DE2343825A1 - PROCESS FOR THE PREPARATION OF 2-SUBSTITUTED 1,3,4-THIADIAZOL-5THIOLS - Google Patents

Description

PATENT ADVOCATE DR. I. MAAS 8 MUNICH 40

SCHLEiSSHEIMER STR. 2 ^ TEL35? 22Q1 / 2O4

CASE: X-3628

ELI LILLY AND COiMPANY, Indianapolis, Indiana / USA

"Process for the preparation of 2-substituted thiadiazole-S ^ -thi oils"

The invention relates to a process for the preparation of 2 · substituted 1 ^ i ^ -thiadiazole-ij-thiols of the general Formula I.

N-N CC

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in which R is a low molecular weight alkyl group with 1 to 4 carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms, an eenzyl group or a phenyl group. According to the invention, the 2-substituted 1,3 ^ -thiadiazole-5-thiols are obtained with improved yields of about 85 bx3 about 90 % by using a one-pot process which consists in successively adding equimolar amounts of a thioamide in an inert solvent general formula II

(ID RC-NH _n

in which R has the meanings given above or an imino ether salts (or imido ethers) of the general formula III

NH

(RC-OR ') _n. H _n X (III)

in which R has the meanings given above, η 1 or 2, R 'is a low molecular weight alkyl group having 1 to 3 carbon atoms and when η is 1, X is a chlorine atom, a bromine atom or an NO ^ group and when η is 2, an SCv group mean, hydrazine and a base and carbon disulfide are converted in excess and acidified to obtain the product.

The thiols prepared according to the invention are useful intermediates for certain cephalosporin antibiotics.

2-Substituted 1,3, ^ - thiadiazole-5-thiols are valuable Intermediate products for the production of biologically active

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Cephalosporins, e.g. for the preparation of 7- (sydnone-3-acetamido) -3- (5-ethyl-1,3,4-thiadiazol-2-yl-thiomethyl) -3-cephem - ^ - carboxylic acid and 7- (sydnone-3-acetamido) -3- (5-phenyl-1,3, '4-thiadiazol-2-yl-thiomethyl) -3-cephem-4-car boric acid, both of which are known from US Pat. No. 3,530,123. Others 2-substituted 1, ^,. ^ - Thiadiazole-S-thiol-cephalosporin derivatives are from the South African patent specification No. 68 / 02,695 and Chem.Ab-str. 71, 124 ^ 58r (1969) known.

So far, 2-methyl-1,3) 4-thiadiazol-5-thiol has been prepared by the following process by Sandstrom and Wennerbeck (Acta.Chem. Scand. 20, 57 (1966)), which 2-methyl-l, 3,4-thiadiazole-5-thiol with a yield of 74 % according to the method of Goerdeler et al. (Chem. Ber. 89, 153 ¹ J (1956)), the last-mentioned process for the preparation of 2-methyl-1,3, '4-thiadiazole-5-thiol being that 2-amino 5-methyl-1,3,4-thiadiazole

(a) Diazotized and with hydrobromic acid in 2-bromo-5-methyl-1,3,4-thiadiazole convicted and

(b) 2-Bromo-5-methyl-l, 3, l ^1-thiadiazol by treatment with thiourea in the presence of a base in 2-methyl-l, 3> ¹ * - thiadiazol-5-thiol

converts.

The preparation of 2-phenyl-l, 3, l ^{i-thiadiazol-5-thiol} of Thiobenzoesäurehydrazid, potassium hydroxide and carbon disulfide has been described by Young and Wood (J. Amer. Chem. Soc. 77, iJOO (I955)).

Further, 2-benzyl-l, 3, ¹ J-thiadiazol-5-thiol of Phenylacetothiohydrazid, carbon disulfide and potassium hydroxide, according to the Jensen and Pedersen (Acta.Chem.Scand. 15 1124

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(1961) and Chem. Abstr. 56, I4162i (1962)) manufactured.

Japanese patent application published August 17, 1972 No. 32071/72 (Fujisawa) relates to the manufacture of 2-substituted 1,3,4-thiadiazole-5-thiols via dithiocarbazate picolinium salts und'iminoether salts in isopropanol. -

The aim of the invention is to provide an economical process for the production of 2-substituted 1,3,4-thiadiazole-5-thiols, which are valuable intermediates for the production of cephalosporin antibiotics. Another object of the invention is to provide a suitable one-pot process for the preparation of said compounds.

