GB2081265A

GB2081265A - Process for the Manufacture of 3-acylazopropionic Acid Esters and Isomers Thereof

Info

Publication number: GB2081265A
Application number: GB8123067A
Authority: GB
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1980-07-31
Filing date: 1981-07-27
Publication date: 1982-02-17
Also published as: IE811734L; PL129167B1; RO82381B; PH18326A; PL232401A1; FI812302A7; JPS5754158A; SE8104388L; ATA332681A; YU163881A; FI812302L; LU83517A1; JPS606938B2; FR2487825B1; HU182364B; PT73444B; NZ197844A; CA1162926A; FR2487825A1; AU7360181A

Abstract

3-Acylazo-propionic acid esters of the general formula I <IMAGE> and isomers thereof (in which R1 represents C1-C6-alkyl and R2 represents alkoxy or amino), suitable as starting materials for the manufacture of 1,2,3-thiadiazole-5- carboxylic acid derivatives, are prepared by a process which comprises reacting an acrylic acid ester of the general formula H2C=CH-COOR1 with a hydrazine derivative of the general formula H2N-NH-CO-R2 to form a 3- acylhydrazino-propionic acid ester of the general formula <IMAGE> and oxidizing this ester in an inert solvent with an oxidizing agent.

Description

SPECIFICATION Process for the Manufacture of 3-Acylazopropionic Acid Esters and Isomers Thereof The present invention is concerned with a new process for the manufacture of 3-acylazopropionic acid esters and also isomers thereof including the isomeric formylacetic acid ester acylhydrazones thereof.

Processes for the manufacture of formylacetic acid ethyl ester semicarbazone [W. Wislicenus, H. W. Bywaters, Liebigs Ann. Chem. 356, 50 (1907)] and formylacetic acid ethyl ester ethoxycarbonylhydrazone [R. Raap, R. G. Micetich, Can. J. of Chem. 46,1057 (1968)] are already known. These compounds can be manufactured by reacting the sodium salt of the formylacetic acid ester in question with the corresponding hydrazine derivative, which process requires the synthesis and isolation of the formylacetic acid ester sodium salt. The latter can, however, be manufactured only by using complicated and lengthy working procedures and, moreover, only in unsatisfactory yields (German Patent Specification No.708,513; British Patent Specification No. 568,512).

The problem upon which the present invention is based has therefore been to provide a process that permits the manufacture of 3-acylazo propionic acid esters and also the isomers thereof in a technically simple manner and in high yields.

This problem is now solved according to the process of the present invention.

The present invention accordingly provides a process for the manufacture of a compound selected from a 3-acylazo-propionic acid ester of the general formula I

in which R, represents a C1-C6-alkyl group and sR2 represents an alkoxy group, preferably a C1-C4-alkoxy group, or an amino group, and isomers thereof of the general formula V

in which R, and R2 have the meanings given above, and of the general formula VI

in which R, and R2 have the meanings given above, which comprises reacting an acrylic acid ester of the general formula II

in which R, has the meaning given above, with a hydrazine derivative of the general formula Ill H2N-NH-CO-R2 (III), in which R2 has the meaning given above, if desired with the use of an inert solvent and/or in the presence of a catalyst, to form a 3acylhydrazino-propionic acid ester of the general formula IV

in which R1 and R2 have the meanings given above, and oxidizing this compound of the general formula IV in an inert solvent with an oxidizing agent.

As alkyl groups there may be mentioned, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec.-butyl, n-pentyl and n-hexyl groups.

As alkoxy groups there may be mentioned, for example, methoxy, ethoxy, propoxy and butoxy groups.

The process of the present invention thus makes use of readily available starting materials and makes possible a technically simple and safe manufacture of the desired process products in high yields.

