DE2612761A1 - SUBSTITUTED, HETEROCYCLIC THIOLS AND METHOD FOR MANUFACTURING IT - Google Patents

Description

DR A VAN DER WERTH DR. FRANZ LEDERER REINER F. MEYER

DlPL-ING. (1934-1974) DIPL-CHEM. DlPL-ING.

8000 MUNICH 80 LUCILE-GRAHN-STRASSE 22

TELEPHONE: (089) 472947 TELEX: 524624 LEDERD TELEGR .: LEATHER PATENT

February 27, 1976 PLC.246 (PC. 5734)

Pi ¹ IZER COEPOMTIOIi Calle 15 1/2, Avenida Santa Isabel, Colon, Panama

Substituted heterocyclic thiols and methods for their

Manufacturing

The invention relates to substituted, heterocyclic thiols, in particular substituted 1,3 »4-thiadiazole, 1,3,4-oxadiazole or 1,2,4-triazole-5-thiols and a process for their preparation.

Thiols are, for example, useful intermediates in the preparation of cephalosporins and, in particular, of cephalosporins which have a substituted 1,3,4-thiadiazole, 1,5,4-oxadiazole or 1,2,4-triazole-5 in the 3-position -ylthiomethyl group. Certain cephalosporins of this type are described in the applicant's patent application with the same filing date and the title "Cephalosporxn derivatives, processes for their preparation and pharmaceuticals containing them" (corresponding British patent applications 12813/75 and 43955/75). _609841/1034

The invention therefore relates to new, heterocyclic thiols of the following general formula:

N N

^ H

where R is a radical of the following formula:

-CH ₂ OCH ₂ COOH, -CH ₂ OCH ₂ C00- (C ₁ -C ₄ -alkyl),

1 2
wherein R and R independently of one another are hydrogen or C _x , -C _z , -

1 2 i 2 ir

Are alkyl, or -CONR R, in which R and R are as defined above, and

X = O, S, NH, NCH, or NB, where B is a benzyl radical or p-methoxybenzyl radical means;

as well as ammonium or alkali metal salts thereof.

The alkali metal salts are preferably the sodium or potassium salts.

When R is a -CH ₂ OCH ₂ COOH group, the salts can be di ~ (alkali metal) or diammonium salts, e.g. B .:

NN, _{T n}

uj (IA)

KS ^^ T ^

X is preferably 0, S, NH or IMe. R is particularly preferably a -CONHp group. In another embodiment, R is preferably a -CE ₂ OCH ₂ C00- (C 1 -C 4 alkyl) or -CH ₂ OCH ₂ group. The most preferred thiols are those in which:

B 0 9 8 / * 1/1 0 3 4

(a) X = NH and R = -

(b) X = NK and R = -

(c) X = NH and R = - ₂₂

(d) X = S and R = -CH ₂ OCH ₂ COOH,

(e) X = S and R = -CH ₂ OCH ₂ COOEt and

(f) X = 0 and R = -CH ₂ OCH ₂ COOH.

Here "means Et = ethyl and Me = methyl.

The connections can be made in a number of ways including in the following ways:

(1) The thiadiazoles according to the invention can be acid-catalyzed Cyclization of a compound of the following general formula:

NH NH

I I (ii)

wherein R has the meaning given for formula (I), or an alkali metal salt thereof can be prepared.

In a typical procedure, the compound of formula (II) is slowly converted to concentrated sulfuric acid at a low temperature, e.g. B. 0 ⁰ C, added. After a short period of time, the reaction mixture can be carefully added to an ice / water mixture to precipitate the desired product, which can then be filtered off, washed with water and dried.

The compounds of formula (II) can be prepared by conventional methods, e.g. B. by implementing a connection using the following formula:

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RCONHNH ₂ (III)

with carbon disulfide in the presence of a base.

(2) The oxadiazoles of the formula (I) can be prepared by base-catalyzed cyclization of a compound of the formula (II) or an alkali metal salt are made from it.

In a typical reaction, compound (II) can be mixed in a suitable solvent with potassium hydroxide in absolute alcohol implemented.