The process according to the invention gives 2-substituted 1,3,4-thiadiazole-5-thiols of the general formula I

N-N

CC
" ^ ^V SH

in which R is a low molecular weight alkyl group with 1 to 4 carbon atoms, denotes a cycloalkyl group with 3 to 6 carbon atoms, a benzyl group or a phenyl group, in excellent yields using a one-pot process carried out on an industrial scale can and that consists in that one in an inert solvent successively equimolar amounts of hydrazine with a Thioamide or an imino ether salt of the general ones given above Formulas and a base and carbon disulfide in excess and the mixture to obtain the product acidified.

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The process consists in that first a thioamide of the general formula I or an imino ether salt of the general formula Formula III is reacted with an equimolar amount of hydrazine in an inert solvent and at least 1 molar equivalent of a base and at least 1 molar equivalent of the Carbon disulfide at a temperature of 0 to about 60 ° ( added to allow the reaction to proceed to completion. The mixture is then acidified to remove the insoluble product to release from the salt form. .,

Examples of compounds of general formula I that can be produced by the process of the invention are the following:

2-methyl-1,3,4-thiadiazole-5-thiol,
2-ethyl-l, 3,4-thiadiazole-5-thiol,
2-propyl-1,3> 4-thiadiazole-5-thiol,
2-Isopropyl-1,3,4-thiadiazole-5-thiol, 2-tert-butyl-1,3> ¹ t-thiadiazole-5-thiol, 2-cyclohexyl ^{-1,3, J} J-thiadiazole-5 thiol, 2-benzyl-1,3,4-thiadiazole-5-thiol and 2-phenyl-1,3,4-thiadiazole-5-thiol.

The thioamides of the general formula II used as starting material for the process according to the invention

R-C-NH

are commercially available or can be prepared by methods known per se (E.E. Reid, "Organic Chemistry of Bivalent oulfor, "Volume IV, Chemical Publishing Co., Inc., New York, N.Y. 3. ^ 5-52 (1962)). Examples of thioamides, which can be used in the process according to the invention

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nen, are thiοacetamid, thiobenζamid, thiobutyramid, isothiobutyramid, Thiophenylacetamide and thiopivalic acid amide.

The imino ether salts of the general formula III used as starting materials in the process according to the invention is obtained by using methods known per se by the simultaneous action of alcohols and acids on nitriles- the general formula

RCN

in which R has the meanings given above, in one anhydrous medium (see ACS Monograph No. IO5, V. Migrdichian, "The Chemistry of Organic Cyanogen Compounds", Reinhold Pub. Corp., New York, N.Y., 19 * 17, CH. 5, pp. 84-96; Chem. Rev. £ 1.179 (1961)). The ones with ethanol, methanol, propanol or isopropanol, hydrobromic, hydrochloric and sulfuric acid salts of the imino ethers are used as starting materials suitable for the method according to the invention. The imino ether is preferably formed from methanol and gaseous hydrogen chloride, both in anhydrous Form are available, as the moisture is harmful to the imino ether formation. The imino ether formation takes place with Methanol at least three times as fast as with ethanol. Representative imino ether hydrochlorides, such as acetimidomethyl ether, Phenylacetimidomethyl ether, isopropionimidomethyl ether, Propionimidomethylether, pivalinimidomethylether, cyclohexylacetimidomethylether and benzimidomethyl ethers are preferred, although other imidoethyl, propyl and isopropyl ether salts are also preferred can be used in the process according to the invention.

The method according to the invention is carried out as follows. First, 1 mol equivalent of thioamide or imino ether salt and hydrazine for about 1 hour at a temperature between

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see O and 6O ⁰ C implemented in an inert solvent. The amount of solvent used is not critical.

If you use a thioamide as the starting material, you can normally use this in technical quality. However, it is preferable to use a poor quality raw material cleaned before use. Thioamides that are darkly colored due to impurities can be tested before they are used can be decolorized in the process according to the invention by treatment with carbon. One can use anhydrous Use hydrazine, although it is more economical and convenient to use the hydrate. The order in which one Combining hydrazine and thioamide together is not important, although the use of the reactants in one Molar ratio of 1: 1 is important in that the formation of a 3> 6 ~ disubstituted tetrazine as a by-product is kept low, whereby higher yields of thiadiazoles are achieved.