Particular embodiments of the process of the present invention consist in that, the reaction of the acrylic acid ester of the general formula II with the hydrazine derivative of the general formula Ill is carried out at a temperature within the range of from -200C to 1 500C, preferably within the range of from OOC to 500C, and at a pressure within the range of from 1 to 10 atmospheres, preferably at 1 atmosphere, if desired as a baseor acid-catalysed reaction and that approximately equimolar amounts of the acrylic acid ester of the general formula II and of the hydrazine derivative of the general formula III are used, and that the oxidation of the 3-acylhydrazino-propionic acid ester of the general formula IV is carried out with an oxidizing agent, for example a conventional oxidizing agent, at a temperature within the range of from -200C to 1000C, preferably from C to 500 C, and that a 3-acyl-hydrazino-propionic acid ester of the general formula IV is used which is not isolated from the reaction mixture in which it is formed, so that the formation of this ester and the oxidation thereof may be a continuous process.

The process of the present invention is carried out in a technically simple and elegant manner.

The synthesis of the 3-acylhydrazino-propionic acid esters of the general formula IV may be carried out according to the process of the present invention starting with an acrylic acid ester of the general formula II and reacting it with an approximately equimolar amount of a hydrazine derivative of the general formula III in an aqueous medium, in an inert organic solvent, preferably in an aqueous or alcoholic medium, or, if desired, even using no solvent at all.

Advantageously, the acrylic acid ester is added, in portions or diluted with a solvent, for example a C1-C4-alcohol, to a solution of the hydrazine component which is diluted with water or a Ci C4-alcohol. In so doing, the mixing ratio of alcohol/water can vary within wide limits, since both alcohol on its own and water on its own can be used. The ratio by weight of alcohol/water can preferably be 1:1. The reactants may also be added in the reverse order.

The reaction takes place at temperatures of from -200C to 1 500C, preferably from OOC to 500C. The pressure can be from 1 to 10 atmospheres, preferably, however, 1 atmosphere.

Solvents that are inert with respect to the reactants are, for example, C1-C4-alcohols, for example methanol, ethanol, propanol, isopropanol, butanol, sec.-butanol and tert.butanol, halogenated hydrocarbons, for example methylene chloride, chloroform and carbon tetrachloride, aliphatic and aromatic hydrocarbons, for example petroleum ether, pentane, cyclohexane, benzene, toluene and xylene, ethers, for example diethyl ether, tetrahydrofuran, dioxan and ethylene glycol diethylether, carboxylic acid nitriles, for example acetonitrile, and carboxylic acid amides, for example dimethylformamide.

The reaction may be carried out advantageously using a basic or alternatively an acidic catalyst. As basic catalysts there are most frequently used alkai hydroxides, alkali alcoholates, tertiary amines, for example triethylamine and N,N-dimethylaniline, benzytrialkyl ammonium hydroxides, for example benzyltrimethyl ammonium hydroxide, and dialkylcarboxylic acid amides, for example dimethyl-formamide and dimethylacetamide. For the acidic catalysis there may be used sulphuric acid, phosphoric acid, acetic acid, lactic acid and boron trifluoride.

After the reaction has taken place the reaction mixture is worked up, if desired in a manner known per se. After any solvent has been removed, the residue is either fractionally distilled under reduced pressure or recrystallized from suitable solvents, for example ketones, alcohols, nitriles, esters, ethers and chlorinated hydrocarbons, for example acetone, methanol, ethanol, acetonitrile, ethyl acetate, diisopropyl ether and chloroform. The reaction products are obtained in the form of colourless crystals or as colourless liquids that are stable at room temperatures.

When, however, a continuous process is chosen; the reaction product of the general formula IV does not need to be isolated, but can be further processed directly.

The 3-acylazo-propionic acid esters of the general formula I may then be produced according to the process of the present invention by reacting the 3-acylhydrazino-propionic acid esters of the general formula IV with conventional oxidizing agents in an aqueous medium, or in organic solvents that are inert with respect to the reactants, the oxidizing agents being used either in stoichiometric amounts or in excess.

Advantageously, the oxidizing agent is added, in portions as an aqueous solution or altematively" diluted with a solvent, to a solution of the 3acylhydrazino-propionic acid ester which is diluted with water or a solvent. The reactants may also be added in the reverse order. This reaction step takes place at temperatures within the range of from -200C to 1000C, preferably from -50C to 50"C. The reaction time can be between 0.5 hour and 5 hours depending on the reaction temperature.

