DD254938A1 - PROCESS FOR PREPARING NEW 4-CARBAMIMIDOYLMERCAPTO-PYRAZOLIN-5-ONES - Google Patents

Abstract

The invention relates to a process for the preparation of novel 4-carbamimidoylmercapto-pyrazolin-5-ones. The aim and the object are to produce in a simple manner, new isothioureido compounds of pyrazolin-5-ones in good yields and high purity. According to the invention, 2-pyrazolin-5-ones are reacted with a thiourea in the presence of aprotic solvents at 10 to 150 ° C. to give the corresponding isothiuronium salts and after neutralization with bases contains the 4-carbamimidoylmercapto-pyrazolin-5-ones R 1 alkyl, haloalkyl, alkenyl, Aryl, cycloalkenyl, carbamoyl, thiocarbamoyl, heterocycle, R 1 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heterocycle, carbamoyl, thiocarbamoyl, alkoxycarbonyl, alkoxy, aryloxy, alkylthio, carboxyl, amino, amido, anilino, N-alkylacylamino, N-arylacylamino , Ureido, thioureido, R 2 is halogen, R 3 is hydrogen, halogen, R 4, R 5, R 6, R 7, identical or different, alkyl, cycloalkyl, aryl, heterocycle. Formulas I to IV

Description

Field of application of the invention

The invention relates to a process for the preparation of new carbamimidoylmercapto-pyrazoline-S-onen in pure form.

Characteristic of the known technical solutions

It is of general interest to substitute heterocycles via heteroatoms.

In the case of 5-membered ring heterocycles, existing hydrogen atoms are often acid, once due to substituents with an electrophilic character, or because there are U - deficiency systems with respect to the aromatic state.

Acidic hydrogen atoms can readily undergo substitution to form polar transition states or intermediates. Often, however, a variety of products are formed, so that the choice of working conditions crucially determines the final product of the process and its yield. Hydrogen atoms of the 4-position can easily be exchanged with halogens or sulfuryl halides in glacial acetic acid in pyrazolium ions with substitution. In this case, preference is given to working in inert solvents at room temperature (US Pat. No. 2,728,658). 4-Halogenpyrazolinone are usually not stable and react to dihalo and unsubstituted compounds. Nitrogen atoms are in the 4-position of 2-pyrazolin-5-ones, e.g. introduced by nitrosation. By subsequent reduction amines can be obtained. It is also possible to couple pyrazolinones with diazonium compounds and to cleave the azo derivatives formed by hydrogenation into the amines. Examples are in Jap. Kokai 74 / 53,435 and 74 / 53,436. Furthermore, oxygen atoms can be introduced by oxidation of the heterocycle with nitrosamines and subsequent cleavage of the azomethine in acidic solution. The 2-pyrazoline-4,5-diones prepared by this process can be further modified by reduction of the carbonyl groups (US Pat. Nos. 3,311,476 and 3,419,391, DE-OS 2607040). It is also possible to substitute once introduced substituents by others again. Halogens are particularly suitable for this purpose. In pyrazolinones, the exchange of the halogen with nucleophiles z. As oxygen or nitrogen nucleophiles usually not to form uniform products and only with poor yields. So far, u.a. Sulfinic acids, thiophenols and thiosubstituted heteroaromatics used with satisfactory yields for halogen exchange. Examples are by O. Angeiini, A. Martiani, Ann. Chem. (Rome) 45,156 (1955), U.S. Patent 3,006,759 and DE-OS 2015814. Another method of substitution of pyrazolinones is based on the use of sulfenyl chlorides, this is carried out with elimination of hydrogen halide sulfur functionalization. It is known that it is possible to prepare unsubstituted or acylamino-substituted pyrazolinones having isothiourea groups in the 1-position by reacting the halides of the pyrazolinones in alcohols with thiourea. However, this method is not suitable for differently substituted pyrazolinones and provides the desired compounds only in low yields or in highly contaminated form.

Object of the invention

The aim of the invention is to produce in a simple manner, new 4-carbamimidoylmercapto-pyrazolin-5-ones.