If an imino ether is used as the starting material, an amount of solvent should be used that is sufficient to to at least a partial solution of the imino ether salt used to ensure. The imino ether salt is preferably added to the hydrazine. If you do in reverse works, the product is generally obtained in lower yields. The iminoether salt is available as a solid or in the form of a solution in the inert solvent, for which purpose methanol is preferably used. The cold imino ether saline solution is quickly added to alcoholysis of the imino ether to the corresponding orthoester as low as possible, otherwise the yields deteriorate.

Then at least 1 mol equivalent of a base and at least 1 mol equivalent of carbon disulfide to the

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cold reaction mixture added. Appropriately there the base and the carbon disulfide are added in the form of a solution in the inert solvent, these components being added can also be added separately and in whatever order. If you use two equivalents of base, the reaction is over in about 2 hours. It is preferred to use at least a twofold excess Carbon disulfide to ensure a complete reaction.

Since carbon disulfide is a highly toxic substance with a low flash point, the addition of carbon disulfide and the alkali metal hydroxide is preferably carried out at a temperature which is lower than room temperature, and preferably between about 0 and 10 ^° C. At these temperatures, the dangers associated with the use of large amounts of carbon disulfide are kept to a minimum.

For the process according to the invention, bases are those with carbon disulfide do not respond, suitable. Examples of such bases are N-methylmorpholine, N-methylpiperidine, N-methylpyrrolidine, picoline, pyridine, quinoline, sodium ethylate, Triethylamine and, more preferably, alkali metal hydroxides, such as lithium, potassium or sodium hydroxide.

After the reactants have been combined in the cold, the process is carried out at a temperature of about 30 to 60 ^° C., whereupon the product is obtained by acidifying the reaction mixture. The method may also at higher temperatures be carried out, for example at the reflux temperature of the solvent system, _t which the excess carbon disulfide is evaporated is however to be noted that this does not yield improvements are achieved.

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Ala solvents which can be used in the process according to the invention are those which are usually used Reaction solvents that are inert to the starting materials and products. Low molecular weight alcohols such as * methanol, ethanol and propanol are suitable. if if a thioamide is used as the starting material, an aqueous ethanol solution is used as the preferred reaction medium.

If an imino ether salt is used as the starting material, then methanol is a particularly good solvent for that Amidrazone salt formed in situ as an intermediate product. If, for example, acetimidoethyl ether hydrochloride with one mol equivalent Reacting hydrazine in ethanol as a solvent, acetamidrazone hydrochloride is obtained as an intermediate formula

/ NH ₂
CH ₃ C = NNH ₂ -HCl

which is insoluble in ethanol and, if desired, can be isolated and characterized. By reacting the Acetamidrazonsalzes with carbon disulfide and potassium hydroxide to 3 is-methyl-l 2,, ⁱ l ~ thiadiazol-5-thiol in a yield of at least 75% * The amidrazone must be 'not isolated in the-process of the invention, so that the reaction can be carried out in a single reaction vessel.

Mineral acids such as hydrochloric acid, phosphoric acid or sulfuric acid can be used to acidify the reaction mixture v / earth. A preferred mineral acid is sulfuric acid. The insoluble reaction product, namely the 2-substituted one 1,3j ^ -Thiadiazole-S-thiol falls out of the acidified RoaktionsmiGchung from and is obtained by filtration.

409811/1164 ^:

If a thioamide is used as the starting material, hydrogen sulfide gas is obtained as a by-product of the process, so that in this case the sequence of the reaction temperatures used is modified accordingly in order to delay the release of the gas up to the acidification stage. If the addition of carbon disulfide and potassium hydroxide is ^{carried out at about 30 °} C., 60 % of the hydrogen sulfide is released in about 10 minutes. When the temperature is kept during the addition of carbon disulfide below about 10 ⁰ C and then raised to about 30 ° C for reaction, the gas to be released prior to acidification less than 5%. Most of the hydrogen sulphide is then released during the acidification so that the evolution of hydrogen sulphide gas can be regulated by controlling the addition of acid. For example, with a controlled gas release, effective absorption is possible in gas scrubbers operated under alkaline conditions.

According to a preferred embodiment of the invention

1 mol equivalent of hydrazine hydrate was added to thioacetamide in ethanol ^{at a temperature of about 1O 0 C.} The reactants are stirred for about 1 hour after which the reaction mixture is cooled to about 0 ° C. Then will

2 molar equivalents of carbon disulfide were added, the temperature of the reaction mixture being kept below 10 ^° C. Then 1 mol equivalent of potassium hydroxide dissolved in alcohol is added to the cold mixture. After the addition of the alcoholic alkali metal hydroxide solution has ended, the reaction mixture is ^{heated to about 30 °} C. and stirred at this temperature for 2 hours.