The following may be mentioned as solvents that are inert with respect to the reactants: aliphatic and aromatic hydrocarbons, for example cyclohexane, heptane, ligroin, benzene, toluene and xylene, and halogenated hydrocarbons, for example chlorobenzene, methylene chloride, chloroform, carbon tetrachloride and 1,2dichloroethane.

In the presence of these solvents, further processing can be carried out even with the crude solutions, since these solvents also behave in an inert manner in the following optional steps.

The following may be mentioned as examples of conventional oxidizing agents which correspondingly determine the choice of solvent: nitric acid, potassium dichromate, potassium permanganate, mercury oxide, ammonium nitrate and sodium nitrate, sodium chlorate, chlorine, alkali metal hypochlorites and alkaline earth metal hypochlorites, ammoniacal hydrogen peroxide, iron (III) chloride, dinitrogen trioxide and lead (IV) oxide.

After the reaction has taken place, the reaction mixture may be worked up in a manner known per se, for example by distilling off the solvent used at a reduced or normal pressure or by extraction, it being possible to use the organic solvents employed in the course of the reaction also as agents for extracting the 3-acylazo-propionic acid esters. The extracts may then be worked up in a known manner, for example after suitable drying by distilling off the solvent used at normal or a reduced pressure. In this manner the 3-acylazopropionic acid esters are obtained in the form of slightly yellow-coloured crystals or oils in an extremely pure form and in very high yields, so that they can be reacted without further purification.

By the oxidation of the 3-acylhydrazinopropionic acid esters of the general formula IV, primary compounds of the structural general formula I are formed as can be seen by examining the nuclear magnetic resonance spectra.

In solution these compounds have the tendency to rearrange to form formylacetic acid ester acylhydrazones of the general formula V

which accordingly represent isomers of the compounds of the general formula I.

The manufacture of the compounds of the general formula V, that is the formylacetic acid ester acylhydrazones, is therefore also included within the scope of the present invention.

The compounds of the general formula V are, on the other hand, in an isomeric equilibrium with compounds of the general formula VI

the manufacture of which is therefore also included within the scope of the present invention.

If desired, an irreversible rearrangement of the compounds of the structural general formula I into the isomeric form(s) of the structural formula(e) V and/or VI can be carried out in a controlled manner, which rearrangement is also included within the scope of the process of the present invention.

According to this optional step of the process of the present invention, the 3-acylazo-propionic acid esters of the general formula I are treated with catalysts, optionally using an inert solvent, R, and R2 having the meanings given above.

One particular embodiment of this process feature consists in that a 3-acylazo-propionic acid ester of the general formula I is rearranged, at a temperature within the range of from --20 OC to 500 C, preferably at a temperature within the range of from ooh to 300C, to form the acylhydrazone of the formylacetic acid ester of the general formula V and to form the enhydrazine of the general formula VI.

This reaction may be carried out using both acid or Lewis acid catalysts and also basic catalysts. The following may be mentioned as examples of acid catalysts: hydrochloric acid, sulphuric acid and nitric acid, HgCI2, (NH4)2SO4, NH4CI, NH4Br, HgBr2, (CH3)3SiOSO2CF3, SnCI4, BF3, p-toluenesulphonic acid hydrate, acetic acid and trifluoroacetic acid.

The following may be mentioned as basic catalysts: oxides, hydroxides, alcoholates and carbonates of the alkaline earth metals and alkali metals, ammonia, tertiary amines, for example triethylamine and N,N-dimethylaniline, and pyridine bases. The isomerization reaction advantageously takes place in an aqueous medium and/or in organic solvents.

The following may be mentioned as inert solvents: halogenated hydrocarbons, for example methylene chloride, chloroform, 1,2- dichloroethane, carbon tetrachloride and chlorobenzene, aliphatic and aromatic hydrocarbons, for example petroleum ether, pentane, heptane, cyclohexane, benzene, toluene and xylene, ethers, for example diethyl ether, tetrahydrofuran, dioxane and diisopropyl ether, and alcohols, for example methanol and ethanol.

The reaction may take place at a temperature within the range of from -20"C to 500C, preferably at a temperature within the range of from OOC to 300C.