(3) The compounds of the formula (I) in which X = NMe, can be obtained by cyclizing a compound of the formula (IV) which itself is obtained by reacting a compound (III) with methyl isothiocyanate is prepared according to the following reaction scheme getting produced:

CH ₅ NCS cyclization RCONHNH ₀ ^ NH NH ■ - ■> Ν ——— Ν

¹ I -KJ

, C ^ C HS XST—

S " ^X NH 0 R CH ₇ .

(in) χ ^ c _n hs ^ -iK ε

NH 0

(I B)

In some cases, the compound (IV) can be cyclized to the compound (I B) by mere heating, although the Presence of a base, e.g. B. sodium hydride, is sometimes required.

A typical reaction will be a solution of methyl isothiocyanate in a suitable solvent, e.g. B. dry

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Tetrahydrofuran, slowly to a solution of the hydrazide (III) in a suitable solvent, e.g. B. absolute alcohol, added, and the reaction mixture is then at room temperature stirred for several hours, filtered, and the filtrate evaporated in vacuo and washed with z. B. dry ether triturated to obtain the intermediate product (IV). However, it is not absolutely necessary to use the intermediate product isolate. The intermediate can then be added to a solution of sodium hydride in a suitable solvent, e.g. B. dry Ethanol, are added and the reaction mixture can e.g. B. heated under reflux for several hours, cooled and with z. B. dilute hydrochloric acid to a lower pH, e.g. B. pH = 2, acidified * The organic solvent can be removed in vacuo, and the aqueous residue can be extracted with a suitable solvent, e.g. ethyl acetate and the organic phase can be dried and evaporated to dryness to obtain the desired product.

(4) The compounds of the formula (I) in which X = NH can be _{prepared by procedures similar to those described above under (3), but using isothiocyanic acid f} HiTCS instead of methyl isothiocyanate.

However, preference is given to the compounds in which X = NH, via compounds in which X = NB, by cyclization a compound of the following general formula:

NH NH

AA ^(T)

S IiH 0 R

where B is a benzyl radical or a p-methoxylbenzyl radical, to produce a compound of the following general formula:

609841/1034

ir

Ci c)

and then made by removing the B group.

In general, the "compound (V)" cyclizes on heating, although the presence of a base such as sodium hydroxide may sometimes be required. Group B can, if necessary removed, e.g. B. by reaction with trifluoroacetic acid (or another suitable strong acid) or by reduction with hydrogen.

The compounds of the formula (V) can be prepared by reacting a compound of the following general formula:

KCO3mUH ₂ (III)

made with benzyl or p-kethoxybenzyl isothiocyanate will. Often the compound (V) cyclizes under the reaction conditions to the compound (I C).

In a typical reaction, therefore, the isothiocyanate and the compound (III) e.g. B »under reflux in a suitable solvent, e.g. B. absolute alcohol, for several Heated for hours. The reaction mixture is then filtered, the filtrate is evaporated in vacuo and the oil obtained is with z. B. triturated dry ether to obtain the intermediate of formula (I C). The intermediate product is then preferably removed from the protecting group by a suitable strong acid, e.g. B. trifluoroacetic acid, exempted. This is typically done by heating the intermediate in a mixture of fluoroacetic acid and anisole for a few

609841/1034

Hours, cool, evaporation of the reaction table in the Performed vacuum and trituration of the product obtained with a suitable solvent.

Alternatively, intermediates (V) in which R = or -CH ₂ OCH ₂ CONH ₂ can be prepared as follows:

R-C00- (C ₁ -C ₄ alkyl) + B-NHCSNHNH ₂ > BNHCSNHNHCOR.

(R = only CONR ¹ Ii ² or ¹²

(5) The compounds of the formula (I) ₁ in which R is a -CH ₂ OCH ₂ CONR ¹ R ² - or ~ CONR ¹ R ² group, can be selected from the corresponding compounds in which R is a -

₂₂ ^

alkyl) - or a -COO- (C _{/ 1} -C ^ -alkyl) group, by reaction

1 2
with a compound of the formula RR NH. When ammonia is used, it is preferably in the form of ethanol saturated with ammonia.

The compounds in which R is a -COO- (C ^ -C ^ -alkyl) group can be prepared according to the methods (1) to (4) described above, but starting materials are used in which R is a - Is COO (C _y . _{-C z} ^ alkyl) group.

