HU182999B - Process for producing 1,2,3-thiadiazol-5-yl-urea derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of 1,2,3-thiadiazol-5-yl-ureas of the general formula I. The process of the invention is characterized in that a 1,2,3-thiadiazole-5-carboxylic acid azide of the Reacting formula II with an amine of the formula III dissolved in an inert organic solvent and the reaction product isolated in a conventional manner. By the invention, a method is provided, which allows a technically simple and safety-friendly production of 1,2,3-thiadiazol-5-yl-ureas.

Description

The present invention relates to a novel process for the preparation of 1,2,3-thiadiazol-5-yl urea derivatives.

Methods for the preparation of said urea derivatives are already known (German Patent Publication Nos. 22 14 632 and 26 36 994). These processes require starting material, 5-amino-1,2,3-thiadiazole, which is not readily available and is not completely harmless.

It is an object of the present invention to provide a process which

The 1,2,3-thiadiazol-5-yl urea derivatives are technically simple and safely produced.

According to the invention, the 1,2,3-thiadiazol-5-yl-urea derivatives of formula (I) wherein R 1 is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, butyl or allyl,

R ₂ is methyl, ethyl, allyl, cyclopropyl, cyclohexylphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,

2-isopropylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-methoxyphenyl, 2-nitrophenyl,

3-nitrophenyl _; 4-nitrophenyl, 2- (trifluoromethyl) phenyl,

3- (trifluoromethyl) phenyl, 2-chloro-6-methylphenyl, pyridyl, pyrimidyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl2-pyridyl -, 6-methyl-2-pyridyl, 4-methyl-2-pyrimidyl or 5-chloro-2-pyridyl, or

R 1 and R ₂ together form a morpholino, piperidino, or pyrrolidino group by preparing 1,2,3-thiadiazole-5-carboxylic acid azide of formula (II) wherein R 1; and R ₂ is as defined above - is reacted with an amine in an organic solvent at a temperature between 20 and 180 ° C, preferably between 50 and 120 ° C, and the reaction product is isolated in a manner known per se.

The process according to the invention is preferably carried out by carrying out the reaction at the boiling point of the solvent mixture;

reacting equimolar amounts of the azide (II) and the amine (III);

reacting the azide of formula (II) with the amine of formula (III) in one step; and 1,2,3-thiadiazole-5-carboxylic acid azide of formula (II), which is prepared by a known method and is not isolated from the resulting reaction mixtures, so that a continuous process is possible.

The 1,2,3-thiadiazole carboxylic acid azide of formula (II) may be prepared by the following procedures known per se:

a) reacting a 1,2,3-thiadiazole-5-carboxylic acid of formula IV with a chloroformic acid ester of formula V in an inert solvent in the presence of acid scavengers to form a mixed anhydride of formula VI and then reacting with a solution of an alkali metal amide of the formula; obsession

b) reacting 1%, 3-thiadiazole-5-carboxylic acid halide (VIII) in an inert organic solvent with an aqueous solution of the alkali metal azide (VII); obsession

c) 1,2,3-thiadiazole-5-carboxylic acid hydrazide of formula XI in an inert solvent with a solution of alkali metal nitrite of formula X or alkyl nitrite of formula XI in the presence of an acid of formula 1,2,3 -thiazole-5-carboxylic acid azide in the formulas

R ₃ is C 1-6 alkyl;

Me is a monovalent metal atom, preferably sodium, potassium or lithium, and

X is halogen, preferably chlorine.

The resulting azide of formula (II) is preferably not isolated from the resulting reaction mixtures, but can be used directly for the process of the invention.

It is a great technical advantage that the 1,2,3-thiadiazole-5-carboxylic acid azide of formula (II) does not have to be isolated from the reaction mixtures after preparation, but that these mixtures can be directly reacted with an amine of formula (III).

It is particularly surprising that this procedure produces the desired product and does not, as expected, replace the azide with the amine to 1,2,3-thiadiazole-5-carboxylic acid amide.

For example, the process of the present invention may be carried out by dropwise addition of an equimolar amount of the crude azide to an inert solvent at a reflux temperature, or by adding a solution of the azide to a solvent diluted amine at the reflux temperature of the mixture.

The reflux intensity provides a control option for the spontaneous reaction run.

However, the azide may also be heated in the presence of a solvent inert to the amine.