Concentrated sulfuric acid is then added to the reaction mixture at a rate such that the released hydrogen sulfide by the for this purpose

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provided alkaline gas scrubber is absorbed. After the addition of acid has ended, the reaction mixture is ^{cooled to below 30 °} C. and stirred for about 30 minutes. The reaction mixture is then cooled to about 15 ° C. and a vacuum is applied for 90 minutes in order to remove traces of hydrogen sulfide. The pressure is then equalized and the mixture is diluted with water. Subsequently, water and alcohol are distilled off under reduced pressure at a temperature of 50.degree. Then, the mixture was diluted again with water at atmospheric pressure and cooled to about 1O ⁰ C to give 2-methyl-l, 3, ¹ * - precipitate thiadiazol-5-thiol. The product is filtered and the filter cake is washed with water, dried to remove sulfate salts and at 60 ⁰ C.

The 2-methyl-1,3,4-thiadiazole-5-thiol thus formed usually contains 1 % or less of 2,5-dimercapto-1,3,4-thiadiazole. The impurity is removed by reprecipitation of the product from water or by recrystallization of the product.

According to a further preferred embodiment of the invention, a cold methanolic solution of 1 mol equivalent of acetimidomethyl ether hydrochloride is added to hydrazine in absolute methanol at a temperature of about 0 ° C. The reactants are stirred in the cold for about 1 hour. Then a methanolic solution of 2 molar equivalents of potassium hydroxide and 2 molar equivalents of carbon disulfide are added to the cold reaction mixture. After completion of the addition, the reaction mixture is heated .to about 40 ⁰ C and stirred for about 2 hours at this temperature. The reaction mixture is then diluted with water and cooled ^{to about 0 ° C.} The cold reaction mixture is acidified with sulfuric acid and the methanol is evaporated off under reduced pressure. To the original volume

^ 0981 ^ / 1184

To adjust again, water is added to the reaction mixture. The aqueous mixture is then cooled to about 15 ° C. and the precipitated product is filtered off. The crude 2-methyl-1,3,4-thiadiazol-5-thiol obtained in this way is obtained by reprecipitation from a basic solution or by
Recrystallization from a suitable solvent purified in the usual way.

The following examples are intended to explain the invention further without, however, restricting it.

example Preparation of 2-methyl-1,3,4-thiadiazole-5-thiol

(A) Acetimidomethyl ether hydrochloride

41.05 S (1 mol) of anhydrous acetonitrile are dissolved in 35.6 g (1.1 mol) of absolute methanol in 150 ml of anhydrous toluene. 40.0 g are then passed in over the course of about 40 minutes
(1.1 moles) of gaseous hydrogen chloride into the stirred
Reaction mixture, with the reaction temperature with
^{Keeps below 20 0} C using an ice bath. The reaction mixture is then heated at 20 ^° C. for about 6 hours
touched. The reaction mixture is cooled to about -10 ⁰ C and the product filtered off. The salt comes with
75 ml of anhydrous toluene washed, whereby 99.3 g
(90.8 %) acetimidomethyl ether hydrochloride, F = about 97
up to 99 ⁰ C. The material can also be characterized by the NMR spectrum in deuterodimethyl sulfoxide, the following characteristic bands being obtained: 2.46 (s, CH ₃ , 3p) j 4.13 (s, OCH ₃ , 3p); 11.8cT (s (wide),
NH ₂ , sp). The product is sensitive to moisture.

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(B) 2-methyl-1,3,4-thiadiazole-5-thiol

3.21 g (0.1 mol) of anhydrous hydrazine are dissolved in 25 ml of absolute methanol and the solution is cooled to about -10 ° C. in a dry atmosphere. Then dissolving 10.96 g (0.1 mol) Acetimidomethyläther hydrochloride in 50 mL of methanol and cool the solution to about 0 ⁰ C from. The cold Imidoätherlösung is added dropwise to the reaction mixture, keeping the temperature below 0 ⁰ C. The reaction mixture is then stirred ^{at Q 0 C for about 1 hour.}