The compounds in which R is a -CHpOCH ^ COOH group, can from their C ^ -C ^ -alkyl esters by acidic or alkaline Hydrolysis can be produced.

It should be noted that when R in routes (1) to (4) described above is _{a -CH 2 OCH 2} C00- (C ₁ -C ^ -alkyl) group, hydrolysis of this group to the corresponding, free one Acid can occur automatically under the reaction conditions, especially in base-catalyzed cyclizations.

609841/1034

The esters can be obtained from the corresponding acids by esterification, e.g. B. with a C.-C.-alkanol.

The reactions described above under (5) can be carried out before or after group B has been removed.

(6) The salts of compounds of formula (I) can be prepared by conventional methods, e.g. B. through implementation of the thiol with an aqueous or ethanolic solution of the suitable alkali metal hydroxide.

It should be noted that the thiols of formula (I) also be in a tautomeric form, d. H";

• π I

It should be noted that the following tautomerism is also is possible:

The thiols according to the invention can be used for the production of cephalosporins, as they are described in the applicant's aforementioned patent application, e.g. B. by reacting the thiols with a compound of the following formula:

609841/1034

CONH

COOH ρ
wherein: R = H or OH, Y = OH, KH ₀ or a protected one

Is amino or hydroxyl group, and R is a readily removable Group, for example chlorine, bromine, iodine or acetoxy. Alternatively the reaction of the thiols with the group R can be carried out before the acylation of the 7-amino group, whereby this Acylation is carried out subsequently.

The invention is illustrated in more detail by means of the following examples.

example 1

a) Potassium 3- (ethoxycarbonylinethoxyacetyl) dithiocarbazate. 15 g of ethoxycarbonylmethoxyacetohydrazide (EtOXOXH ₂ OCH ₂ were suspended in 200 ml of ethanol at 0 ° C., and 26.7 ml of carbon disulfide were added dropwise. A solution of 5-6 g of potassium hydroxide in 60 ml of ethanol was then added over 30 minutes, and the Reaktionsgeinisch was stirred for another 30 minutes at 0 ⁰ C. Finally, the refrigerant was removed and the reaction mixture was stirred overnight. Bas product, potassium 3- (äthoxycarbonylmethoxyacetyl) -dithiocarbazat (EtOXOXH ₂ OCHpCOIIH MICS ₂ K) was obtained from the The reaction mixture was filtered off, washed successively with ethanol and then ether and finally dried in vacuo. The yield was 4-3.5 g. This product was used in the next stage without further purification.

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4 g of the product obtained under a) were added in portions with stirring over 15 minutes to 20 ml of ice-cold, concentrated sulfuric acid. After the last addition, the reaction mixture was stirred for a further 10 minutes and it was then carefully added to 200 g of an ice / water mixture. The insoluble product, 2- (Äthoxyearbonylmetho: xymethyl) -i ', J> , 4-thiadiazol-5-thiol, was filtered off, washed with water and finally dried in a vacuum. The yield was 2.4 g. A small analytical sample was recrystallized from 20% ethanol / water in the form of x ^ Eissen needles with mp = 80-82 ^0C.

Analysis for C ₇ H ₁₀ U ₂ O ₃ S ₂ :

calculated: C = 35.90 H = 4.30 N = 11.96 % found: C = 35.83 H = 4.25 IT = 11.85%

Example 2

6.0 g of the product from Example 1 b) were added to a stirred solution of 4.5 g of potassium hydroxide in 150 ml of absolute alcohol, and after one hour the insoluble product was filtered off, washed successively with alcohol and ether and finally im. Vacuum dried. The yield of the pale yellow solid was 7 »0 g. The analysis showed that the Ilonohydrat of the dipotassium salt of 2- (carboxymethoxymethyl) -1,3,4-thiadiazol-5-thiol with mp = 269 - 270 was ⁰ C (dec.).

Analysis for C ₅ H ^ N ₂

calculated: C = 20.00 H = 2.00 N = 9.33 % found: C = 20.5 H = 1.92N = 9.19%

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Example 3

2- (carbamoylmethoxymethyl) -1,3,4-thiadiazole-5-thiol with

F. = 216-217 ° C was made from the product of Example 1 through its treatment with ethanol saturated with ammonia in a similar procedure as in the following example 15, c) described, manufactured.