As mentioned, the temperature is preferably 20-180 ° C, preferably 50-120 ° C. However, the reaction is most preferably carried out at the reflux temperature of the reaction mixture.

Suitable solvents for the reaction partners include aliphatic and aromatic hydrocarbons such as cyclohexane, heptane, petroleum ether, benzene, chlorobenzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran, diisopropyl ether, esters such as ethyl acetate and malonate, such as acetone, methyl isobutyl ketone, isophorone and cyclohexanone, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, carboxylic acid nitriles such as acetonitrile.

After completion of the reaction, the reaction mixture is worked up in a manner known per se, for example by distillation of the solvent at atmospheric or reduced pressure, precipitation with water or, in most cases, simple filtration of the desired reaction product. In this way, 1,2,3-thiadiazol-5-ylurea derivatives are obtained in extremely pure form and in almost quantitative yield and no further purification step is required for further use. Partitioning problems such as the reaction of 5-amino-1,2,3-thiadiazole with isocyanates are by-products of excellent symmetrical ureas.

The following examples illustrate the process of the present invention.

Example 1 Preparation of 1-Phenyl-3- (1,2,3-thiadiazol-5-yl) urea

1,2,3-thiadiazole-5-carboxylic acid chloride.

In a three-necked 250 ml round-bottomed flask equipped with a stirrer and thermometer, 9.1 g (0.14 mol) of sodium azide in 40 ml of water was mixed with 40 ml of toluene. A solution of 14.8 g (0.1 mol) of 1,2,3-thiadiazole-5-carboxylic acid chloride in 80 ml of toluene is then added dropwise at 15 to 20 ° C over 15 minutes with vigorous stirring. The reaction mixture was stirred for an additional 1.5 hours at 15-20 ° C, the toluene layer was separated and dried over magnesium sulfate. The anhydrous solution of 1,2,3-thiadiazole-5-carboxylic acid azide

-2182,999 at room temperature with 9.14 ml (0.1 mol) of aniline. Meanwhile, in a 250 mL three-necked round bottom flask equipped with a stirrer, thermometer and reflux, 80 mL of toluene was heated to 110 ° C. A solution of the carboxylic acid azide and aniline is added dropwise over a period of 10 minutes to an internal temperature of 100-110 ° C. Slightly yellowish crystals are precipitated immediately during strong gas evolution. After refluxing, the reaction mixture was stirred for 5 minutes, cooled to 5 ° C, and the crystals were filtered off and dried under vacuum at 40 ° C to constant weight.

Yield: 19.5 g (88.6%).

Melting point: 217 ° C (dec.).

Thin layer chromatography:

eluent: acetic acid: Rf = 0.25.

Example 2 Preparation of 1-Phenyl-3- (1,2,3-thiadiazol-5-yl) urea from 1,2,3-thiadiazole-5-carboxylic acid hydrazide.

14.4 g (0.1 mol) of 1,2,3-thiadiazole-5-carboxylic acid hydrazide are dissolved in 100 ml of water and 12 ml of concentrated hydrochloric acid solution in a three-necked 500 ml round-bottom flask equipped with a thermometer and a stirrer. The solution was then mixed with 200 mL of toluene. To this mixture is then added dropwise a solution of 7.25 g (0.105 mol) of sodium nitrite in 20 ml of water at 0-5 ° C for 30 minutes. The reaction mixture was then stirred for another 15 minutes at 0-5 ° C, then the toluene layer was separated and dried over magnesium sulfate. The anhydrous 1,2,3-thiadiazole-5-carboxylic acid azide solution was mixed with 9.14 ml (0.1 mol) of aniline at room temperature.

In a 500 ml round-bottomed three-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 50 ml of toluene was heated to 110 ° C. The anhydrous carboxylic acid azide / aniline mixture is added dropwise over a period of 10 minutes to an internal temperature of 100-110 ° C. Immediately yellowish crystals are precipitated during strong gas evolution. The reaction mixture was stirred at reflux for a further 5 minutes, then cooled to 5 ° C and the crystals were filtered off and dried under vacuum at 40 ° C to constant weight.

Yield: 16.2 g (73.6%).

Melting point: 217 ° C (dec.).

Thin ony layer-k ro matography:

eluent: ethyl acetate: Rf = 0.25.

