DD295364A5 - PROCESS FOR THE PREPARATION OF HETEROCYCLIC THIOETHERS - Google Patents

Abstract

The invention relates to a process for the preparation of heterocyclic thioethers which are used in the chemical industry as intermediates and end-products for pharmaceuticals, herbicides and fungicides as well as DIR couplers and DIR compounds for property improvement in photographic silver halide color recording materials. The aim of the invention is a synthesis that provides reaction products in high quality and yield with only little process engineering effort and has a wide range of applications. According to the present invention, a CH-acidic compound having a symmetrical heterocyclic disulfide (s) in an organic polar solvent in the temperature range of 25 ° C to the boiling point of the solvent is converted to the heterocyclic thioether {heterocyclic thioether; DIR couplers; DIR compounds; Silver halide color recording materials; CH-acidic compound; symmetric heterocyclic disulfide; organic, polar solvent; large application width}

Description

is reacted in an organic polar solvent in the temperature range of 25 ° C to the boiling point of the solvent, wherein in the general formulas 1-3

R ^{1 is} a hydrogen atom, an alkyl or aryl group, an alkyl or aryl group, a

Alkyl or arylcarbonyl group, an alkoxy or aryloxycarbonyl group, an alkyl

or arylcarbamoyl group or a cyano group; R ^{2 is} a carboxyl group, an alkoxy or aryloxycarbonyl group, an alkyl or

Arylcarbamoyl group, an arylcarbonyl group, a cyano or nitro group; or R ¹ and R ² together with -CHr- part of an optionally substituted cycloalkanol, cycloalkanedione, indanone, vetralon, piperidone, homophthalimide, oxazolin-2-one,

Thiazolin-2-one, imidazolin-2-one or pyrazolin-5-one ring; and A atoms necessary to complete an optionally substituted

Azole ring, preferably an imidazole, benzimidazole, thiazole, benzthiazole, oxazole,

Benzoxazole, 1,2,4-triazole, 1.3.4-thiadiazole, 1.3.4-oxadiazole or tetrazolrinoes.

2. The method according to claim 1, characterized in that as CH-acidic compound of the general formula 2, a compound having pKs = 20 is used.

3. The method according to claim 1 and 2, characterized in that are used as organic, polar solvents acetonitrile, glacial acetic acid, propionic acid, dimethyl sulfoxide or dimethylformamide.

4. The method according to claim 1 to 3, characterized in that the reaction is carried out in a temperature range of 45 ⁰ C to 118 ° C.

Field of application of the invention

The invention relates to a process for the preparation of heterocyclic thioethers which are used in the chemical industry as intermediates and end-products for pharmaceuticals, herbicides and fungicides as well as in photographic recording materials.

Characteristic of the known state of the art

It is known that heterocyclic thioethers are widely used as organic intermediates and end products in the chemical industry. Many members of this broad class of compounds are valuable synthons for organic chemical syntheses of pharmaceuticals, herbicides, and fungicides. Further, heterocyclic thioethers have been gaining importance for years as so-called DIR (development inhibitor releasing) couplers and DIR compounds for property improvement in photographic silver halide color recording materials. The mechanism of action of these compounds is reviewed in a review by C.R. Barr, J.R. Thirtle and P.W. Vittum in Photogr. Sciene and Engineering 13, 74 (1969).

DIR couplers are first mentioned in US-PS 3227554, such. 4-thio-substituted pyrazolin-5-one magenta couplers or α-thio-substituted α-acylacetanilide yellow couplers. Of particular interest are the azolylthio substituted substituents, for example color couplers which carry the 1-phenyltetrazol-5-ylthio substituent in the coupling position.

DE-AS 1547640 is to be regarded as the original patent of the classic DIR compounds. The first structural type of this new category of photographically active compounds was described by P. Marx, R. Otto and W. Pelz as DIR-acetophenones and their derivatives. Since the publication of this patent in 1969, more than 20 new structural types of DIR compounds have been developed, including azolylthio-substituted cycloketones (eg in DE-OSs 2359295, 2429892, 2448063 and 2850626) and a variety of different azolylthio-substituted heterocycles (eg German Offenlegungsschriften 2,405,442,250,292,2,540,959, 2,617,310,270,7489 and 2,729,213). General synthetic methods for thioethers are in Houben-Weyl, Methods of Organic Chemistry, Vol. IX, 4. On l "Georg Thieme Verlag Stuttgart (1955), pp. 97-143 and in the extension and follow-up to the 4th edition E11, Georg Thieme Verlag Stuttgart, New York (1985), pp. 158-187. For the preparation of heterocyclic thioethers, however, the scope of application of these general synthetic methods is limited. Especially in the patent literature a whole series Heterocyclylthioethersynthese has been worked out, which lead to very special classes of compounds, for example:

Synthesis of ω-azolylthio-substituted acetophenones from phenacyl halides and alkali metal salts of mercaptoazoles (D! AS 1547640, DE-OS 2362752, 2547691 and 2835073) or by reacting azolyl sulfenyl halides with acetophenones (DE-AS 1547640);