Explanation of the essence of the invention

It is the object of the invention to provide a process for the preparation of novel 4-carbamimidoylmercapto-pyrazolin-5-ones with good yields and in high purity.

According to the invention, the object is achieved by reacting 2-pyrazolin-5-ones of the general formula

2

_R

R

R is alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkyl, aryl, substituted aryl, carbamoyl, thiocarbamoyl, heterocycle

R ^{1 is} hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, carbamoyl, thiocarbamoyl, alkoxycarbonyl, alkoxy, aryloxy, alkylthio, carboxyl, amino, amido, N-alkylacylamino , N-arylacylamino, ureido, thioureido

R ^{2 is} halogen R ^{3 is} hydrogen, halogen, with a thiourea of the general formula _t

wherein R

R ⁵ , R ⁶ , R ^{7 are} identical or different alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,

Heterocycle, substituted heterocycle,

in the presence of aprotic solvents in a temperature range of 10 to 150 ⁰ C to the corresponding isothiuronium salts and then by neutralization with organic or inorganic bases, the 4-carbamimidoylmercapto-pyrazolin-5-one of the general formulas _/

S_C

S-C

N '

or

wherein R, R ¹ , R ⁴ , R ^s , R ⁶ , R ⁷ , have the meaning indicated.

The process according to the invention for the preparation of the new 4-carbamimidoylmercapto-pyrazolin-5-ones is generally carried out by initially introducing the pyrazolinone in the solvent, adding the thiourea and stirring it. The mixture is conveniently heated to 30 to 100 ^° C. for 1-12 hours. After cooling to about 20 ° C is separated from the existing precipitate. Thereafter, it is possible, the precipitate in a water-miscible solvent z. For example, methanol, ethanol, dimethylformamide and to give in an aqueous solution. It is convenient to work so that the temperature does not rise above 8O ⁰ C, advantageously working at 10 to 40 ⁰ C. The precipitated solid is filtered off and, if necessary, from a suitable solvent, for. As ethanol, dioxane or acetonitrile recrystallized.

It is also possible to proceed by introducing the pyrazolinone without halogen substitution and to the halogen and the

Thiourea there and then processed as described the approach continues.

It is surprising that virtually no by-products are formed despite the simple procedure and the use of relatively high temperatures. Thus, these complicated compounds were synthesized for the first time.

Examples of compounds that can be obtained by the process according to the invention are in the table

contain.

Suitable bases for the neutralization of the primary halides (isothiuronium salts) are organic and inorganic compounds. For example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium acetate, but also triethylamine or

Pyridine.

The new pyrazolin-5-ones prepared by the new process are solids. At higher temperatures, they melt

under decomposition.

With mineral acids, the compounds react to form salts and thereby become partially water-soluble.

Another advantage of the compounds is their wide scope. Individual representatives show fungicidal or bactericidal activity, other agents can be used as antistatic agents or their salts as latent acid donors.

Furthermore, individual agents have anti-inflammatory activity or may be used against obesity

come.

embodiments

The yields, physical constants and elemental analysis of the compounds of the invention are shown in Table 1.

example 1

i-phenyl-S-methyl -carbamimidoylmercapto-Z-pyrazoline-B-one (compound 1)

0.1 mol (25.3 g) of 1-phenyl-3-methyl-4-bromo-2-pyrazolin-5-one and 0.1 mol (7.6 g) of powdered thiourea are stirred in 100 ml of acetonitrile for 48 hours at room temperature. The precipitated hydrobromide is filtered off with suction, dissolved in 50 ml of methanol and added dropwise to a solution of 0.1 mol (4 g) of caustic soda in 350 ml of water. The precipitated solid is sucked off and out

Example 2

1-phenyl-a-methyl-fN-dodecylcarbamimidoylmercaptol-a-pyrazoline-S-on (Compound 6) 0.1 mol (20.9 g) of i-phenyl-S-methyl-chloro-pyrazolin-6-one and 0.1 mole (24.5 g) of pulverized Laurylthioharnstoff are stirred in 200 ml of dioxane for 4 hours at 5O ⁰ C. The hydrochloride is filtered off, dissolved in 100 ml of ethanol and added dropwise to a solution of 0.1 mol (8.2 g) of sodium acetate in 400 ml of water, the precipitated solid is filtered off with suction and recrystallized from acetonitrile.