Compounds listed in the following table were prepared analogously to Example 2 using the same molar ratios (0.1 mol of 1,2,3-thiadiazole-5-carboxylic acid azide) and reaction conditions.

Table 1

The name of the compound Yield: Physical constant (m.p. 1- (4-chlorophenyl) -3- (1,2,3- 19.1 g thiadiazol-5-yl) urea 75.1% 256 (decomposes) 1-cyclohexyl-3- (1,2,3- 10.2 g thiadiazol-S-yl-urea 45.3% 215 (decomposes) l- (3-chlorophenyl) -3- (U, 3- 11.3 g -thiadazo-1- (5-yl) -carbam 44.5% 244 (decomposes) l- (4-methylphenyl) -3- (l, 2,3- 18.2 g -thiadiazol-5-yl) -bromamide 77.9% 228 (decomposes) 1- (3-methylphenyl) -3- (1,2,3- 17.9 g -thiadazo-1- (5-yl) -carbamide 76.6% 208 (decomposes) l-dichloro-3,4-a feril) -3- 41,2,3-1 iiad iazo 1-5-yl) - 15.2 g -urea 52.6% 236 (decomposes)

Continuation of Table 1

The name of the compound Yield: Physical constant (melting point ° C) 1-methyl-3- (1,2,3-thiadiazol-5-yl) urea 8.1 g 51.2% 174 1,1-dimethyl-341,2,3-thiadiazol-5-yl) urea 9.2 g 53.5% 222 (decomposes) 1- (1,2,3-Thiadiazol-5-yl) -3- (3-trifluoromethyl-phenyl) -urea 19.0 g 66.0% 234 (decomposes) 1- (4-Nitrophenyl) -3- (1,2,3-thiadiazol-5-yl) arbamide 15.0 g 56.6% 262 (decomposes) 1- (2-Chlorophenyl) -3- (1,2,3-thiadiazol-5-yl) arbamide 18.0 g 71.0% 237 (decomposes) 1- (2-Methylphenyl) -3- (1,2,3-thiadiazol-5-yl) urea 17.2 g 73.5% 197 (decomposes) 1- (2-Nitrophenyl) -3- (1,2,3-thiadiazol-5-yl) arbamide 15.4 g 58.2% 229 (decomposes) 1- (3-nitrophenyl) -3- (1,2,3-thiadiazol-5-yl) urea 15.9 g 60.0% 252 (decomposes) 1-Methyl-1-phenyl-3- (1,2,3-thiadiazol-5-yl) -amide 19.0 g 81.2% 184 (decomposes) 1-Ethyl-1-phenyl-3- (1,2,3-thiadiazol-5-yl) -amide 19.2 g 77.5% 200 (decomposes) 1-Phenyl-1-propyl-3- (1,2,3-thiadiazol-5-yl) -amide 17.2 g 65.7% 190 (decomposes) 1-butyl-l-phenyl-3- (1,2,3-thiadiazol-5-yl) urea 15.4 g 55.8% 198 (decomposes) 1-Methyl-1- (2-methylphenyl) 3- (1,2,3-thiadazol-5-yl) 4c arbamide 16.2 g 65.2% 215 (decomposes) 1,1-Diethyl-3- (1,2,3-thiadiazol-5-yl) -bromamide 10.0 g 50.0% 189 92 (decomposes) Pyrrolidine-1-carboxylic acid (1,2,3-thiadiazol-5-yl) -aines 9.2 g 46.5% 262 (decomposes) 1- (2-Methoxyphenyl) -3- (1,2,3-thiadiazol-5-yl) arbamide 14.2 g 56.8% 245 (decomposes) Piperidine-1-carboxylic acid (1,2,3-thiadiazol-5-yl) -amide 11.0g 51.9% 246 (decomposes) Morpholine-1-carboxylic acid (1,2,3-thiadiazol-5-yl) -amide 8.3 g 38.8% 255 (decomposes) l- (2-chloro-6-methylphenyl) -3 (1,2,3-thiadiazol-5-yl) 4carbamid 13.9 g 51.7% 210 (decomposes) 1-Allyl-1-phenyl-3- (1,2,3-thiadiazol-5-yl) -carbatides 15.9 g 61.0% 205-08 (decomposes) 1-Isopropyl-1-phenyl-3- (1,2,3-thiadiazol-5-yl) urea 16.2 g 61.8% 215 (decomposes) 1- (2-Isopropyl-phenyl) -3- (1,2,3-thiadiazol-5-yl) -amide 17.3g 65.1% 184-86 (decomposes) 1-Cyclopropyl-3- (1,2,3-thiadiazol-5-yl) urea 9.2 g 50.0% 202 1-Propyl-3- (1,2,3-thiadiazo-15-yl) -bromamide 10.1 g 54.3% 140 1,1-diallyl-3- (1,2,3-thiadiazol-5-yl) arbamide 11.9g 53.1% 120 l-isobutyl-l-phenyl-3- (l, 2,3- thiadiazol-5-yl) urea 10.2 g 36.9% 212 (decomposes) 1-b util-3- (1,2,3-thiadiazol-5-yl) -bromamide 10.1 g 50.5% 140 (decomposes) 1-sec-Butyl-1-phenyl-3- (1,2,3-thiadiazol-5-yl) -carbamide 17.2 g 62.3% 170-80 1-Benzyl-1-methyl-3- (1,2,3-thiadiazol-5-yl) -amide; 19.2 g 77.5% 185-88 (decomposes) 1-Cyclohexyl-1-propyl-3- (1,2,3-thiadiazol-5-yl) -amide 11.3 g 42.5% 180 (decomposes) 1- (1,2,3-thiadiazol-5-yl) -312- / trifluoromethyl / phenyl) carbamic 20.2 g 70.2% 225 (decomposes) clod 1-Benzyl-3- (1,2,3-thiadiazol-5-yl) urea 19.3 g 82.4% 194 (decomposes) l-cyclohexyl-l-isopropyl-341,2,3-thiadiazol-5-yl) urea 17.6 g 65.6% 255 1- (5-chloro-2-pyridyl) -3- (1,2,3-thiadiazol-5-yl) 4c arbamide 16.3 g 63.8% 255 (decomposes) 1- (4-Methyl-2-pyridyl) -3- (1,2,3-thiadiazol-5-yl) urea 14.2 g 60.5% 233 (decomposes) 144-methyl-2-pyrimidyl) -3- (1,2,3-thiadiazol-5-yl) urea 15.9 g 67.4% 235 (decomposes) 1- (4-pyridyl) -3- (1,2,3-thiadiazole- 18.2 g