Preparation of a-azolylthio-substituted a-acylacetanilide yellow coupler by reaction of sulfenyl chlorides of heterocyclic thiols with the corresponding four-equivalent couplers (e.g., DE-AS 1124356, U.S. Patent 3,227,554);

- Synthesis of a-azolylthiosubstituted malondianilides from sulfenyl halides of the mercaptoazoles and the malondianilide bases described, for example, in US Pat. No. 4,141,886;

- Preparation of 2-azolylthiosubstituierter cycloketones, indanones and tetralones from the corresponding 2-halo ketones and Alkalimercaptiden the heterocyclic thiols (DE-OS 2359295,2547691) and by condensation of sulfenyl chlorides to the cycloaliphatic ketones, indanones or tetralones (DE-OS 2359295.2850626 );

- Synthesis of 2-Azolylthiosuccinimiden by addition of mercaptoazoles to maleimides (DE-OS 2250136);

- Preparation of azolylthiosubstituierter homophthalimides from Azolylsulfenylhalogeniden and homophthalimides (DE-OS 2502892);

Synthesis of δ-azolylthiooxazoline ^ -ones (DE-OS 2540959) and 5-azolylthiothiazolin-2-ones or -imidazolin-2-ones (DE-OS 2707489) preferably by reacting the sulfenyl halides of mercaptoazoles with the corresponding Position unsubstituted heterocyclic bases;

Preparation of 4-azolylthio-substituted pyrazolin-5-ones from 4-halo-pyrazolin-5-ones and the corresponding thiols in the presence of proton acceptors or by condensation of sulfenyl halides of heterocyclic thiols with unsubstituted 4-pyrazolin-5-ones. (GB-PS 953454, US-PS 3227554.3615506).

These examples show that three synthetic routes are of particular interest for the preparation of heterocyclic thioethers:

- Synthesis path A

Reaction of heterocyclic thiols with reactive halogen compounds in the presence of bases or reaction of the salts of heterocyclic thiols, preferably the Alkalimercaptide, with the corresponding halogen compounds;

- Synthesis path B

Condensation of heterocyclic sulfenyl halides with CH-acidic compounds;

- Synthesis path C

Addition of heterocyclic thiols to double bonds.

It proves to be disadvantageous that these synthetic routes are heavily eingeschämkt in their scope. In addition, considerable technical expenses for the synthesis of the corresponding starting compounds in the quality required for the reactions are often necessary.

Thus, for example, the preparation of reactive halogen compounds of pyrazoline-5-ones for the synthesis route A can only be achieved with the aid of complicated processes which often require multi-stage reactions. 4-Halo-pyrazolin-5-ones, which readily undergo disproportionation or condensation reactions, can be prepared by halogenation of pyrazolin-5-ones in the presence of Friedel-Crafts catalysts (British Patent 1645973, U.S. Patent No. 3,006,739) or by reduction of 4.4- Dihalogenpyrazolin-5-ones such. Example, using phosphites in a two-stage process (US Patent 4021445) or with ascorbic acid as a reducing agent (M. J. Sepulnik, Synthesis 1985, 299). Since the synthesis of pure 4-halo-substituted pyrazolin-5-ones, the uniformity of which is a prerequisite for the successful preparation of 4-thio-substituted pyrazolin-5-ones, turns out to be problematic, special procedures have been used for the S-functionalization of pyrazolin-5-ones elaborated.

DE-AS 2343378 describes a process for the direct reaction of 4,4-dihalogenpyrazolin-5-ones with three times the molar amount of a thiol to give the desired 4-thio-substituted pyrazolin-5-one and the corresponding disulfide.

A new process has also been proposed which allows 4-thio-substituted pyrazolin-5-ones to be obtained from the unsubstituted pyrazolin-5-ones. Characteristic of this new synthetic route is the preparation of an equilibrium mixture consisting of 4-unsubstituted, 4-bromo-substituted and 4,4-dibromo-substituted pyrazolin-5-one, and its reaction with salts of thiols to give 4-thio-substituted pyrazolin-5-ones. A second disadvantage of the synthesis route A is that in the reaction of particularly reactive halogen compounds, for example of haloketones, with thiols, the halogen atom is replaced by hydrogen and the thiol can be oxidized to disulfide. Such a side reaction was z. B. in the reaction of ω-bromoacetophenone with mercaptans observed (V. Prelog, V. Hahn, H. Brauchli, H. C. Beyermann, HeIv. Chim. Acta 27, 1210 (1944)).

The condensation of heterocyclic sulfenyl halides with CH-acidic compounds according to synthesis route B also has disadvantages. The sulfenyl halides required for the process are prepared from the corresponding thiols or their disulfides and halogens, e.g. B. analogous to that in Org. Synth. Coil. Vol. II, p. 455 for 2-Nitrophenylsulfenylchlorid indicated method. The quality and yield of the heterocyclic thioether obtained according to synthesis route B depends crucially on the extent to which it is possible to prepare the sulfenyl halides in the required purity. It is known that there are great problems in the implementation of hydrophilically substituted mercaptoazoles with halogens. Especially

It is difficult to functionalize phenyl-1-phenyl-1-phenyl-5-mercaptotetrazoles substituted by hydroxy, amino, sulfo or sulfonamido groups.

