazino, 3-alkyl (aryl) amino, 3-aryl and 3-alkyl-pyrazoles from 1,3,4-thiadiazines and 1> 3 »4- ~ to develop selenadiazines, in which no side reactions occur.

e) DESCRIPTION OF THE NATURE AND THE FEATURES OF THE INVENTION According to the invention, pyrazoles of the general formulas are represented,

where R is an aryl, benzyl, amino, hydrazino, alkyl

2 amino, arylamino, dialkylamino or acylamino group R and R ^ an aryl radical or a lower linear or

branched alkyl group and R is a lower straight-chain or branched AlkyIrest by 6-substituted-6H-1,3,4-thiadiazines or 6H-1,3,4-selenadiazines in polar or nonpolar organic solvents in the presence of triphenylphosphine or Triethyl phosphite to temperatures of 50 - 160 ⁰ C heated.

f) embodiments

Example 1;

3-methylamino-4,5-diphenyl-pyrazole

2.81 g (10 mmol) of 2-methylamino-5,6-diphenyl-6H-1,3,4-thiadiazine and 2.62 g (10 mmol) of triphenylphosphine are refluxed in 60 ml of n-butanol for 3 hours heated. Upon cooling, triphenylphosphine separates out, which is filtered off and recrystallized from: ethanol, mp 160.5 ° C. The filtrate of the reaction is mixed with 1 ml of conc. Hydrochloric acid and allowed to drip into ether. Here, the 3-methylamino-4, -5-diphenyl-pyra, zol hydrochloride separates out. The free base is obtained from the ethanolic solution of the hydrochloride by adding ammonia. Y. 2.06 g (.83%). Colorless Leaflets (from ethanol), mp 176 ^° C.

Example 2:

3-n-propylamino-4,5-diphenyl-pyrazole

a) 3 »O9 g (10 mmol) of 2-n-propylamino-5,6-diphenyl-6H-1,3,4-thiadiazine and 2.62 g (10 mmol) of triphenylphosphine are dissolved in 50 ml of n-butanol for 3 hrs heated under reflux. Further workup analogous to Example 1. Ausb. 2.24 g (81%). Colorless needles (from benzene / petroleum ether), F .. 181 ⁰ C.

b) 3i56 g (10 mmol) of 2-n-propylamino-5,6-diphenyl-6H-1,3,4-selenadiazine and 2.62 g (10 mmol) of triphenylphosphine

are refluxed in 50 ml of n-butanol for 4 hrs. When cooling in ice, a precipitate separates from triphenylphosphine selenide. Colorless rods (from ethanol), F · 185-186 ⁰ C. (Lit. H. Michaelis and H. v Soden, Liebigs Ann Ghem 22 £ (1885) 308 F. 183 184 ⁰ G...). Further work-up analogously to Example 1. Yield * 2.3 g (83%). Colorless Charging In (from benzene / petroleum ether), m.p. 181 ⁰ O.

Example 4:

3-tert-butylamino-4,5-diphenylpyrazole zo 1

a) 3.23 g (10 mmol) of 2-tert-butylamino-5,6-diphenyl-6H-1,3,4-thiadiazine and 2.62 g (10 mmol) of triphenylphosphine in 30 ml of toluene for 2 hr. Under Reflux heated. Upon cooling, triphenyl phosphine sulfide separates out, which is sucked off. From the filtrate 15 ml of toluene are distilled off. It is cooled in% s, the pyrazole crystallized out. Y. 2.62 g (90 %) . Colorless rods (from ethanol), m.p. 211-212 ⁰ G.

ti) 3 »70 g (10 mmol) of 2-tert-butylamino-5,6-diphenyl-6H-1,3,4-selenadiazine and 2.62 g (10 mmol) of triphenylphosphine are in 40 ml of toluene for 3 hr. Under Reflux heated. 212 ⁰ G. - by "separation of Triphenylphosphinselenids 20 ml of toluene 2.5 g (86%) · Colorless rods (from ethanol), m.p. 211 are distilled off from the filtrate upon cooling in ice, the pyrazole separates y...