-3182,999

Continuation of Table 1

The name of the compound Yield: Physical constant (melting point ° C) -5-yl) urea 82.3% 215 (decomposes) 1- (3-pyridyl) -3- (1,2,3-thiadiazole- 12.2 g 5-yl) urea 55.3% 218 (decomposes) 1- (2-Pyrimidyl) -3- (1,2,3- 10.3 g thiad and zol-5-yl) -carbamide 46.4% > 270 (decomposes) 1- (3-methyl-2-pyridyl) -3- (1 ', 2,3- 13.2 g -tiadiazoI-5-yl) urea 56.2% 234 (decomposes) 1- (5-methyl-2-pyridyl) -3- (1,2,3- 15.4 g thiadiazol-5-yl) urea 65.8% 230 (decomposes) 1- (6-methyl-2-pyridyl) -3- (1,2,3- 16.1 g thiadiazol-5-yl) carbamide 68.4% 234 (decomposes) l- (2-pyridyl) -3- (1,2,3-thia- 16.4 g thiadiazol-5-yl) urea 74.2% 227 (decomposes)

The following examples illustrate the preparation of starting materials.

Example 3

1.2.3- Thiadiazole-5-carboxylic acid hydrazide

In a 100 mL three-necked round bottom flask equipped with a thermometer, a solution of 31.6 g (0.2 mol) of ethyl ethyl 1,2,3-thiadiazole-5-carboxylate in 50 mL of ethanol was treated with 11.0 g (0.22 mol) of hydrazine. with hydrate for 5 minutes at room temperature. Slowly raising the temperature to 50 ° C, yellow crystals are formed. The reaction mixture was stirred for an additional hour at room temperature and the crystals were filtered off and dried at 40 ° C under vacuum to constant weight.

Yield: 27.4 g (95%).

145-148 ° C.

W hite Layer Ro mography:

eluent: ethyl acetate, Rf = 0.195.

Example 4

1.2.3- Thiadiazole-5-carboxylic acid chloride.