In practice the process is carried out in such a manner that an appropriate catalyst is added to the crude solution of the 3-acylazo-propionic acid ester and then the reaction products, which are normally solid, are isolated in the form of colourless crystals by filtration, by freezing-out or by removing the solvent. These can be readily recrystallized from suitable organic solvents, for example ketones, alcohols, nitriles, esters, ethers and chlorinated hydrocarbons, for example acetone, methanol, ethanol, acetonitrile, ethyl acetate, diisopropyl ether and chloroform, and are stable at room temperature. The compounds are generally, however, produced in such a highly pure form that they can be further reacted in the un-recrystallized state.

The products manufactured according to the process of the present invention represent important starting materials for the manufacture of 1 ,2,3-thiadiazole-5-carboxylic acid derivatives from which valuable plant protecting agents and pest-controlling agents and also pharmaceutical products can be manufactured.

This manufacture of 1 ,2,3-thiadiazole-5carboxylic acid derivatives of the general formula VII

in which R1 has the meaning given above, can be carried out, for example, in a manner known per se by reacting the process products of the general formula(e) V and/or VI with thionyl chloride.

The process of the present invention offers, in addition, a new advantageous method of manufacture for the compounds of the general formula VII, by directly reacting the primarily formed process products of the general formula I with thionyl chloride of the formula SOCI2 to form the desired products of the general formula VII, as a result of which one step of the process is avoided (as compared with the reaction of thionyl chloride with compounds of the general formula(e) V and/or VI). This process feature is also included within the scope of the process of the present invention.

The synthesis of the 1 ,2,3-thiadiazole-5carboxylic acid esters of the general formula VII is carried out in this case by starting from 3-acylazopropionic acid esters of the general formula I and reacting them with thionyl chloride. The reaction is carried out at a temperature within the range of from -200C to 1000C, preferably from -50C to 500C. The reaction time can be between 1 hour and 20 hours depending on the reaction temperature.

For the synthesis of the 1 ,2,3-thiadiazole-5carboxylic acid esters, the reactants can be used in approximately equimolar amounts. Thionyl chloride may, however, alternatively be used in a large excess quasi as a solvent.

Advantageously, however, the molar ratio of the 3-acylazo-propionic acid ester to the thionyl chloride used for the reaction is 1:3. The reaction may also proceed in the presence of solvents that are inert with respect to the reactants. As such solvents there may be mentioned: halogenated hydrocarbons, for example methylene chloride, chloroform and carbon tetrachloride, aliphatic and aromatic hydrocarbons, for example petroleum ether, pentane, cyclohexane, benzene, toluene and xylene, ethers, for example diethyl ether, tetrahydrofuran, dioxan, ethylene glycol diethyl ether and diethylene glycol diethyl ether, and esters, for example ethyl acetate.

The 3-acylazo-propionic acid ester, optionally dissolved or suspended in a suitable solvent, is normally added in portions to the thionyl chloride optionally diluted with an organic solvent, but the reactants may also be added in the reverse order.

The hydrogen chloride that is formed during the reaction can be removed continuously from the reaction vessel by means of an inert gas current or by applying a vacuum.

After the reaction has taken place, the reaction mixture may be worked up in a manner known per se.

After distilling off the solvent and any excess thionyl chloride, the residue can be fractionally distilled; alternatively, however, any excess thionyl chloride is destroyed with a saturated soda solution, sodium bicarbonate solution, potassium bicarbonate solution or sodium acetate solution or with a sodium hydroxide solution or potassium hydroxide solution or directly with water and the reaction solution is subjected to steam distillation or extraction, it being possible to use the solvents employed in the course of the reaction also as extracting agents.The extracts may then be worked up in a known manner; for example, after appropriate drying and distillingsff of the solvent, the residue is fractionally distilled under a reduced pressure or simply digested with a suitable solvent, for example an aliphatic hydrocarbon, for example pentane, hexane, cyclohexane or petroleum ether.

The 1 ,2,3-thiadiazole-5-carboxylic acid esters are thus obtained in an extremely pure form and in very high yields, so that they can be further reacted to form the desired end products without being purified.