Example 5t

3-anilino-4,5-diphenyl-pyrazole

a) 3 »43 S (10 mmol) of 2-anilino-5,6-diphenyl-6H-1,3> 4-thiadiazine and 2.62 g (10 mmol ·) of triphenylphosphine are dissolved in 80 ml of n-butanol for 6 hours. heated to reflux. Further work-up analogously to Example 1. Yield * 2.8 g (90%). · Colorless needles (from benzene), mp 182 ^° C.

b) 3.90 g (10 mmol) of 2-anilino-5,6-diphenyl-6H-1,3,4-selenadiazine and 2.62 g (10 mmol) of triphenylphosphine are refluxed in 60 ml of toluene for 9 hours , After separation of the triphenylphosphine selenide, 40 ml of toluene are distilled off from the filtrate. When cooling in% s, the pyrazole separates out. Y. 2.7 g (87 %) . Colorless needles (from benzene), mp 182 ⁰ C.

Example 6:

3-Dimethylamino-4,5-diphenyl-pyrazole 2.95 g (10 mmol) of 2-dimethylamino-5,6-diphenyl-6H-1,3 * 4-thiadiazine and 1.66 g (10 mmol) of triethyl phosphite are refluxed in 50 ml benzene for 10 hrs. Then be. Distilled off 30 ml of the solvent. Upon cooling, the pyrazole separates out · Ausb. 2.11 g (80%). Colorless platelets (from ethanol), mp 202 - 203 ⁰ O.

Example 7t

3-piperidino-4,5-diphenyl-pyrazole

3.35 S (10 mmol) of 2-piperidino-5,6-diphenyl-6H-1,3,4-thiadiazine and 2.62 g (10 mmol) of triphenylphosphine are refluxed in 30 ml of ethanol for 8 hours. Working up analogously to Example 1 · Yield · 2.7 g (89%) · Colorless needles (from ethanol), mp 207 ^° C.

Example 8:

3-morpholino-4,5-diphenyl-pyrazole

From 3.37 g (10 mmol) of 2-morpholino-5,6-diphenyl-6H-1,3,4-thiadiazine and 2.62 g (10 mmol) of triphenylphosphine as described in Example 6. Yield · 2.7 g (87 %) · Colorless needles (from ethanol), mp 222 ^° C.

Example 9:

3-amino-4,5-diphenyl-pyrazole

From 2.67 S (10 mmol) of 2-amino-5,6-diphenyl-6H-1,3,4-thiadiazine and 2.62 g (10 mmol) of triphenylphosphine analogously to Example 1. Yield. 2.0 g (85%). Colorless prisms (from trichlorethylene), mp 146 ⁰ G.

Example J10J

3-hydrazino-4,5-diphenyl-pyrazole

From 2.82 g (10 mmol) of 2-hydrazino-5,6-diphenyl-6H-1,3,4-thiadiazine analogously to Example 1. Ausb. 2.0 g (80%). Colorless leaflets (ethanol), P. 181 ⁰ C.

Example 11;

3-Anilino-4-methyl-5-phenyl-pyrazole 2.81 g (10 mmol) of 2-anilino-5-phenyl-6-methyl-6H-1,3,4-thiadiazine and 2.62 g (10 mmol ) Triphenylphosphine are refluxed in 20 ml toluene for 24 hrs. Distilled 10 ml of toluene. Upon cooling, a mixture of iriphenylphosphine sulfide and pyrazole separates out. Dissolve in warm ethanol. The precipitated during cooling Triphenylphosphinsulfid is filtered off. Work-up analogous to Example 1. Ausb. 1.79 g (72%). Colorless leaflets (of trichlorethylene), mp 140 ^° C.

3-anilino-4-ethyl-5-phenyl-pyrazole

From 2.95 S (10 mmol) of 2-anilino-5-phenyl-6-methyl-6H-1,3,4-thiadiazine analogously to Example 11. Ex. 1.84 g (70%). Colorless needles (from dilute ethanol), F. I27 ⁰ O.