In a three-neck, 250 ml round-bottomed flask equipped with a stirrer, condenser, thermometer and gas outlet, 30.0 g (0.23 mol) of 1,2,3-thiadiazole-5-carboxylic acid was heated with 125 ml of thionyl chloride for 2 hours under reflux. The light brown solution was concentrated at 40 ° C and 20 mbar and the residue was fractionally distilled.

Yield: 25.0 g (73.4%).

Boiling point (14.7 mbar): 73-76 ° C.

Example 5

1.2.3- Thiadiazole-5-carboxylic acid ethyl ester.

In a 500 ml round-bottomed flask equipped with a stirrer, thermometer, reflux condenser, drying tube and gas outlet, 50.1 ml (0.69 mol) of thionyl chloride was cooled to -15 ° C and then, under slightly reduced pressure, for 30 minutes, 36.2 g ( 0.21 mole) of ethyl formylacetic acid semicarbazone in ethyl acetate at -15 ° C to -10 ° C. The brown solution was stirred for an additional hour at -10 ° C and then diluted with 130 ml of chloroform. The excess thionyl chloride was carefully mixed with 130 mL of saturated potassium bicarbonate solution while maintaining the temperature between -10 ° C and 20 ° C. The chloroform layer was separated, washed with 50 mL of saturated potassium bicarbonate solution, dried over magnesium sulfate and evaporated in a vacuum oven at 40 ° C. The residue was fractionally distilled.

Yield: 28.6 g (86%).

Boiling point (14.7 mbar): 95-100 ° C.

TLC: eluent = ethyl acetate.

Rf value: 0.600.

Example 6

1,2,3-Thiadiazole-5-carboxylic acid.

In a 3-neck, 4-L round-bottom flask equipped with a stirrer, a thermometer and a reflux condenser, 152 g (1.1 mol) of potassium carbonate were heated to 90 ° C in 1 liter of water and 50 g (0.5 mol) of 5-methyl-1,2 3-thiadiazole. A solution of potassium permanganate (158 g, 1.0 mol) in water (1.5 L) at 95-100 ° C is added dropwise over an hour. After heating for 30 minutes under reflux until the reaction mixture completely decolorized, the precipitated manganese dioxide was filtered off and washed with 1 liter of hot water. The filtrate is then concentrated in vacuo to about 1 liter at 50 ° C and acidified with concentrated sulfuric acid (80 ml) at 20 ° C. It is then extracted well with 5 x 300 ml of ethyl acetate. The ethyl acetate extracts were dried over magnesium sulfate and evaporated to dryness under vacuum in a vacuum oven at 40 ° C.

Yield: 211.7 g (33.3%).

Melting point: 106 ° C (dec.).

Claims (5)

Patent claims A process for the preparation of 1,2,3-thiadiazol-5-yl-urea derivatives of formula I: wherein: R1 is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or allyl, R ₂ is methyl, ethyl, allyl, cyclopropyl, cyclohexyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-isopropylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 28 (trifluoromethyl) phenyl, 3- (trifluoromethyl) phenyl, 2-chloro-6-methylphenyl, pyridyl, pyrimidyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl- 2-pyridyl, 6-methyl-2-pyridyl, 4-methyl-2-pyrimidyl40 or 5-chloro-2-pyridyl, or R 1 and R ₂ together form a morpholino, piperidino, or pyrrolidino group, characterized in that the 1,2,3-thiadiazole-5-carboxylic acid azide of formula (II) is represented by the formula: wherein R ] and R ₂ is as defined above - is reacted with an amine in an organic solvent at a temperature between 20 and 180 ° C, preferably between 50 and 120 ° C, and the reaction product is isolated in a manner known per se. 2. A process according to claim 1, wherein the reaction is carried out at the reflux temperature of the reaction mixture. 3. The process according to claim 1, wherein the amount is equimolar 55 is reacted with an azide of formula II and an amine of formula III. 4. A process according to claim 1 wherein 1,2,3-thiadiazole-5-carboxylic acid azide of formula II is prepared by a known method and is not isolated from the resulting reaction mixture. 5. A process according to claim 1 for the preparation of 1-phenyl-3- (1,2,3-thiadiazol-5-yl) urea, characterized in that the starting material is ani65 line and 1,2,3-thiadiazole. 5-yl-carboxylic acid azide was used.