Then 13.2 g (0.2 mol) of 85% potassium hydroxide and 15.2 g (0.2 mol) of carbon disulfide are dissolved in 50 ml of absolute methanol. The two reactants are added dropwise to the reaction mixture, raising the temperature to about 25 ° C. The reaction mixture is then heated ^{to 40 ° C. for about 2 hours.} Then 50 ml of water are added to the reaction mixture and this is cooled to about 0 ° C., 20 ml of concentrated sulfuric acid being added dropwise. The methanol is then evaporated off in vacuo, whereupon the original volume of the reaction mixture is restored by adding water. The aqueous mixture is ^{cooled to about 50 °} C., whereupon the precipitated product is filtered off. The crude product is washed with water, collected and dried to obtain 12.04 g (91%) of 2-methyl-l, 3 _J 4-thiadiazol-5-thiol, m.p. = 177-182 ⁰ C.

10 g of the crude product are suspended in 75 ml of water and the pH is brought to a value of 8.5 with about 8 ml of concentrated ammonium hydroxide. The mixture is filtered and the solids are washed with 10 ml of water. The Wanchwäsoer are combined with the piltrate and the pH of the filtrate is brought to a value of 5.5 with glacial acetic acid in order to precipitate the thiadiazole. The mixture is stirred for about 1.5 minutes and the thiadiazole is filtered off. The solid is washed with 50 ml of water, filtered and

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0AD OBlSlNAL

dried and 8.95 g (89.5 %) of 2-methyl-1,3,4-thiadiazole

Crystals.

thiadiazole-5-thiol, P = 182 to 184 ⁰ C, in the form of colorless

Example 2

Production of 2-benzyl-1,3,4-thiadiazole-5-thiol

(A) phenylacetimidomethyl ether

1 mol of phenylacetonitrile is dissolved in 150 ml of toluene which contains 35.6 g (5 ml, 1.1 mol) of absolute methanol. The mixture

is cooled to about 0 ° C., whereupon 40.0 g (1.1 mol) of gaseous hydrogen chloride are dissolved in the reaction mixture with stirring. Are employed the reaction at a temperature of about 20 ⁰ C for about 20 hours continuously, the Iminoätherhydrochlorid fails. The pesticide is filtered off, washed with anhydrous toluene and dried, 148.6 g of phenylacetimidomethyl ether hydrochloride, P = 86 to 90 ^° C., being obtained.

(B) 2-Benzyl-1,3,4-thiadiazole-5-thiol

37.1 g (0.2 mol) of phenylacetimidomethyl ether hydrochloride are dissolved in 150 ml of absolute methanol and the solution is cooled. Then dissolved 6.42 g (0.2 mol, 6.34 ml) of anhydrous hydrazine in 50 ml of absolute methanol and the solution was cooled to about -1O ⁰ C. The cold solution of the iminoether is added dropwise to the Hydrazinmiachung to give keeps the temperature below ~ b ° C. The reaction mixture is then stirred at 0 ° C. for about 1 hour. 26.4 g (0.4 mol) of 85% potassium hydroxide and 24 ml of carbon disulfide are then dissolved in 100 ml of absolute methanol and the solution is cooled to ⁰ ° C. The cold methanolic solution of the reactants is added dropwise at a temperature of 0 C to the reaction mixture.

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ben. The reaction mixture is then heated to 40 ° C. for about 2 hours, diluted with 1.00 ml of water and cooled to 0 ° C. while 40 ml of concentrated sulfuric acid are added dropwise. The methanol is then evaporated in vacuo, whereupon the original volume of the reaction mixture is restored with water. The precipitated product is filtered off, the solid is washed with water and dried, giving 36.7 g '(88.5 %) of 2-benzyl-1,3, ^ - thiadiazole-5-thiol, P = 114 ° to 117 ° C, in the form of pale yellow crystals.

15 g of the crude product are suspended in 150 ml of water, whereupon the pH of the suspension is brought to a value of 8.5 with about 6 ml of ammonium hydroxide. The mixture is filtered and the solids are washed with water, whereupon 60 ml of a solid, mp = 105-112 ° C, is isolated. The washing waters are combined with the filtrate and the pH of the filtrate is brought to 5.5 with acetic acid. The precipitated product is filtered off, whereupon the solid is washed with water, filtered and dried and 14.0 g (93.5 % yield) of 2-benzyl-1,3, ^ - thiadiazole-S-thiol, F = 115 to 117 ° C.