Moreover, in the synthesis of sulfenyl halides, the choice of reaction conditions is severely limited. Thus, only the use of less solvent, preferably of carbon tetrachloride or other halogenated hydrocarbons or dioxane, as the reaction medium leads to positive results. For large-scale application of these solvents, especially their toxicity limits. Similar limitations also apply to the reaction of the sulfenyl halides with CH-acidic compounds to the desired heterocyclic thioethers.

The synthesis of heterocyclic thioethers by addition of corresponding thiols to double bonds according to synthesis route C is a very simple process which, compared to the synthesis routes A and B, gives reaction products of good quality and high yield without major expense; however, its application is' if a small number of structurally limited heterocyclic thioethers, ζ. Β. 2-azolyl thiosuccinimides limited.

Object of the invention

The aim of the invention is to develop a process for the preparation of heterocyclic thioethers, which provides reaction products in high quality and yield with only little process engineering effort and has a wide range of applications.

Explanation of the essence of the invention

The invention has for its object to develop a process for the preparation of heterocyclic thioethers dei general formula 1 under simple reaction conditions, with high yields and starting from easily accessible compounds, which makes it possible to represent a variety of structurally different thioethers.

A ^ .- S-CH

This object is achieved in that a CH-acidic compound of general formula. 2

with a heterocyclic disulfide of general formula 3 A S-SS- < \

in an organic polar solvent in the heat; R is reacted from 25 ° C to the boiling point of the solvent, wherein in the general formulas 1-3

R ^{1 is} a hydrogen atom, an alkyl or aryl group, an alkyl or arylcarbonyl group, an alkoxy or

Aryloxycarbonyl group, an alkyl or arylcarbamoyl group or a cyano group; R ^{2 is} a carboxyl group, an alkoxy or. Aryloxycarbonyl, an alkyl or. Arylcarbamoyl group, one

Arylcarbonyl group, a cyano or nitro group; or R ¹ and R ² together with -CHr- component of an optionally substituted cycloalkanones cycloalkanedione, indanone, tetraion, piperidone, homopthalimide, oxazolin-2-one, thiazolin-2-one, imidazolin-2-one or pyrazolin-5-one ring

are; and A atoms necessary to complete an optionally substituted azole ring, preferably one

Imidazole, benzimidazole, thiazole, benzthiazole, oxazole, benzoxazole, 1,2,4-triazole, 1.3.4-thiadiazole,

1.3.4-oxadiazole or tetrazole ring represents.

Surprisingly, it has been found that a plurality of CH-acidic compounds of the general formula 2 with symmetrical, heterocyclic disulfides of the general formula 3 at elevated temperature in a suitable reaction medium to form heterocyclic thioethers of the general formula 1 and of heterocyclic mercaptans of the general formula 4 according to equation ( 1) react:

CH ₉ + A ^ .- SS-. ^ A - = -> A ^ .- S-CH +

• R ² ^ 3 ^N 'R ²

s * '

HS- / λ

wherein R ¹ , R ² and A in the general formulas 1-4 have the abovementioned meaning.

The compounds of general formula 2 must have sufficient CH acidity. Suitable CH-acidic compounds according to the invention are preferably those with pK _s S 20. This can be, for example, acetophenone derivatives of the general formula 5,

R ³ CH ₉ CO-

R ⁴

, wherein R ^{3 is} a hydrogen atom, an alkyl or aryl group or an optionally substituted heterocyclyl group with 5 bis

6 ring links; R ^{4 is} a hydrogen atom, a halogen atom, an alkyl or aryl group, an amino group, a nitro group, an aikoxy group, an optionally substituted alkyl or Arylcarbonamidogruppe, an optionally substituted

Alkyl or arylsulfamoyl group, an alkyl or aryloxycarbonyloxy group, a sulfo group or their salt; and R ^{5 is} an alkyl group and a is an integer between 0 and 3;

α-acylacetanilides of general formula 6,

R ⁷ R ⁶ - COCH ₀ CONH- / % 6

in the

R ^{6 is} an alkyl group, preferably a tert-butyl group, or an aryl group which may be optionally substituted; R ^{7 represents} a hydrogen atom, a halogen atom, preferably a chlorine atom, or an aikoxy group; and R ^{8 is} a hydrogen atom, an alkyl group, an optionally substituted alkyl or. Arylcarbonamidogruppe, an optionally substituted alkyl or Arylsulfonamidogruppe, an optionally substituted alkyl or

Arylsulfamoyl or an optionally substituted alkoxy or aryloxycarbonyl group represents:

Malondianilides of general formula 7

NHCOCH ₂ CONH- /

in which

R ^{9 is} a hydrogen atom, a halogen atom, preferably a chlorine atom, or an aikoxy group; and R ^{10 is} a hydrogen atom, an alkyl group, an optionally substituted alkyl or Arylcarbonamidogruppe, an optionally substituted alkyl or Arylsulfonamidogruppe, an optionally substituted alkyl or.