The following Examples illustrate the invention: Example 1 a) Manufacture of 3-Semicarbazido-Propionic Acid Methyl Ester In a three-necked 2 litre round-bottomed flask equipped with a stirrer, thermometer and reflux condenser having a drying tube, 173.0 g (1.5 moles) of pulverized semicarbazide hydrochloride were suspended in 300 ml of methanol; to this a sodium methoxide solution freshly prepared from 34.4 g (1.5 moles) of sodium and 500 ml of methanol was added dropwise in the course of 10 minutes, the temperature in the flask being kept at between 1 50C and 200C. The reaction mixture was then stirred for a further 1 5 minutes at and then the sodium chloride was filtered off with suction.The filtrate was collected in a three necked 2 litre round-bottomed flask and 90 ml (1.0 mole) of acrylic acid methyl ester were added whilst stirring at 200C in the course of one hour.

The mixture was left to stand for 3 days at room temperature, was then filtered again and then the filtrate was concentrated in vacuo at 400 C. 205 g of a yellow oily product was obtained which was then extracted by stirring for a further hour, at room temperature, with 1 litre of ethyl acetate.

The undissolved material was filtered off and the filtrate was then concentrated to 500 ml at 400C.

White crystals were obtained by trituration which were filtered off with suction and dried in vacuo at room temperature until their weight was constant.

Yield: 134.4 g = 83.4% of the theoretical yield.

M.p: 67-690C.

bl) Manufacture of 3-Carbamoylazo Propionic Acid Methyl Ester In a three-necked 1 litre flask equipped with a thermometer and stirrer, 16.1 g (0.1 mole) of 3 semicarbazido-propionic acid methyl ester were dissolved in 100 ml of water and, whilst cooling with ice, 246.0 g (0.3 mole) of an approximately 10% freshly prepared sodium hypochlorite solution were added in the course of 20 minutes, the temperature in the flask being kept at between 5 and 70C. After stirring the yellow reaction solution so obtained for 10 minutes in an ice bath, 85 g of sodium chloride were added and the mixture was extracted carefully five times, with 400 ml of chloroform each time. The extracts, dried over magnesium sulphate, were concentrated in vacuo at 400C.A yellow crystalline product was obtained.

Yield: 12.9 g = 81.1% of the theoretical yield.

M.p.: 85-870C with decomposition.

b2) Manufacture of 3-Carbamoylazo propionic Acid Methyl Ester In a three-necked 1 litre flask equipped with a stirrer and a thermometer, 16.1 g (0.1 mole) of 3 semicarbazido-propionic acid methyl ester were dissolved in a mixture of 1 50 m of water and 10.3 g of approximately 95% sulphuric acid. Whilst cooling with ice, a solution of 9.79 g (0.0333 mole) of potassium dichromate in 70 ml of water and 13.8 g of approximately 95% sulphuric acid were added dropwise, in the course of 10 minutes, at a reaction temperature of from 70C to 1 00C. The mixture was then left to react for a further 10 minutes and then 20.0 g of solid potassium bicarbonate were added. Yellow crystals separated. The reaction solution was extracted intensively five times, with 300 ml of chloroform each time. The chloroform extracts, dried over magnesium sulphate, were concentrated in vacuo at 400C. Yellow crystals were obtained.

Yield: 9.0 g = 56.5% of the theoretical yield.

M.p.: 85-870C with decomposition.

c) Manufacture of 3-Semicarbazonopropionic Acid Methyl Ester In a three-necked 250 ml flask equipped with a thermometer and a stirrer, 15.9 g (0.1 mole) of 3carbamoylazo-propionic acid methyl ester were dissolved in 100 ml of chloroform and 0.5 ml of triethylamine was added, the temperature in the flask being kept at 300C by cooling. The mixture was then stirred for a further hour at room temperature and then the resulting crystalline magma was concentrated to dryness by evaporation in vacuo at 400C. The residue was digested with 1 50 ml of diisopropyl ether, filtered with suction and dried in vacuo until its weight was constant.

Yield: 14.5 g =91.1% of the theoretical yield.

M.p: 1 590C with decomposition.