Analysis for C ₁ -Hr ₇ N ^ O ₂ S ₂ :

calculated: C = 29.23 H = 3.44 N = 20.46 % found: C = 29.13 H = 3.48 N = 19.51 %

Example 4

2- (N-Hethylcarbamoyl) 1,3,4-thiadiazole-5-thiol was prepared from the corresponding 2-ethoxycarbony compound by reaction with methylamine. The 2-ethoxycarbonyl compound used as starting material was prepared in a manner similar to that in Example 1, but starting from the ethyl ester of oxalic acid moriohydrazide (EtOCX) .CONENH ₂ ) and carbon disulfide.

Example 5

A solution of 0.22 g of potassium hydroxide in 2.5 ml of alcohol was added to a suspension of ethoxycarbonylmethoxyacetohydrazide in 4 ml of alcohol, followed by 0.95 ml of carbon disulfide and 0.54 ml of dimethyl sulfoxide. The reaction mixture was then refluxed for 12 hours, cooled, filtered and the filtrate evaporated in vacuo. The resulting oil was dissolved in water, filtered, and the filtrate was acidified to pH = 2.0 with aqueous 2N hydrochloric acid. The extraction of the reaction mixture with ethyl acetate and evaporation of the solvent gave the product, 2- (Äthoxycarbonylmethoxymethyl) -1,3,4-oxadiazol-5-thiol, in the form of 0.5 g of white solid with mp = 101-103 ⁰ C.

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Analysis on

calculated: C = 38.53 H = 4.62 N = 12.84-%

found: C = 38.82 H = 4.4-5 N = 12.86 ° / Ό

Example 6

2.0 g of the product from Example 5 were stirred at room temperature in 20 ml of aqueous 2N potassium hydroxide solution for 4 hours. The resulting solution was covered with a layer of ethyl acetate, and aqueous 2N hydrochloric acid was added to lower the pH to 2.0. The organic layer was separated off, _{dried (with WgSO 4} ) and evaporated to give a solid which, in the Thin-layer chromatographic analysis showed that it still contained a small proportion of unreacted starting material. 1.0 g of the solid was then stirred overnight with a solution of 0.5 g of potassium hydroxide in 10 ml of ethanol, and the insoluble solid obtained, namely the dipotassium salt of 2- (carboxymethoxymethyl) -1,3j4 ~ oxadiazole-5- thiol, was filtered off, washed with alcohol and dried in vacuo. The yield was 1.0 g; F. = 207 210 ⁰ C (dec.).

A sample of the salt was converted to the free acid by treatment with dilute hydrochloric acid, they had a melting point of 126 - '129 ⁰ C and the following analysis:

Analysis for C ₅ H ₆ N ₂ O ₄ S:

calculated: C = 31.58 H = 3.16 N = 14.74% found: C = 31.69 H = 3.15 N = 14.63%

609841/1 03-4

26127B1

Examples 7-10

The following oxadiazoles were prepared by reacting 2-ethoxycarbonyl-1,3, ^ - oxadiazole-5-thiol with ammonia, methylamine, ethylamine or dimethylamine in a manner similar to that described in Example 15 c) below. The 2-ethoxycarbony compound used as the starting material was prepared in a manner similar to that in Example 5, except that EtOOCCOKHKR ₂ ″ was used as the starting hydride.

HS

-K

E.g.

F. ( ⁰ C)

Analysis values in %

(calculated values in

Brackets)

7th -COWH ₂ 3 2 237 (Decomp.) 24.92
(24.82 2.09
2.08 29! 95) 8th -COIiHCH, - - - _ - 9 -CONHEt 210 (Decomp.) 35.00
(34.67 4.14
4.08 24.00
24.26) 10 185 - 187 34.81
(34.67 3.99
4.08 23.76
24.26)

Example 11

a) A solution of 3.52 g of methyl isothiocyanate in 20 ml of dry Tetrahydrofuran became a suspension over 30 minutes of 8.50 g ethoxycarbonylmethoxyacetohydrazide in 50 ml added absolute alcohol, and the reaction mixture was stirred for a further 2 hours. The solution was filtered, and the clear filtrate was evaporated in vacuo.