Example 13:

3-amino-4-methyl-1-5-phenyl / 1-pyrazole hydrochloride 2.05 g (10 mmol) of 2-amino-5-methyl-6-phenyl-6H-1,3,4-thiadiazine and 2 , 62 g (10 mmol) of triphenylphosphine are refluxed in 20 ml of ethanol for 15 hours. After cooling, the precipitated crystals of triphenyl phosphine sulfide are filtered off with suction. Y. 3.7 g (63%). The solvent is i. Yak. distilled off and the residue boiled with water. Small amounts of a residual resinous product are discarded. Gesamt.wird the substance is recrystallized three times from water. Then it is dried over -P ^ O ₁₀ at 50 ⁰ C. The substance is dissolved in ether and precipitated by passing hydrochloric acid gas, the hydrochloride. Y. 1.2 g (61%). Colorless irregular

Prisms, F. 176 - 177 ⁰ C (Zers.).

Example 14-:

3-Aynino-4-eyl-5-plien-7-pyrazole hydrochloride From 2.19 g (10 mmol) of 2-amino-5-phenyl-6-ethyl-6H-1,3,4-thiadiazine and 2 , 62 g (10 mmol) Tripheny! Phosphine in 40 ml ethanol as described in Example 13. Subject to recrystallization from water gives the monohydrate of 3-AmirLO-4-ethyl-5-phenyl-pyrazole in colorless threads, P. 80 - 81 ⁰ C. Ausb. 1.4 g (68%). The mixture is then dried over P ^ P-io ^ ^ei ^ ⁰ ° ^C and the amorphous product is converted by dissolving in ether and passing hydrochloric acid gas into the well-crystalline hydrochloride. Y. 1.45 g (65%). Colorless Leaflets, F. 171 - 172 ⁰ C (dec.).

example

3,4,5-T? Iphenyl-pyrazole

From 3.28 g (10 mmol) of 2,5,6-triphenyl-6H-1,3,4-thiadiazine and 2.62 g (10 mmol) of triphenylphosphine are refluxed in 30 ml of toluene for 3 hrs. Work-up analogous to Example 4. Ausb. 2.46 g (83%). Colorless threads (made of ethanol). F. 269 - 270 ⁰ C.

Example IjSt ₁

3-Benzyl-4,5-diphenyl-pyrazole

From 3.42 g (10 mmol) of 2-benzyl-5,6-diphenyl-6H-1,3,4-thiadiazine analogously to Example 4. Ausb. 2.7 g (87%). Colorless threads (from ethanol), mp 172 ⁰ C.

Example 17;

1-Methy1-3,4-diphenyl-5-isopropylamino-pyrazol

a) 3.23 g (10 mmol) of 2-isopropylimino-3-methyl-5,6-diphenyl 2,3-dihydro-6H-1,3,4-thiadiazine and 2.62 g (10 mmol) of triphenylphosphine are in 3 ml of n-butanol is refluxed for 24 hours. Work-up analogous to Example 1. Ausb. 2.4 g (82%). Colorless rod (diluted from. Ethanol), mp 88 ⁰ C.

"b) 3" 7O g (10 mmole) of 2-isopropylimino-3-niethyl-5>6-diphenyl-2,3-dihydro-6H-1,3> 4-selenadiazine and 2.62 g (10 mmole) of triphenylphosphine 28 h. Working up in 40 ml of n-butanol heated to reflux. analogously as described in example 2 b). Yield. 2.3 g (79%) · Colorless rods (from dil. ethanol), mp C 88 ⁰ ,

Claims (2)

Process for the synthesis of pyrazoles of the general formulas, characterized in that in the 6-position substituted 1,3j4-thiadiazines or 1,3> 4 ~ selenadiazines in polar or non-polar organic solvents in the presence of triphenylphosphine or triethyl phosphite to 50 - 160 ⁰ G heated, wherein in the general R is an aryl, benzyl, amino, hydrazino, alkylamino, arylaiaino ^, · dialkylamino 2 1
or acylamino group R and - ¹ Br is an aryl group or a lower straight-chain or branched alkyl radical and R is a lower straight-chain or branched alkyl radical.