Example 2 a) Manufacture of 3 Ethoxycarbonylhydrazino-propionic Acid Methyl Ester In a three-necked 1 litre flask equipped with a stirrer, thermometer and reflux condenser, 114.4 g (1.1 moles) of hydrazinoformic acid ethyl ester were dissolved in 600 ml of ethanol and 90 ml (0.1 mole) of acrylic acid methyl ester was added at 200C in the course of one hour. The mixture was left to stand for 4 days at room temperature in a sealed flask and then the reaction solution was concentrated in vacuo at 400 C. The liquid so obtained was distilled in vacuo.

Yield: 111.1 g = 58.4% of the theoretical yield.

B.p.: 110--1110C/0.1 torr.

b) Manufacture of 3-Ethoxycarbonylazopropionic Acid Methyl Ester In a three-necked 250 ml flask equipped with a stirrer and a thermometer, 9.5 g (0.05 mole) of 3ethoxycarbonyl-hydrazinopropionic acid methyl ester were dissolved in 50 ml of water and 82 g (0.1 mole) of an approximately 10% freshly prepared sodium hypochloride solution were added in the course of 20 minutes, the temperature in the flask being kept at between 50C and 70C. A yellow oil separated. The mixture was then stirred for a further 10 minutes in an ice bath, extracted three times, with 75 ml of chloroform each time, and a yellow viscous oil was obtained after drying over magnesium sulphate and concentrating the chloroform phases by evaporation in vacua at 400C.

Yield: 8.7 g = 92.4% of the theoretical yield.

no20: 1.4424.

c) Manufacture of 3 Ethoxycarbonylhydrazino-propionic Acid Methyl Ester In a three-necked flask equipped with a stirrer and a thermometer, 18.8 g (0.1 mole) of 3ethoxycarbonylazo-propionic acid methyl ester were dissolved in 100 ml of chloroform and 0.5 ml of triethylamine was added at 300C, during which operation the mixture had to be cooled owing to the exothermic course of the reaction.

Stirring was then subsequently carried out for a further hour at room temperature and then the reaction solution was concentrated in vacuo at 400C. The oil remaining as residue was digested with 50 ml of diisopropyl ether and the crystals so obtained were filtered with suction and dried.

Yield: 17.9 g = 95.2% of the theoretical yield.

M.p: 60-61 OC.

Example 3 Manufacture of 3-Semicarbazono-propionic Acid Methyl Ester (continuous) In a three-necked 1 litre flask equipped with a thermometer and a stirrer, 16.1 g (0.1 mole) of 3semicarbazido-propionic acid methyl ester, prepared as described in Example 1 a), were dissolved in 100 ml of water and, whilst cooling with ice, 141.6 g (0.2 mole) of an approximately 10% freshly prepared sodium hypochlorite solution were added in the course of 20 minutes, the temperature in the flask being kept at between 50C and 70C. The yellow reaction solution was then stirred for a further 20 minutes in an ice bath, 66 g of sodium chloride were added and then the mixture was extracted carefully five times, with 400 ml of the chloroform each time.

The chloroform phases, dried over magnesium sulphate, were concentrated to 100 ml at 400C in vacua. 0.5 ml of triethylamine was added to the chloroform solution concentrated to 100 ml, the temperature in the flask being kept at 300C by cooling. After stirring for one hour at room temperature, the resulting crystalline magma was concentrated to dryness at 400C in vacua. The residue was digested with diisopropyl ether, filtered with suction and dried in vacuo until its weight was constant.

Yield: 12.0 g = 75.5% of the theoretical yield.

M.p.: 158.5-1 59.50C with decomposition.

Example 4 Manufacture of 3-Ethoxycarbonylhydrazonopropionic Acid Methyl Ester (continuous) In a three-necked 500 ml flask equipped with a stirrer and a thermometer, 19.0 g (0.1 ml) of 3ethoxyca rbonylhydrazino-propionic acid methyl ester, prepared as described in Example 2a), were dissolved in 100 ml of water and 141.6 g (0.2 mole) of an approximately 10% sodium hypochlorite solution were added in the course of 20 minutes, the temperature in the flask being kept at between 50C and 70C. A yellow oil separated.