15 g of the crude product are ml n-hexane, 100 ml of benzene recrystallized by the addition of 50 to give 13.9 g (92.5% yield) of the product with a melting point of 118 ⁰ C to II6.

Analysis: C ₉ H ₈ N ₂ S ₂ MW 208

51 C. 3 H 13th N 30th S. ber .: 51 , 99 3 , 81 13th 30th , 79 found : , 69 , 84 , 36 , 85

A 0 9 8 1

Example 3

Preparation of 2-pbenyl-1,3,4-thiadiazole-5-thiol

(A) Eenzimidoethyl ether hydrochloride

Dissolve 103.1 g (1 mol) of benzonitrile in 53.3 g (1.1 mol) of 95 SSigern ethanol and the solution is cooled to about 0 ⁰ C from. Then, at a temperature of about 0 ⁰ C in the course of 50 minutes HO g is dissolved (1.1 WOI) of gaseous hydrogen chloride in the Koaktionamischung. The reaction mixture is then stirred for 24 hours, the product precipitating out. The reaction mixture is then diluted with 100 ml of ether and the solid product is filtered off. The solid is washed with ether and dried, 39.8 g of benzimidoethyl ether hydrochloride, P = 128 to 130 ^° C. (decomposition), being obtained.

(B) 2-phenyl-1,3,4-thiadiazole-5-thiol

3.21 g (0.1 mol, 3.17 ml) of anhydrous hydrazine are dissolved in 25 ml of absolute methanol and the solution is cooled to about -10.degree. Then you solve 18.6. g (0.1 mol) Benzimidoäthylätherhydrochlorid in 75 ml of absolute methanol and the solution is cooled to about O ⁰ C from. The cold imido ether solution is added dropwise over 10 minutes to the cold hydrazine solution, whereupon the stirring is continued for about 1 hour at 0 ° C. During this time a solid separates out of the solution. 13.2 g (0.2 mol) of 85% potassium hydroxide are then dissolved in 50 ml of absolute methanol. The basic methanol solution is cooled and replaced with 12 ml of carbon disulfide. The reactants are then added quickly and dropwise to the reaction mixture, which is heated ^{to 40 ° C. for about 2 hours.} Then 50 ml of water are added and the reaction mixture is cooled in an ice bath,

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while adding 20 ml of concentrated sulfuric acid dropwise. The methanol is then evaporated off under reduced pressure and made up to the original volume with water. The solid product is filtered off, washed, filtered and dried, and 13.8 g (71 %) of crude 2-phenyl-1,3,4-thiadiazole-5-thiol, melting point 209 to 213 ° C., are obtained

The crude product is then suspended in 100 ml of water and the pH is adjusted to 8.5 with about 7 ml of concentrated ammonium hydroxide solution. The solution is filtered off and the filtrate is brought to pH 5.5 with concentrated hydrochloric acid. The solid thus obtained is filtered off, washed with water, filtered and dried, giving 9.58 g (yield 96 %) of 2-phenyl-1,3,4-thiadiazole-5-thiol, F = about 212.5 to 214 , 5 ° G.

Analysis: CgHgNgSg MW 194

CHNS

calc .: 49.46 3.11 14.42 33.01

Found: 49.30 3.38 14.48 33.28

Example4

To 0.32 g (10 mmol) of anhydrous hydrazine in 50 ml of ethanol 0.75 g (10 mmol) of thioacetamide are added at room temperature. The mixture is stirred for about 30 minutes and then dissolved 0.56 g (10 mmol) of potassium hydroxide in the reaction mixture. 25 ml of carbon disulfide are then added to the reaction mixture and stir for about 30 minutes. The reaction mixture is then cooled down and carefully treated with concentrated sulfuric acid acidified to release the insoluble product from the salt form. The product is collected and dried, whereby

09811/1164 ^SA ^ ORiQ _iNAL

1.08 g (77 %) of 2-methyl-1,3,4-thiadiazole-5-thiol, P = about 183 ^° C., are obtained.

analysis

27 C. 3 H 21 N 48 3 ber .: 27 , 28 3 , 05 20th , 21 48 , 46 found : , 96 , 15 , 94 , 37

Example 5

Using the procedure given in Example 1 is thiobenzanide with 1 mol equivalent of hydrazine in ethanolic Solution implemented. Then 1 mol equivalent of potassium hydroxide is dissolved in the reaction mixture and excess is added Carbon disulfide too. The reaction is brought to an end by warming up on the steam bath. Then the The reaction mixture was cooled in an ice bath and carefully acidified with concentrated sulfuric acid. The precipitated one Product is collected, dried and purified to give 2-phenyl-1,3,4-thiadiazole-5-thiol, P = about 26 ° C.

