DD275870A1 - PROCESS FOR THE PREPARATION OF DIFFERENTLY SUBSTITUTED 3-AMINOTHIOPHENE-4-CARBONITRILES IN 5-POSITION - Google Patents

Abstract

The invention relates to a process for the preparation of 5-position variously substituted 3-aminothiophene-4-carbonitriles (I) which have as substituents in the 5-position a substituted oxy, amino or cyanomethylene group and in the 2-position an aroyl or acyl radical or a carboxyl substituent. It is the object of the invention, in addition to the already known from the literature 3-amino-5-methylaminothiophene-2,4-dicarbonitrile and some already known 3-amino-2-benzoylthiphene-4-carbonitriles with secondary amino substituent in the 5-position other, not yet make famous representatives of this class. The task is to find a technically feasible synthetic route. The object is achieved by the reaction of 5-alkylsulfonyl-3-aminothiphene-4-carbonitriles with nucleophilic reactants. The compounds obtained are of pharmaceutical interest. Formula I

Description

where R 'and R ^{2 have} the abovementioned meaning, are reacted.

2. The method according to claim 1, characterized in that the reaction using auxiliary bases, such as. B. tert.Amine or alkali carbonates, alcoholates or hydroxides is performed.

3. The method according to claim 1, characterized in that the compounds III are used as alkali metal or tert.Ammoniumsalze.

4. The method according to claim 1-3, characterized in that the reaction using a solvent such. As alcohol, DMF, acetonitrile or Oioxan is performed.

5. The method according to claim 1-4, characterized in that the reaction mixture is heated under reflux.

Field of application of the invention

The compounds according to the invention can acquire significance as biologically active preparations or as intermediates for the pharmaceutical industry.

Characteristic of the known state of the art

Various processes for the preparation of 5-substituted 3-aminothiophene-4-carbonitriles are described in the literature. Depending on the nature of the substituents in the 2- and 5-position of S-Amlnothlophorvi-carbonitrile, the following methods can be distinguished:

1. Preparation of S-Alkylthio-S-aminothiophenM-carbonyltrilone with Carboxyl Function in the 2-Position from Malodinitrile, Carbon Disulfide and Alkylating Agents (R.Gomppor, E. Kutter, W. Töpfl, Liobigs Ann. Chem. 659 (1962) 90; KA Jenson, L.Henrlkson, Acta Chem. Scand. 22 (1968) 1107)

2. Preparation of B-hydroxy-n-amino-thiophene-'i-carbonitrile with Bonoyl Substituent in 2-Position from Malodinitrile, Carbon Oxysulfide and Phonacyl Bromide (H. Schaafor, K. Gowald, J. Prakt. Chem. 317 (1975) 337)

3. Preparation of SS-iunsubstitularOdlamlnothlophon ^ -Dicarhonitrile from Malodinitrile and Sulfur (K.Gowald, M. Kloinort, B.Thiole, M.Hontschol, J. Prakt. Chom. 314 (1972) 303, H. Junok, P.Wibmor , Swiss 583224 [1976]) and preparation of 3,5- (unsubstituted) dieminothiophene-4-carbonitrile with alkoxycarbonyl substituent in the 2-position from malodinitrile, cyanosulforus and Schwofet (M. Mittelbach, H. Junok, Liobigs Ann. Chom. 1986.533)

4. Horolysis of 6-arylamino-S-aminothlophone carbonyltrin with carboxyl function in 2-position from malodinitrile, aryl isothiocyanates and alkylating amide (R.Compper, E. Kutter, Angow., Chom. 74 (19621251)

6. Horstollung of 5- (Mothylamlno odor bonzylamlno odor) arylamino> 3-aminothiophene-2,4-dicarbonitriles by

Ring transformation clay from ^ -dicyanomethylenethiazolines (K.Gewald, M.Hentschel, J. Prakt. Chem. 318 (1976) 343; K.Gewald, U.Hain, P. Hardening, Monatsh. Chem. 112 [1981] 1393)

6. Preparation of 5-dimethylamino (or Piperidino or Morpholino) -3-aminothiophene-4-carbonitriles with Aroyl Substituents in the 2-Position by Ring Transformation from 1.2 Oxathlolium Salts (K.Hirüi, K.Sugimoto, T.lshiba, J. Org. Chem. 45 [1980] and ref. Lit .; P. Czerny, H. Hartmann, J. Prakt. Chem. 325 (1983) 551) or by ring transformation from 2-dialkylimmonium-1,3-oxathiols (K. Hirai, T. Ishiba, Chem. Pharm. Bull. 20 (1972) 2384)

7. Preparation of 5-aryl (or hetaryl) -3-aminothiophene-4-carbonitriles with Carboxyl FunMion in the 2-Position either by Method 6 from 1,3-Oxathiolium Salone (H.H & rtmann, Z. Chem. 11 [1971] 421; Hartmann, H. Schaefer, K.Gewald, J. Prakt. Chem. 316 (1973) 497; T. Tomlnaga, Y. Mattsuda, G. Kebayashi, Heterocycles 1975, 9) or from 3-chloro-2-cyanimiditrile and mercaptomethylenecarbonyl compounds (K.Gewald, U.Hain, E. Schindler, DO 146952 [1979])

All of these processes have the disadvantage that mr 3-Amnnothiophen-4-carbonitriles with a fixed substituent pattern

either in the 2- or in the 5-position or with a fixed substituent pattern in the 2- and 5-position are accessible.