Arylsulfamoylgruppe, or an optionally substituted alkoxy or. Aryloxycarbonyl group; cyclic ketones of general formula 8 or 9,

"12

r ^R §

in which

R ^{11 represents} a hydrogen atom, an alkyl or aryl group, an alkoxy group or an alkyl, aryl or heterocyclylthio group; R ^{12 is} a hydrogen atom or an alkyl group;

B necessary atoms or bonds to complete a cyclopentanone or cyclohexanone ring; R ^{13 is} a hydrogen atom, an alkyl group, an optionally substituted Heterocyclylgruppe.zB a 2-Octadecenylsuccinimidogruppe, an optionally substituted alkoxy or aryloxy group, an alkylthio group, an amino group, a nitro group, an optionally substituted alkyl or. Arylcarbonamido group, an optionally substituted alkyl or arylsulfonamido group or an optionally substituted alkyl or arylsulfamoyl group;

R ^{M is an} alkyl group;

b is an integer between 0 and 2; such as

C are necessary atoms or bonds to complete an indanone or tetraione ring; N-alkylpyrrolidones or N-alkylpiperidones of general formula 10,

R "

10 R ¹⁵

R ^{16 is an} alkyl group;

R ^{16 is} a hydrogen atom, an alkyl or. Aryl group, an alkoxy group or a heterocyclylthio group; and D necessary atoms or bonds to complete a pyrrolidin-2-one, pyrrolidin-3-one, piperidin-2-one,

Piperidin-3-one or piperidin-4-one ring; N-substituted homophthalimides of general formula 11,

in the

R "is an optionally substituted alkyl, aryl or heterocyclyl group; and R ^{18 is} a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, a nitro group, an optionally substituted alkyl or arylcarbonamido group or an optionally substituted alkyl or

Arylsulfonamido group;

Oxazolin-2-ones, thiazolin-2-ones or imidazolin-2-ones of general formula 12,

R ¹⁹ .

X 12

in which

X represents an oxygen atom, a sulfur atom or an optionally substituted imino group; and R ^{19 is an} optionally substituted alkyl or aryl group, e.g. A 2 (n-tetradecyloxy) phenyl group; or pyrazolin-5-ones of the general formula 13,

_R 21

R ^{20 is} an alkyl or an optionally substituted aryl group, 2. B. a 2.4.6-trichlorophenyl or a

4- (Y- (2,4-di-tert-amylphenoxy) butyramido) phenyl; and R ^{21 represents} an alkyl group, an optionally substituted aryl group, a heterocyclyl group, e.g. A pyrrolidino group, an optionally substituted alkoxy or aryloxy group, an amino group, an optionally substituted alkyl or

Arylamino group, a dialkylamino group or an optionally substituted alkyl or arylcarbonamido group,

z, B represents a 3 - [(2,4-di-tert-amylphenoxy) acetamido] benzamido group.

As symmetrical, heterocyclic disulfides of the general formula 3, only those are suitable which are derived from n-electron-deficient heterocycles. Due to the strong electron acceptor effect, the disulfide bond may undergo fragmentation.

The following are some examples, without limiting the scope of the invention: bis (1-phenyltetrazol-5-yl) disulfide, bis [1- (3-hydroxyphenyl) tetrazol-5-yl] disulfide, bis (1 - (4-hydroxyphenyl) tetrazol-5-yl) disulfide, bis [1- (3-carboxyphenyl) tetrazol-5-yl] disulfide, bis (1- (4-aminophenyl) tetrazol-5-yl] disulfide, Bis (benzimidazol-2-yl) disulfide, bis (benzthiazol-2-yl) disulphide, bis (benzoxazol-2-yl) disulphide, bis (3-mercapto-4-amino-1,2,4-triazole) 5-yl) disulfide, bis (3-methylthio-4-amino-1,2,4-triazol-5-yl) disulfide, bis (3-ethylthio-4-amino-1,2,4-triazol-5-yl) disulfide, bis (3-methyl-4-phenyl-1,2,4-triazol-5-yl) disulfide, bis (2-mercapto-1,3,4-thiadiazol-5-yl) disulfide, bis (2-methylthio -1,3,4-thiadiazol-5-yl) disulfide, bis (2-ethylthio-1,3,4-thiadiazol-5-yl) disulfide, bis (2-carboxymethylthio-1,3,4-thiadiazol-5-yl) disulfide ,