The mixture was then stirred for 10 minutes, and extracted three times, with 1 50 ml of chloroform each time, and the chloroform phase was concentrated to 100 ml after drying over magnesium sulphate.

0.5 ml of triethylamine was added to the chloroform solution concentrated to 100 ml, during which operation the temperature should not exceed 300C. After subsequent stirring for one hour at room temperature, the reaction solution was concentrated by evaporation in vacuo at 400 C; the oily residue was then digested with 50 ml of diisopropyl ether and the colourless crystals formed were filtered with suction and dried.

Yield: 12.9 g = 68.5% of the theoretical yield.

M.p. 59-61 OC.

Example 5 Manufacture of 3-Ethoxycarbonylhydrazono- propionic Acid Methyl Ester In a three-necked 500 ml flask equipped with a stirrer and a thermometer, 19.0 g (0.1 mole) of 3 ethoxycarbonylhydrazino-propionic acid methyl ester, prepared as described in Example 2a), were dissolved in 1 50 ml of water and a solution of 9.79 g (0.0333 mole) of potassium dichromate in 70 ml of water and 17.2 g (0.167 mole) of 95% sulphuric acid were added in the course of 1 5 minutes. The temperature in the flask was kept at between -20C and OOC for 30 minutes. The mixture was then extracted twice, with 40 ml of chloroform each time. After drying over magnesium sulphate, the chloroform solution was concentrated by evaporation in vacuo at 400C.

The oil remaining as residue was digested with diisopropyl ether and the resulting crystals were filtered with suction.

Yield: 12.4 g=65.9% of the theoretical yield.

M.p.: 57-61 OC.

Example 6 Manufacture of 1,2,3-Thiadiazole-5-carboxylic Acid Methyl Ester In a three-necked 250 ml roundbottomed flask equipped with a stirrer, thermometer and a condenser having an outlet into the fume cupboard, 21.8 ml (0.3 mole) of thionyl chloride were cooled to -1 00C and 15.91 g (0.1 mole) of 3-carba moylazo-propionic acid methyl ester, prepared as described in Example 1 b1) or 1 b2), were added in portions in the course of 15 minutes, the temperature in the flask being kept at between -50C and OOC. After the addition had been completed the yellow reaction solution was stirred for a further two hours, while allowing the temperature in the flask to rise slowly to +20C.

The solution was then diluted with 60 ml of chloroform and carefully decomposed with 60 ml of a saturated potassium bicarbonate solution, the temperature in the flask being kept at between 100 and 200C. The chloroform phase was separated off, washed until neutral with 30 ml of a potassium bicarbonate solution, dried over maqnesium sulphate and concentrated in vacuo at 400C. The resulting liquid was distilled in a water jet vacuum.

Yield: 11.6 g = 80.5% of the theoretical yield.

B.p.: 1 10--1 1 1 or/14 torr.

Claims

Claims:

1. A process for the manufacture of a compound selected from a 3-acylazo-propionic acid ester of the general formula I

in which R, represents a C1-C0-alkyl group and R2 represents an alkoxy group or an amino group, and isomers thereof of the general formula V

in which R, and R2 have the meanings given above, and of the general formula VI

in which R, has the meanings given above, with a hydrazine derivative of the general formula Ill H2N-NHO-R2 (III), in which R2 has the meaning given above, to form a 3-acylhydrazino-propionic acid ester of the general formula IV

in which R, and R2 have the meanings given above, and oxidizing this compound of the general formula IV in an inert solvent with an oxidizing agent.

2. A process as claimed in claim 1, wherein R2 represents a C,C4-alkoxy group.

3. A process as claimed in claim 1 or 2, wherein the reaction of the acrylic acid ester of the general formula II with a hydrazine derivative of the general formula Ill is carried out in an inert solvent.

4. A process as claimed in any one of claims 1 to 3, wherein the reaction of the acrylic acid ester of the general formula II with the hydrazine derivative of the general formula III is carried out in the presence of a catalyst.