example

A distiller with a capacity of 3785 liters (1000 gallons) is charged with 920 liters of ethanol and 123.5 kg of thioacetamide and the mixture is stirred at about 30 ° C. until the thioacetamide has completely dissolved. The solution is filtered into a brine container and cooled ^{to a temperature of 0 ° C.} Then 106 kg of hydrazine hydrate are added at such a rate that the temperature does not rise to more than about 15 ° C. The reactants are then stirred at 10 ° C. for about 1 hour. Then the reaction mixture is cooled to about 0 C and with

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198 liters of carbon disulfide are added, the temperature being kept below 10 ° C. Then, while maintaining the temperature, a unter110 ⁰ C a solution of 91 kg of potassium hydroxide in 500 1 of ethanol to the reaction mixture. After the addition of alcohol / alkali has ended, the reaction mixture is heated to about 30 ° C. and stirred at this temperature for 2 hours. The reaction mixture is then diluted with 500 ml of deionized water, whereupon 330 kg of concentrated sulfuric acid are added to the reaction mixture at such a rate that the hydrogen sulfide released is absorbed by the alkaline gas scrubbers provided for this purpose. After completion of the acidification, the mixture is cooled to below 35 C and stirred bei.etwa 30 ⁰ C for 30 minutes. NaGhdem has the mixture cooled to about 50 ⁰ C, hydrogen sulfide traces are removed in vacuo. The pressure is then brought to atmospheric pressure and the reaction mixture is diluted with 500 ml of deionized water. The ethanol is then distilled off at reduced pressure and at a temperature of 50.degree. The reaction mixture is then kept at about 50 ° C. under reduced pressure for 30 minutes, after which the pressure is brought to atmospheric pressure and the mixture is diluted with 300 l of deionized water. The diluted mixture is cooled to about 10 ° C. and the precipitated product is filtered off. The filter cake is washed to remove the sulfate salts, is dried and the product at 6O ⁰ C. 2-Methyl-1,3,4-thiadiazole-5-thiol is obtained in a yield of 185 kg (85 %) . The purity of the product, determined by non-aqueous titration, is 99.6 % _t

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Claims (7)

PATENT CLAIMS: Process for the preparation of 2-substituted thiadiazole-5-thiols of the general formula I. N-N c c R S SH in which R is a low molecular weight alkyl group with 1 to U carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms, a benzyl group or a phenyl group, characterized in that one (a) Molar equivalents of a thioamide of the general formula II (II) in which R has the meanings given above, or an imino etherate of the general formula III NH
(RC-OR ¹ ) _n H _n X (III) 409811/1164 in which R has the meanings given above, η 1 or 2 j Ii 'is a low molecular weight alkyl group having 1 to 3 carbon atoms and X, if η is 1, a chlorine atom, a Bpqmatom or a ΝΟ -, - group and if η is 2, a SOj, group and hydrazine in an inert solvent at a temperature between 0 ⁰ C and 60 ⁹ C converts » (b) "to the reaction mixture at least .1 molar equivalent adding a base and at least 1 mol equivalent of carbon disulfide, (c) acidifying the reaction mixture with a mineral acid and Cd) the 2-substituted l ^^ - thiadiazole-S-thiol from the Reaction mixture isolated. 2. 'The method according to claim 1, characterized in that that the imino ether salt is acetimidomethyl ether hydrochloride begins. 3. Process according to claims 1 or 2, characterized in that the inert solvent is absolute Methanol used. 4. The method according to claim 1, characterized in, that thioacetamide is used as the thioamide. 5 · Method according to claims 1 or 4, characterized characterized in that the inert solvent used is ethanol. 6. The method according to claims 1 to 5, characterized 4 Q 9 8 1 1/11 6 4 characterized in that the mineral acid used is sulfuric acid. 7. The method according to any one of claims 1 to 6, characterized in that the base used is potassium hydroxide . 4 09811/1164 23A3825 Compounds of the general formula I N-N ti It (I) SH wherein R is a lower alkyl group having 1 to ¹ I carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a benzyl group or a phenyl group, obtainable by a process of claims 1 to. 7 409811/1164