The symmetrical heterocyclic disulfides of the general formula 3 are for the most part commercially available or readily accessible from the corresponding heterocyclic mercaptans. For the preparation of these disulfides are in principle all in Houben-Weyl, Methods of Organic Chemistry, Vol. IX, 4th ed. Georg Thieme Verlag Stuttgart (1955), pp. 59-74 specified methods, but preferably the oxidation of heterocyclic mercaptans , The oxidizing agents are in particular hydrogen peroxide, halogens, for example iodine, iron EDI chloride (G. Hilgetag, A. Martini, Preparative Organic Chemistry, John Wiley & Sons, London [1972], p.666), potassium hexacyanoferrate (III), oxygen, hypohalites or nitric acid. If the structural element A in general formula 3 contains further mercapto groups or other readily oxidizable substituents, it is preferable to use mild selective oxidizing agents. Thus, for example, bis (2-mercapto-1,3,4-thiadiazol-5-yl) disulfide is obtained by oxidation of 2,5-di-mercapto · 1.3.4-thiadiazole with alcoholic iodine solution (E.Ziegele, J. Prakt. Chem. 60.40 [1899]).

The CH-acidic compounds of general formula 2 are reacted with the disulfides of general formula 3 in the molar ratio 1: n, where η is any number between 1 and 2. Preference is given to working in the equimolar ratio (n = 1) or with a slight excess of the disulfide taking advantage of the law of mass action (1 <nä 1.1). If the compound of general formula 2 has CH-acidic centers and if the introduction of m heterocyclylthio groups is desirable, this compound is reacted with the corresponding disulfide in the molar ratio 1: (m χ η), where m is a natural number greater than one and η has the meaning given above.

Suitable solvents for the process according to the invention are dipolar aprotic solvents, for example acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, tetramethylurea or sulfolane and also polar protic solvents, in particular lower aliphatic carboxylic acids or lower alcohols. The term "lower" in the context of the definition of the chain length of aliphatic compounds means that they preferably contain 1-4 carbon atoms.The purity and drying of the solvents used have not been more stringent, and in most cases the purity of technically available substances is sufficient The reaction can be carried out in true solution (Example 1 or 4) or in suspension (Example 8), but thorough mixing of the reactants is necessary and is conveniently achieved by mechanical stirring of the reaction solution or suspension according to the solubility or aggregation of the starting materials and can be varied within wide limits.

The reaction temperature range for the process according to the invention depends on the reactivity of the starting materials and the solvent used in each case. It is between -5 ° C and the boiling point of the solvent. Preferably, work is carried out between 45 ° C and 118 ° C. Some pyrazolin-5-ones associate with strongly acceptor-substituted disulfides, e.g. B. bis (1 phenyltetrazol-5-yl) disulfide, but even at room temperature (Example 6). Other CH-acidic compounds, for example acetophenones or α-acylacetanilides, cause higher reaction temperatures and thus also the choice of specific solvents (Examples 1 and 2). At temperatures above 120 ° C., fewer CH-acidic compounds react with disulfides of the general formula 3. For example, it is also possible to introduce heterocyclylthio groups in the 4-position of 1-hydroxy-2-naphthamides in good yields. A variant which can be used universally for the preparation of a large number of heterocyclic thioethers of the general formula 1 is the implementation of the process according to the invention at the boiling point of the solvent. For this procedure, the use of acetonitrile has proven particularly useful (Examples 3,4,5,7 and 9).

The reaction times are between 30 minutes and 24 hours, preferably between 30 minutes and 3 hours. The heterocyclic thioethers of the general formula 1 are isolated in a manner known per se.

The heterocyclic mercaptan of the general formula 4 which forms during the reaction,

A '' 'V-SH

wherein A has the meaning given above, can be separated or recovered after isolation of the heterocyclic thioether and re-oxidation to the disulfide of the general formula 3 are used again in the inventive method (Examples 4, 6-8). For this, come to the above-mentioned oxidants in question. Such a procedure is particularly recommended for very valuable mercaptans. The advantage of the process according to the invention over the processes for the preparation of heterocyclic thioethers from reactive halogen compounds and mercaptoazoles is the circumvention of the multistage and the difficulty in the functionalization of pyrazolones. The advantage over the Sulfenylhalogenid method is that you can work in technical solvents. Above all, the inventive method is characterized by a wide range of applications for the production of a variety of structurally different classes of compounds. A particular advantage is that no unwanted by-products arise. The inventive method is extremely environmentally friendly. In the following overview, some structural examples are given for the heterocyclic thioethers of the general formula 1 prepared according to the invention, without, however, limiting the scope of the invention:

TE-I _ *

./ VcO-CH ₉ -S-

ON · »- - N -CO-CH ₂ -S- / l |

TE-3 Χ '

(CH ₃ ) ₃ CCO-CH-CONH

NHCO (CH ₉ ) ^ Of V ^ H ₁ "-t S

Cl TP-4

CH ₃ O- / ^ -CO-QH-CONH- / \

\ ^N C00C, ₉ H _9c; ~ n N c =. N _C00H

-00-, CH-CONH-Z ^- A-SO ₀ N- (CH ₀ ), - / ~ \

ι w

pi ³ f

/ ^ -NHCO-CH-CONH- / ^. -3 = * = / C

C00C ₁₂ H ₂₅ -n

N # »** ^is \ N ·

I I \ = /

N  N

C ₂ H ₅ OCO- / ^ -NHCO-CH-CONH- / \ -C00C _o H _c

N N

NC-CH-CN

I "J

-O

N-N

-S-.f Il

^N NN

NHCOCH ₂ O-

- ^C 18 ^H 37 " ⁿ °

-S-II-SH

^ ¹ O i * - "-

r ¹

CH ₃

CH ₃

0 N N

, N N

CH ₃

N N

H ₃₃ - (η)