609841/1034

Trituration of the residue with dry ether gave 8.0 g of the compound CH ₅ HHCSHHMHCOCH ₂ OCH ₂ CO-OEt as a white solid.

Analysis for CgH ₁₅ N ₅ O ^ S:

calculated: C = 38.55 H = 6.02 N = 16.87 % found: C = 38.77 H = 6.21 N = 17.03 %

b) 2.49 g of the product from a) were added to a solution of 0.3 g of sodium hydride in 50 ml of dry alcohol, and the reaction mixture was refluxed for 2 hours. The reaction mixture was then cooled and divided evenly into two parts (i) and (ii). Aqueous 2N hydrochloric acid was added to part (i) to reduce the pH to 2.0 and the organic solvent was then removed in vacuo. Extraction of the aqueous residue with ethyl acetate and evaporation of this dried (via rig SO.) Extract gave 300 mg of 3- (ethoxycarbonylmethoxymethyl) -4-methyl-1,2,4-triazole-5-thiol as a white solid with a melting point of 86-88 ⁰ C.

IR analysis (KBr) i _, ..__ = 1-740 cm "' ¹ (ester carbonyl) NMR analysis (DMSO ,, -) <S = 1.15 (center of the triplet, J« 7 c / s,

₄₆

Ester CH,)

3.5 (singlet, N- ₅

4.1 (ilultiplett, CH ₂ and Ester-CH ₂ )

4.6 (singlet, CH ₂ ) ppm

NMR = nuclear magnetic resonance

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Example 12

This example "describes the preparation of 3-carboxymethoxymethyl-4-methy1-1,2,4-triazole-5-thiol.

Part (ii) of Example 11 was evaporated in vacuo, the residue was dissolved in water, acidified with 2IT aqueous hydrochloric acid, and the solution was then extracted with ethyl acetate. The dried (over MgSO ^,) extract was evaporated in vacuo to give a white solid. TLC analysis showed this to be a 50/50 mixture of the ester of Example 11 and the desired acid. This mixture was then stirred in 2N aqueous sodium hydroxide solution for 2 hours, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The dried (over MgS (X) organic extract was evaporated in vacuo, giving 0.25 g of 3- (carboxymethoxyethyl) -4-methyl-1,2,4-triazol-5-thiol as a white solid with P. = 155 - 156 ⁰ C were obtained.

Analysis for C ₆ HQK ₅ O ₅ S:

calculated: C = 35.46 H = 4.45 N = 20.69% found:. C = 35.68 H = 4.48 ff = 20.73 %

Examples 13 and 14

The following compounds were prepared by reacting ethanolic ammonia with the corresponding compounds in which R = -CH ₂ OCH ₂ COOEt or -COOEt, in a manner similar to that described in Example 15 c) below:

809841/1034

Example R ί ¹ . (C) analysis values in%

(found value in brackets) CHKS

'13 -CH ₂ CCH ₂ COM ₂ 152-153 - ⁺

14 -CONH ₉ 273-275 (dec.) 30.28 3.81 36.20 19.72

^ (30.28 3.82 35.44 20.20)

+) NHR analysis (EKS0 _d6 ) * = 3.45 (singlet, N-CH,

4.10 (singlet,)

4.60 (singlet,

The starting ester for example 14 was prepared in a manner similar to that in example 11, but starting from methyl isothiocyanate and EtOOCCOIiHNH ₂ .

Example 15

a) 3-Äthox2 ^car ^ ^on 2 ^ ~ ^ ~ ^ E§ ^r §zS25 ^ 2S ^ 5 & 5Zi2rlj.? if!; z5 £ iS52l ~ 5z5 ^ ⁰ -'- A solution of 8.95 g of para-methoxybenzyl isothiocyanate and 6 , 8 g EtOOCCOKHm ₂ in 50 ml alcohol was refluxed overnight. The hot solution was filtered, the filtrate was evaporated in vacuo and the resulting oil was triturated with dry ether. The solid thus obtained, namely 7.2 g of 3 - (- ^ 'thoxycarbonyl) -4- (p.-methoxybenzyl) -1,2 _i 4-triazole-5-thiol, was dissolved from alcohol / water to give 4 g of the pure product recrystallized. An analytical sample was obtained by further recrystallization from ethyl acetate / petroleum ether = 60/80 ⁰ with K. C, it had mp = 142-144 ⁰ C.