5. A process as claimed in claim 4, wherein the catalyst is a basic or an acidic catalyst.

6. A process as claimed in any one of claims 1 to 5, wherein the reaction of the acrylic acid ester of the general formula II with the hydrazine derivative of the general formula Ill is carried out at a temperature within the range of from -200C to1 500C.

7. A process as claimed in claim 6, wherein the temperature is within the range of from OOC to 500 C.

8. A process as claimed in any one of claims 1 to 7, wherein the reaction of the acrylic acid ester of the general formula II with the hydrazine derivative of the general formula Ill is carried out at a pressure within the range of from 1 to 10 atmospheres.

9. A process as claimed in claim 8, wherein the pressure is 1 atmosphere.

10. A processs as claimed in any one of claims 1 to 9, wherein approximately equimolar amounts of the acrylic acid ester of the general formula II and of the hydrazine derivative of the general formula Ill are used.

11. A process as claimed in any one of claims 1 to 10, wherein the oxidation of the 3acylhydrazino-propionic acid ester of the general formula IV is carried out with a conventional oxidizing agent at a temperature within the range of from -2O0Cto 1000C.

12. A process as claimed in claim 11, wherein the temperature is within the range of from -50C to 500C.

13. A process as claimed in any one of claims 1 to 12, wherein the 3-acylhydrazino-propionic acid ester of the general formula IV is not isolated from the reaction mixture in which it is formed, and the formation of this ester and the oxidation thereof is a continuous process.

14. A process as claimed in any one of claims 1 to 1 4, wherein a resulting compound of the general formula I is rearranged to form a compond of the general formula V and/or a compound of the general formula VI by treatment with a catalyst.

1 5. A process as claimed in claim 14, wherein the catalyst is an acid or a Lewis acid.

1 6. A process as claimed in claim 14, wherein the catalyst is a base.

1 7. A process as claimed in any one of claims 1 4 to 16, wherein the rearrangement is carried out in a solvent.

1 8. A process as claimed in any one of claims 14 to 17, wherein the rearrangement is carried out at a temperature within the range of from -200C ta 500C to form a compound of the general formula V and a compound of the general formula VI.

1 9. A process as claimed in claim 18, wherein the temperature is within the range of from OOC to 300C.

20. A process as claimed in claim 1, conducted substantially as described herein.

21. A process as claimed in claim 1, conducted substantially as described in any one of Examples 1 to 5 herein.

22. A process as claimed in any one of claims 1 to 13, 20 and 21, wherein a resulting compound of the general formula I is reacted with thionyl chloride of the formula SOCI2 to form a 1 ,2,3-thiadiazole-5-carboxylic acid derivative of the general formula VII

in which R, represents a C1-C6-aI kyl group.

23. A process as claimed in claim 22, wherein the reaction is carried out at a temperature within the range of from -200C to 1 000C.

24. A process as claimed in claim 23, wherein the temperature is within the range of from -50C to 500 C.

25. A process as claimed in any one of claims 22 to 24, wherein the molar ratio of the compound of the general formula I to the thionyl chloride used for the reaction is 1:3.

26. A process as claimed in claim 22, conducted substantially as described herein.

27. A process as claimed in claim 22, conducted substantially as described in Example 6 herein.

28. A process as claimed in any one of claims 1 to 21, wherein a resulting compound of the general formula V and/or a resulting compound of the general formula VI is/are reacted with thionyl chloride of the formula SOCK, to form a 1,2,3- thiadiazole-5-carboxylic acid derivative of the general formula VII

in which R, represents a C1-C6-alkyl group.

29. A 3-acylazo-propionic acid ester of the general formula I given in claim 1, in which R1 and R2 have the meanings given in claim 1, whenever made by the process claimed in any one of claims 1 to 13,20and21.

30. A compound of the general formula V given in claim 1, in which R, and R2 have the meanings given in claim 1 and/or a compound of the general formula VI given in claim 1, in which R, and R2have the meanings given in claim 1, whenever made by the process claimed in any one of claims 1 to 21.

31. A 1 ,2,3-thiadiazole-5-carboxylic acid derivative of the general formula VII given in claim 22, in which R1 represents a C1-C6-alkyl group, whenever made by the process claimed in any one of claims 22 to 28.