N N

N ^ ^ NH

Il Λ ⁿ

N N

n __. n

^C 14 ^H 29-n

OH

il

-V3- ° -i ^HC0NH -O-ir- ¹ " ³ - '·

C ₂ H ₅

jh

Ah,

"I ^N N_N

TG-25 ["

^UII 3 fj 1 ° S ^ ^bH

C.

N N

O- ». ., · -DIi

& P '

NHCOCH

C ₀ H ₁ -O-2 5 ι

N _k , i

 «•« .o

I NHCOCH,

C ₂ H ₅ O-

N

^ N ·

NHCOC ₄ H ₉ -t

TE-29

.N-

N--

U /

Cl

-tCl

TE-30

IN

.-S <f

? 5 ^H ll ^"t

NHCO (CH ₂ J ₃ O- t

TE-31

N-

μ N

-S- S \\

ί-0 ^Νν - ^Ν

NHCO (CH ₂ ) ₃ O-

TE-32

NHCO (CH ₂ ,

-s <f

= 0

N N

NHCOCH-ΟΙ ^C 2 ^H 5

"N N

OH

NHCOCH ₂ O

" ^t

operating room

NHCOC ₅ H _ljL -n

^C 5 ^H h ^t

TE-36

Cl

nC,, H ₉₇ CONHv ^ \ -NH

N N

S- <f ti

COOH

TE-37

Cl // VV-NH-. .-SI _'c J-SCH ₀ COOH

> == / I! I " ^s " ²

nC .-, H ₉₇ CONH

embodiments

example 1

Synthesis of the compound TE-1 ω - [(1-phenyltetrazol-5-yl) thio] acetophenone

6.01 g (0.05 mol) of acetophenone and 17.72 g (0.05 mol) of bis (1-phenyl-tetrazol-5-yl) disulphide are dissolved with stirring in 50 ml of glacial acetic acid and the reaction mixture with further stirring for 3 hours at reflux cooked. After the reaction tent is allowed to cool to room temperature. The precipitated yellow precipitate is filtered off with suction through a glass filter and

rinse with 20ml of ice-cold methanol.

The crude product is recrystallized from 20 ml of methanol. This gives 3.2 g (21% of theory) of a white, finely crystalline

Product of melting point 115-118 ° C.

Elemental analysis calculated for C ₁₆ H ₁₂ N ₄ OS:

% C = 60.79; % H = 4.08; % N = 18.91; % S = 10.82; found:

% C = 60.62; % H = 3.97; % N = 18.53; % S = 10.73.

Example 2

Synthesis of the compound TE-5

α-Benzoyl-al {1-phenyltetrazol-5-yl) thiol-4- [N- (4-methylphenyl) -NY-phenylpropyl) sulfamoyl] acetanilide 5.27 g (0.01 mol) of α-benzoyl-4- [ N- (4-methylphenyl) -N- (Y-phenylpropyl) sulfamoyl] acetanilide and 3.55 g (0.01 mol) of bis- (1-phenyltetrazol-5-yl) disulphide are added to 15O, along with 5 ml of dimethyl sulphoxide with stirring ⁰ C heated. After 30 minutes, allowed to cool and the mixture is mixed with 50 ml of water and 50 ml of 2 N sodium carbonate solution. A plastic mass is obtained which is dissolved in 50 ml of glacial acetic acid. The resulting solution is added dropwise slowly while stirring in 800 ml of water to which 10 g of sodium chloride has been added, the product precipitating as a yellowish solid. This is filtered off with suction on a glass filter, washed with 400 ml of water and dried.

6.7 g of the crude product thus obtained are dissolved in 100 ml of methylene chloride and the solution is extracted with 20 ml of 1N sodium carbonate solution. After the organic phase was separated and dried over sodium sulfate, the solvent is distilled off in vacuo and the residue is crystallized by the addition of dilute acetic acid. It is filtered off, washed with plenty of water and dried. This gives 4.05 g (58% of theory) of a

pale yellow colored amorphous product of melting point 75-83 ° C.

Elemental analysis calculated for C33H34N6O4S2:

% C = 64.94; % H = 4.88; % N = 11.96; % S = 9.12; found:

% C = 65.38; % H = 4.84; % N = 12.03; % S = 9.21.