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Analysis on

calculated: C = 55.25 H = 5.16 N = 14.33% found: C = 53.29 H = 5.12 N »14.70 %

A mixture of 4.8 g of the product from a) in 20 ml of 4: 1 vol .- / vol. Trifluoroacetic acid-anisole was .erhitzt 4 hours at 60 ⁰ C. The solution was cooled, evaporated in vacuo and the residue was triturated with petroleum ether with K. "60/80 ⁰ C to give an orange solid. This solid was then triturated with dry ether to yield 1.9 g of 3-Ä'thoxycarbonyl-1,2,4-triazole-5-thiol as a white solid with mp = 192 - were obtained 193 ⁰ C (dec.).

Analysis for C ₅ H ₇ N ₅ O ₂ S:

calculated: C = 34.69 H = 4.08 N = 24.28% found: C = 34.60 H = 4.07 N = 24.07 %

c) 3-carbamoyl-1 _i 2 _i 4-triazole-5-thiol

14.5 g CLÉS product from b) were heated overnight at 100 ⁰ C in a bomb with 200 ml of ammonia saturated ethanol. The reaction mixture was evaporated in vacuo to give 12.0 g of the ammonium salt of 3-carbamoyl-1,2,4-triazole-5-thiol.

An analytical sample of the free thiol was obtained by acidifying an aqueous solution of the ammonium salt, the free thiol as an off-white solid with mp = 276 ⁰ C (dec.).

609841/1034

Analysis for C ₃ H ₄ N ₄ OS (free thiol):

calculated: C = 25.01 H = 2.80 N = 38.89% found: C = 25.97 H = 3.00 N = 37.75%

IR spectrum (KBr) i _max = 1640 cm "' ¹ (amide carbonyl)

Example 16

Using a similar procedure as described in Example 15 a), 3-ethoxycarbonylmethoxymethyl-4 - (p-methoxybenzyl) -1,2,4-triazole - 5-thiol was prepared, using p-iiethoxybenzyl isothiocyanate and ethoxycarbonylmethoxyacetohydrazide ( EtOOCCH ₂ OCH ₂ COIiEl ^ H ₂ ) was assumed. The ithoxycarbonyl group was then hydrolytically cleaved with the formation of the free acid using aqueous 2ΪΓ i-sodium hydroxide solution, and the p-kethoxybenzyl group was then removed using trifluoroacetic acid in a procedure similar to that described in Example 15 b), with 3-carboxymethoxymethyl-1 , 2,4-triazol-5-thiol with mp = 180 - 182 ⁰ C was obtained.

Analysis on C _t -H ₀ N-
? 2; 5 ° 3 ^S: , 75 H. = 3 , 73 N. = 22 , 22 % calculated: C. = 31 , 13 H. = 3 , 73 N. = 22 % found: C. = 32

Example 17

3-carbamoylmethosymethyl-1,2,4-triazole-5-thiol became from 3-ethoxycarbonylmethoxymethyl-4- (p-methoxybenzyl) -1,2,4-triazole-5-thiol by reaction with ammoniacal ethanol in a similar way Way as in Example 15 c) and subsequent removal of the p-Iiethoxybenzylgruppe with trifluoroacetic acid in a similar manner prepared as in Example 15 b).

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HMR spectrum (D ₂ O) «S» -4-, 5, singlet (methylene)

= 4.05, singlet (methylene)

Example 18

3- (H-ethylcarbamoylmethoxymethyl) -1, 2,4-triazol-5-t] iiol prepared in a manner similar to Example 17, using J-ethoxycarbonylmethoxymethyl- ^ t- (p-methoxybenz; yl) -1,2,4-triazol-5-chiol as in Example 17, but ethylamine was used in place of ammoniacal ethanol.