Example 3

1-phenyl-S-methyl ^ -fN-phenylcarbamimidoylmercaptol ^ -pyrazolin-S-one (Compound 8) 0.1 mol (17.4 g) of 1-phenyl-3-methyl-2-pyrazolin-5-one are dissolved in 350.degree ml of acetonitrile at 20 ° C with 1.0 mol (15.2g) phenylthiourea and added dropwise 0.1 mol (16g) of bromine in 50 ml of glacial acetic acid and stirred for 4 hours.

The mixture is then added slowly in 11 water, the precipitate was filtered off, recrystallized from acetonitrile / ethanol, taken up in 100 ml of ethanol and added dropwise to an aqueous solution of 4.2 g of sodium acetate and 2 g of caustic soda in 350 ml of water. The precipitate is filtered off and recrystallized from acetonitrile.

Example 4 1-Phenyl-3-methyl-4- (N, N, IM ', IM'-tetramethylisothiuronio) -2-pyrazolin-5-one-4-id 0.1 mole (25.3 g) of 1-phenyl 3-methyl-4-bromo-2-pyrazolin-5-one and 0.1 mol (13.3 g) of Ν, Ν, Ν ', Ν'-tetramethylthiourea are stirred in 100 ml of acetonitrile for 10 hours at room temperature. The resulting precipitate is filtered off with suction, dissolved in 25 ml of methanol and added dropwise to 150 ml of ice-water containing 4.0 g of caustic soda. The precipitate is filtered off and can be recrystallized from ethyl acetate. The yield can be improved by extraction with chloroform.

Yield: 2.0 g (51% of theory.) Mp: 103-105 ⁰ C.

About: 18.35% Fe: 18.36%, Over: 10.50% Fe: 10.30%

Table 1: Compilation of i-phenyl-carbamimidoylmercapto-pyrazolin-S-ones

NO"

No. R ¹ R ² Fp A (K) ^s ber. ^s gef. ^N over. ^N gef. ^Cl . ^Cl . ^Br over. ^Br . Total molecular weight 1 CSI 3 4 CJL 6 7 8th 9

2 3 4 .5 6 7 8

9 10 11 12

CH ₃

CH,

-H -H 444 65.7 12,91 22.56 I 12.79 22.76 -CH ₃ p-Cl 456 -457 12.22 21.36 I 49 12.08 21.51 -C ₄ H ₉ o-CI 444.6 -445 11.04 19.29 I 51 11.08 19.33 -C ₆ H ₁₃ m-Cl 437 -438 10.06 17.59 I 67 10.00 17,81 -C ₈ H17 P-CH ₃ 436 -436.5 8.89 15.54 I 77 8.72 15.38 -C ₁₂ H ₂₅ 425 7.96 13.91 I 55 7.81 13.71 -C ₁₈ H ₃₇ 381 6.40 11.19 I ₂ 62 6.54 11.24 414 -415 9.88 17.27 I 60 9.69 17.34 395 8.93 / 9.88 69 8.71 10.04 397 8.93 / 9.88 48 8.79 10.02 407.5 8.93 / 9.88 64 8.77 9.74 395.5 9.47 16.55 I 42 9.21 16.71

CnH ₁₂ N ₄ OS 248.30 C ₁₂ H ₁₄ N ₄ OS 262.31 Ci ₄ Hi ₈ N ₄ OS 290.39 Ci ₆ H ₂₂ N ₄ OS 318.44 Ci ₉ H ₂₃ N ₄ OS 360.52 C ₂₂ H ₃₄ N ₄ OS 402.60 C ₂₉ H ₄₈ N ₄ OS 500.79

Ci ₇ H ₁₆ N ₄ OS 324.40 C ₁₇ H ₁₅ N ₄ OSCI 358.85 C17H15N4OSCI

C ₁₇ Hi ₅ N ₄ OSCI 358.85 C ₁₈ H ₁₈ N ₄ OS 338.43

R ¹

Fp A

(K)

^s about.