Example 3

Synthesis of the compound TE-21

4-phenyl-5 - [{1-phenyl-tetrazol-5-yl) thio] thiazoline-2-one

8.86 g (0.05 mol) of 4-phenylthiazolin-2-one and 17.72 g (0.05 mol) of bis (1-phenyltetrazol-5-yl) disulphide are dissolved with stirring in 150 ml of acetonitrile. The solution is refluxed with further stirring for 10 hours, precipitating a white precipitate, which is filtered off with suction after the reaction time has cooled and the reaction mixture is washed with 50 ml of ice-cold acetonitrile.

The well-dried crude product is recrystallized from 150 ml of n-butanol; This gives 10.1 g (57% of theory) of a white solid of melting point 173-176 ° C.

Elemental analysis calculated for C ₁₆ HuN ₆ OS ₂ :

% C = 54.37; % H = 3.14; % N = 19.82; % S = 18.14;

found:

% C = 54.86; % H = 3.40; % N = 19.83; % S = 18.21.

Example 4

Synthesis of TE-24 compound

1-phenyl-3-methyl-4 - thiolpyrazolin-5-one [(1-phenyl-tetrazol-5-yl)

4.35 g (0.025 mol) of 1-phenyl-3-methylpyrazolin-5-one and 8.86 g (0.025 ml) of bis (1-phenyltetrazol-5-yl) disulfide are dissolved together in 80 ml of acetonitrile and the mixture is taken under Stirred for 2 hours at reflux. Already at boiling heat a white solid precipitates. By cooling the reaction mixture, the precipitate is completed, the precipitate is filtered off with suction and washed with 50 ml of ice-cold acetonitrile.

This gives 8.0 g (91% of theory) of a white, crystalline product of melting point 185-188 ° C.

Elemental analysis calculated for C ₁₇ HuN ₆ OS:

% C = 58.27; % H = 4.03; % N = 23.99; % S = 9.15;

found:

% C = 58.06; % H = 4.23; % N = 23.82; % S = 9.25.

The acetonitrile mother liquor is concentrated in vacuo to dryness and the residue extracted with 85 ml of a 2.5% sodium acetate solution.

After this solution was clarified by filtration, the filtrate is acidified with 15 ml of 2 N hydrochloric acid. The precipitated, flaky precipitate is filtered off with suction, washed and dried. This gives 3.0 g (67% of theory) of 1-phenyl-S-mercaptotetrazole, which, after reoxidation to the disulfide, can be re-introduced into the process.

Example 5

Synthesis of Compound TE-25

1-phenyl-3-methyl-4 - (pyrazolin-5-one (2-mercapto-1,3,4-thiadiazol-5-yl) thio]

8.71 g (0.05 mol) of 1-phenyl-3-methylpyrazolin-5-one and 14.92 g (0.05 mol) of bis (2-mercapto-1,3,4-thiadiazol-5-yl) disulphide are dissolved in 150 ml Acetonitrile with stirring for 3 hours at reflux. It precipitates a lemon yellow precipitate, which is sucked off after cooling the reaction mixture and then washed with 50 ml of ice-cold acetonitrile and 50 ml of ice-cold Methanoi.

After drying, 15.2 g (94% of theory) of a yellow, finely crystalline product of melting point 209-213 ⁰ C.

Elemental analysis calculated for C ₁₂ H ₁₀ N ₄ OS ₃ :

% c = 44.70; % H = 3.13; % N = 17.38; % S = 29.83;

found:

% C = 44.71; % H = 3.18; % N = 17.19; % S = 29.67.

Example 6

Synthesis of Compound TE-27

1 - [(4-Acetamido) phenyl] -3-ethoxy-4 - [(1-phenyltetrazol-5-yl) thiolpyrazolin-5-one 10.4 g (0.04 mol) of 1 - [(4-acetamido) phenyl [-3-ethoxypyrazolin-5-one and 14.5 g (0.041 mol) of bis (1-phenyltetrazol-5-yl) disulphide are introduced with stirring into 300 ml of glacial acetic acid. The reaction mixture is allowed to stir for 24 hours at room temperature.

The precipitate formed is filtered off with suction through a glass suction filter and washed with a little glacial acetic acid.

The crude product is recrystallized from ethanol after drying. This gives 12.8 g (73% of theory) of a pale beige, crystalline product of melting point 167-172 ⁰ C.

Elemental analysis calculated for C ₂₀ Ht ₉ N ₇ O ₃ S:

% C = 54.91; % H = 4.38; % N = 22.41; % S = 7.33;

found:

% C = 55.02; % H = 4.30; % N = 22.38; % S = 7.18.

If the compound TE-27 is prepared by the sulfenyl chloride method, the yield is only 44% of theory! The glacial acetic acid filtrate is concentrated to dryness in vacuo and the residue is extracted with a 1% sodium carbonate solution. The solution is carefully acidified with 1N hydrochloric acid, the white, fluffy precipitate is filtered off with suction, rinsed with plenty of water and dried. If this is converted from benzene to give 5.1 g (71% of Thf orie) 1-phenyl-5-mercaptotetrazole back, which can be reused after Rückoxydation to disulfide.