HMR spectrum (DMSOd ₆ ) «5« 4.7? Singlet (methylene)

= 4.0, singlet (methylene) = 5.35, singlet (J «8 c / s)

(COKHGH ₂ CH ₃ ) = 3.15, doublet (J = 8 c / s)

(COHHCH ₂ CH ₃ ) = 1.05 »center of the iriplet (J« 8 c / s)

(COHHCH ₂ CH ₃ ) ppm

Example 19

a) 1 "-0xaino2l-4- ^ p_-methox2benz2l2z5 ^ i2§®5iS§ £ 5§5i§ 5.4 g» 0.1M sodium methoxide and 21.1 g · 0.1M 4- (p-methoxybenzyl) - thiosemicarbazide was stirred in 200 ml of methanol for 5 minutes, then 11.7 S = 0.1M ethyl oxamate was added and the mixture refluxed for 3 hours, most of the solvent was evaporated under reduced pressure, 200 ml of water was added and the pH was adjusted to 2 with dilute hydrochloric acid. the solid obtained was filtered and dried at 50 ⁰ C in vacuo to give 25.7 1-0xamoyl S-4- (p-methoxybenzyl) thiosemicarbazide in a yield of 91 % mxt Έ. = 185 - 190 ⁰ C were obtained.

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Analysis aiii

calculates G = 46 ₃ 8 Ή = 5 ₃ 00 Έ =

found: G = 4.6.3 S = 4 ₃ 87 ST = 18.83 %

b) 3-Garhamoyl-4- (p-metho: ^ benzffl3-% 0.4 s = D ₃ DIIi lithium hydroxide and 2.82 g = O ₃ OiH i -oxamoyl-4- (p-metho ^ henzyl} -thiosemicarbazide were heated in 20 ml of water on a steam bath for 2 beaches; "The clear solution 'was cooled and mil acidified dilute hydrochloric acid» The obtained solid was filtered and dried at 50 ^D C in vacuo to give 2.5 S 3-Garbamojl! -4- (p-met3ioxybenzyl3-1 _} 2,4-triazol-5-tniol were obtained in 94% yield with Ϊ ¹ »= 240 - 242 ⁰ C» A sample was crystallized from a mixture of dimethylformamide and ether3 Ϊ, = 243 - 245 ⁰ C.

Analysis on G ^

calculated; G = 49.9 Ή = 4.58 U = 21.2 %

found: G = 49.0 H = 4.51 ^ «20.5%

2.0 g β 0.0076M 3-garbamoyl-4 ~ (p-methoxybenzyl) -1,2,4-triazol-5-thiol, 8 ml irifluoroacetic acid and 2 ml anisole were ^{heated to 70 0} G for 3.5 hours » Most of the trifluoroacetic acid was removed by evaporation under reduced pressure and the residue was triturated with ether. The solid was filtered, washed with ether and ^{dried at 50 0} G in a vacuum, 1.0 g of 3-carbamoyl-1,2,4-triazole ~ 5-thiol in 91% yield with Έ. = 276 - 2 - 8 ° C. The IE spectrum. was identical to that of a comparison sample, prepared as in Example 15 c).

6 0 9 8 41/10 3 4

Claims (1)