^s gef.

^N over. ^N gef.

^Cl over

^Cl gef.

^8r over

^Br gef.

Molecular formula Pi / lolgewicht

14 15 16 17 18 19 20 21 22 23 24 25

-CH ₃

-C17H3

0-CH3

m-CH ₃

p-Br

p-F

P-NO ₂

P-OCH ₃

P-COOCH ₃

PN (CH ₃ ) ₂

-H

-CH ₃

-C4H9

402

390.5

409

398

421.5

392.5

411.5

419

431

352

401

397

383

23 50 60

41 -422

68-393

39 -412

57 -420

58 -432

60-353

40 -402

58-398

30-384

32

9.47 9.59 9.47 9.33 7.95 7.85 9.36 9.32 8.68 8.58 9.06 8.91 8.38 8.29 8.72 8.59 6, 78 6.87 6.59 6.58 6.06 6.11 5.48 5.57 5.10 5.06

16.55 16.31 16.55 16.65

16.36

16.44

18.96

19.08

15.81

15.99

14.65

14.76

19.06

18.91

11.85

12.08

11.51

11.48

10.59

10.73

9.58

9.63

8.91

8.84

19.81 19.66

Ci ₈ H ₁₈ N ₄ OS

338.43

C ₁₈ Hi ₈ N ₄ OS

338.43

Ci ₇ Hi ₆ N ₄ OSBr

403.30

C ₁₇ Hi ₆ N ₄ OSF

342.39

Ci ₇ Hi ₆ N ₆ O ₃ S

369.40

Ci ₈ Hi ₈ N ₄ O ₂ S

354.43

Ci ₉ H ₁₈ N ₄ O ₃ S

382.44

C ₁₉ H ₂₁ N ₅ OS

367.47

C ₂₇ H ₄₄ N ₄ OS

472.74

C ₂₈ H ₄₆ N ₄ OS '

486.77

C ₃ IH ₅₂ N ₄ OS

528.85

C ₃₅ H ₆₀ N ₄ OS

584.95

C ₃ SH ₆₈ N ₄ OS

629.05

Claims (3)

Invention claim: 1. A process for the preparation of new ^ carbamimidoylmercapto-pyrazoline-B-ones, characterized in that 2-pyrazolin-5-ones of the general formula 2 R " I R R is alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkyl, aryl, substituted aryl, carbamoyl, thiocarbamoyl, heterocyclic R ^{1 is} hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, carbamoyl, thiocarbamoyl, alkoxycarbonyl, alkoxy, Aryloxy, alkylthio, carboxyl, amino, amido, anilino, N-alkylacylamino, N-arylacylamino, ureido, thioureido R ² halogen R ^{3 is} hydrogen, halogen
mean
with a thiourea of the general formula , 4 S = C ν ·; R ⁴ , R ⁵ , R ⁶ , R ^{7 are the} same or different alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle mean in the presence of aprotic solvents in a temperature range from 10 to 150 ⁰ C to the corresponding isothiuronium salts and then by neutralization with organic or inorganic bases, the ^ carbamimidoylmercapto-pyrazoline B-one of general formulas, .0 N. or IV R, R ¹ , R ⁴ , R ⁵ , R ⁶ , R ^{7 have} the meaning given, released. 2. A process for the preparation of novel A-carbamimidoylmercapto-pyrazoline-S-onen according to item 1, characterized in that as the solvent acetonitrile, dioxane, dimethylformamide, ν tetrahydrofuran or gasoline used. 3. A process for the preparation of new ^ carbamimidoylmercapto-pyrazoline B-ons according to item 1, characterized in that the bases used are sodium hydroxide solution, potassium hydroxide solution, sodium carbonate, sodium acetate or triethylamine.