Example 7

Synthesis of TE-30 Compound

AM {4- [y- (2,4-di-tert-amylphenoxy) butyramido [phenyl} -3-pyrrolidino-4-I (1-phenyltetrazol-5-yl) thiolpyrazolin-5-one 6.83g (0.0125mol) 1- {4- [Y- (2,4-di-tert-amyl-phenoxy) -butyramido] -phenyl} -3-pyrrolidinopyrazolin-5-one and 4.43g (0.0125mol) bis- (1-phenyltetrazol-5-yl) Disulfide are suspended with stirring in 100 ml of acetonitrile and the mixture heated for 1 hour at reflux. After cooling, the precipitated, white precipitate is filtered off with suction and washed with 50 ml of ice-cold acetonitrile.

The dried product is then recrystallized from 550 ml of methanol to give 7.4 g (82% of theory) of a white, finely crystalline product of melting point 138-142 ° C.

Elemental analysis calculated for C ₄₀ He ₀ NeO ₃ S:

% C = 66.45; % H = 6.97; % N = 15.50; % S = 4.43; found:

% C = 66.66; % H = 7.07; % N = 15.04; % S = 4.49.

According to the sulfenyl chloride method, the yield for TE-30 is only 58% of theory.

The acetonitrile filtrate is concentrated in vacuo to dryness. The residue is extracted with 55 ml of 2% sodium acetate solution. After clarification, the filtrate is treated with 8 ml of 2N hydrochloric acid and the resulting flaky, white precipitate is filtered off with suction, washed and dried. This gives 1.7 g (76% of theory) of 1-phenyl-5-mercaptotetrazole back, which can be reused after oxidation to the disulfide.

Example 8

Synthesis of the compound TE-31

1- {4- [Y 2 -4-di-tert-amylphenoxy) butyramido] phenyl} -3-pyrrolidino-4 - {[1- (4-hydroxyphenyl) tetrazol-5-yl] thio} pyrazolin-5-one 10 , 9g (0.02 mol) of 1- {4- [y- (2,4-di-tert-amyl-phenoxy) -butyramido] -phenyl} -3-pyrrolidinopyrazolin-5-one and 8.1 g (0.021 mol) of bis [ 1- (4-Hydroxyphenyl) tetrazol-5-yl] disulphide are suspended in 100 ml of acetonitrile and the mixture is stirred for 24 hours at a temperature of 45.degree. A white precipitate forms from the initially brown suspension. It is allowed to cool, the precipitate is filtered off with suction and washed with 10 ml of ice-cold acetonitrile.

The well-dried crude product is stirred for 2-3 hours with a 1% sodium carbonate solution, filtered off again with suction, washed salt-free and dried. Thereafter, the mixture is recrystallized from methanol to give 10.2 g (69% of theory) of a white, crystalline solid of melting point 182-185 ⁰ C. Elemental analysis calculated for CwH ₆₀ N ₈ O ₄ S:% C = 65.01; % H = 6.82; % N = 15.16; % S = 4.34; found:

% C = 65.54; % H = 6.90; % N = 15.24; % S = 4.28.

If the compound TE-31 prepared by the sulfenyl chloride method, we obtain a yield of 57% of theory. The acetonitrile mother liquor is concentrated to dryness with vacuum and the residue is extracted with 50 ml of a 1% sodium carbonate solution. This solution is carefully acidified with 1N hydrochloric acid to precipitate a white flocculent precipitate, which is filtered off with suction, washed and dried. In this way one obtains 1.2 g (31% of theory) of 1- (4-hydroxyphenyl) -5-mercaptotetrazole back, which can be used after reoxidation to the corresponding disulfide for the next reaction.

Example 9

Synthesis of TE-32 Compound

1- {4- [Y- (2,4-di-tert-amylphenoxy) butyramido] phenyl} -3-pyrrolidino-4 - [(benzthiazol-2-yl) thio] pyrazolin-5-one 6.85g (0.0125mol ) 1- {4- [Y- (2,4-di-tert-amylphenoxy) butyramido] phenyl} -3-pyrrolidinopyrazolin-5-one and 4.16 g (0.0125 mol) of bis (benzthiazol-2-yl) disulfide boiled in 100 ml acetonitrile for 2 hours at reflux. After cooling the reaction mixture, the precipitated, beige precipitate is filtered off with suction and washed with 50 ml of ice-cold acetonitrile.

The dried crude product is then recrystallized from 100 ml of n-propanol. This gives 6.2 g (58% of theory) of a light beige colored solid of melting point 171-174 ° C.

Elemental analysis calculated for C ₄₀ H ₄₈ N ₅ O ₃ S ₂ :

% C = 67.48; % H = 6.94; % N = 9.84; % S = 9.01; found:

% C = 67.63; % H = 6.72; % N = 9.48; % S = 8.97.

Claims (1)

1. A process for preparing heterocyclic thioethers of general formula 1, > S - CH
characterized in that a CH-acidic compound of the general formula 2 R ¹ CH
Vp 2 with a heterocyclic disulfide of general formula 3 • 'Χ / Λ