Patent claims Substituted, heterocyclic thiols of the general formula: (D wherein X = O, S, NH, NuH ₃ or NB, in which B is a benzyl or p-methoxybenzyl radical, and R is a group of the formula -CH ₀ OCH ₉ COOR ¹ , -CH ₀ OCH ₀ CONR ¹ R ² , 12 12 or -CONR R, in which R and R are independently hydrogen or C ₁ -C ₄ -AlJCyI, where, when X is NH, NCH_ or N-benzyl and R is CONR R, at least one of the radicals R and R is hydrogen, as well as ammonium or alkali metal salts thereof. 2. A compound according to claim 1, characterized in that X = 0, S, KH or KMe. 3. A compound according to claim 2, characterized in that R is a -COIHLj group. 4-, compound according to claim 2, characterized in that E is a -CH ₂ OCH ₂ COOH group. 5. A compound according to claim 2, characterized in that R is a -CH ₂ OCH ₂ C00- (C ₁ -C ^ -alkyl) group. 6. A compound according to claim 2, characterized in that R is a -CH ₂ OCH ₂ COHH ₂ -GrUpPe. 609841/1034 7- connection according to any one of claims 1 to 6, characterized characterized in that they are in the form of a sodium or Ealiumsalzes is present. 8. A compound according to claim 1, characterized in that X = HH and R = -COHHo. C- 9. Compound according to Claim 1, characterized in that X = IiH and R = -CH ₂ OCH ₂ GOHH ₂ . 10. A compound according to claim 1, characterized in that X β is HH and R = -CH ₂ OCH ₂ COOH. 11. A compound according to claim 1, characterized in that X = S and R = -CH ₂ OCH ₂ COOH. 12. A compound according to claim 1, characterized in that X = S and R «-CH ₂ OCH ₂ COOEt. 13. Compound according to Claim 1, characterized in that X = O and R a -CH ₂ OCH ₂ COOH. . Process for the preparation of a compound of formula (I) according to claim 1, wherein X = S, characterized in that an acid-catalyzed cyclization of a compound of the following general formula: NH HH I (II) Λ Α 5 SH 0 R 609841/1034 in which B. has the meaning given in tension 1 ", or an alkali metal salt thereof is dujxh 15 · The method according to claim 14, characterized in that the cyclization "at low temperature in the presence is carried out by concentrated sulfuric acid. 16. Process for the preparation of a compound of formula (I) according to claim 1, wherein X = O, characterized in that a "base-catalyzed cyclization of a compound of the formula (II) according to Claim 14 or of an alkali metal salt is carried out from this, 17. The method according to claim 16, characterized in that it is carried out in the presence of xalium hydroxide. 18. A process for the preparation of a compound of the formula (I) according to claim 1, wherein X is »KMe, characterized in that that a compound of the following general formula; IiH I I (IV) UH O E is cyclized » 19- The method according to claim 18, characterized in that the Cyclization is carried out by heating the compound in the presence of a base. 20. The method according to claim 19, characterized in that sodium hydride is used as the base. 609841/1034 21.Vehicles for the preparation of a compound of the formula (I) according to claim 1, wherein Σ = NH or KB, characterized thereby draws that a compound of the following general formula: KH S \ m ο ε wherein R has the meaning given in claim 1 and B is a benzyl or p-methoxybenzyl radical, - for the preparation a compound of the following general formula: N ' Il (I C) is cyclized, and then, if a compound with X = NH is to be produced, the group B Will get removed. 22. The method according to claim 21, characterized in that cyclization by heating and removal of group B, if necessary, by treating the compound (I C) is carried out with trifluoroacetic acid. 2Y. Process for the preparation of a compound of formula (I) according to claim 1, in which R = -CH ₀ OCH ₀ CONR ^ R ² or 12th
-CONR R, characterized in that the corresponding 6 0 9 R 41/1034 26127ΒΊ A compound of the formula (I) in which R = -CH ₂ CCH ₂ C00- (C ₁ alkyl) or -COO- (C 1 -C 4 -alkyl) with a compound 12 1 2 of the formula RRM, wherein R and R are those in claim. 1 have given meaning, is implemented. 24. Process for the preparation of a compound of formula (I) according to. Claim 1, in which R is a -CH ₂ OCH ₂ COOH group, characterized in that the corresponding compound of the formula (I) in which R is a -CH ₂ OCH ₂ COO- (C ₁ -C ^ -alkyl) - Group is hydrolyzed. 25. A process for the preparation of a compound of the formula (I) according to claim 1, wherein R is -CH ₂ OCH ₂ COO- (C ₁ -C ^ -alkyl), characterized in that the corresponding compound of the formula (I) is in which R »-CH ₂ OCH ₂ COOH is esterified. 26. The method according to any one of claims 14 to 22, characterized in that R = -COiIH ₂ . 27. The method according to any one of claims 14 to 22, characterized in that R = -CH ₂ OCH ₂ COOH. 28. The method according to any one of claims 14 to 22, characterized in that R = -CH ₂ OCH ₂ COO- (C, -C ^ -alkyl). 29. The method according to any one of claims 14 to 22, characterized in that R = -CH ₂ OCH ₂ COm ₂ . 609841/1034