Thus, according to method 5, in addition to the already known from the literature S-methylamino-S-aminothiophene ^ adicarbonitrile, also

other S-alkylamino-S-aminothiophene carbonitrides, but can only be obtained with one cyano group in the 2-position. Apart from the 5-dimethylamino (or piperidino or morpholino) -3-amidothiophene-4-carbonitriles already known from the literature, other 5-secondary-amino-3-aminothiophene-4-carbonitriles should also be accessible by method β, but only such compounds, which have a benzoyl radical in the 2-position.

In contrast, the inventive method has the advantage that S-aminothiophene carbonitriles with variable Substituentenmuster can be made in both 2- as well as in the 5-position. Object of the invention The aim of the invention is to produce such Vorbindungen in a simple manner & us readily available starting materials. Explanation of the essence of the invention

The object of the invention is to provide a technically feasible synthesis route for the preparation of 3-aminothiophene> 4-carbonitriles of general formula I which are variously substituted in 5-position,

where R ^{1 is} an alkoxy, aralkoxy, primary or secondary aliphatic amino group or a hydrazino radical or a substituted cyanomethylene group (CH (CN) R with R = CN, CONH ₂ , COAryl) and R ^{2 is} an aroyl or acyl radical or another carboxyl derivative, wiaz.B. CN, CO ₂ alkyl, CONH ₂ , to find.

Invention & according to this object is achieved in that S-alkyl-sulfonyl-S-aminothiophene-carbonitriles of the general formula II,

R ³ - 5 O ₂

where R ^{1 is} a lower alkyl radical (C, -C _e ) and R ^{1 has} the abovementioned meaning, with nucleophilic reactants of the general formula III,

R'-H III

wherein R ^{1 has} the meaning given above, are reacted. While the reactions with the amines mentioned can also be carried out without the use of a solvent, in the reactions with said O- or C-Nucloophllen the use of both a solvent such. As alcohol, DMF, acetonitrile odbr dioxane, as well as the use of an auxiliary base, such as tert.Amino, alkali metal carbonates, alcoholates odor hydroxides, advantageous. The hitherto unknown 6-alkylsulfonyl-3-aminothiophene-4-carbonitriles II wurdon after principle bokannten process from the corresponding 6-alkylthio-3-amlnothlophon-4-carbonitrilon orhalton.

AusfOhrungtbelsplele Example 1 _v Preliminary binding I with R ¹ - OCH, and R ^J «» COOCHj

(Gomeint are slots Gowlststolle)

Add 4.6 ml of Il (R ¹ "COOCI fj, R '° CH ₁ ) wordon to 36 parts of sodium chloride solution of sodium methoxide (0.6 mol / l). you

heated for 5 min under reflux, allowed to cool and sucks off the precipitate. This gives 3.5 parts (92%) of the colorless product, which has a melting range of 219-223 ° C (chlorobenzene).

Compound II (R ² = COOCH ³ , R ³ = CH ₃ ) was obtained as follows: 5 parts of methyl 3-amino-4-yl-5-methyl (methylthio) thiophene-2-carboate are suspended in 50 parts of acetic acid. After addition of 5 parts of 30% H ₂ O ₂ solution, the mixture 7d is stirred at room temperature. The precipitate is sucked off. This gives 4.6 parts (81%) of the compound II (R ² = COOCH ₃ , R ¹ = CH ₃ ), which has a melting range of 237-239 ⁰ C (pyridine).

Example 2 Compound I with R ¹ = morpholine) and R ² = COOCH ₃

4,6TtHeII (R ² = COOCH ₃ , R ¹ = CH ₃ ) are diluted with 15 parts of morpholine. The reaction is heated under reflux for 5 min. After cooling, it is poured into 100 parts of hydrochloric acid (3 mol / l). The precipitate is sucked off. This gives 4.6 parts (95%) of the bright yellow product, which has a melting range of 196-208 ° C (methanol).

BeUpIoI 3

Compound I with R '= piperidino and R ² = COOC ₁ Ht

4.6 part of an intermediate obtained analogously to Example 1 (R ² ° COOC ₂ Hi, R ³ = CH ₃ ) are analogous with 15 parts of piperidine

Step Example! 2 implemented. This gives 4.9 parts (83%) of the light yellow product, which has a melting range of 179-181 ⁰ C (dioxane)

has.

Example·" Compound, g I with R ¹ = NHNH ₂ and R ² = COOCH ₃

4.6TeUCiI (R ² = COOCH ₃ , R ³ = CH ₃ ) are added to 100 parts of methanol and 4.6 parts of 70% hydrazine hydrate solution. The

The mixture is refluxed for 45 minutes. The precipitate is removed and washed with a little methanol. This gives 3.3 Parts (89%) of the colorless product having a melting range of 204-209 ° C (methyl glycol). example Compound I with R '= CH (CN) CONH ₂ and R ² = COOCH ₃

4.6 parts of H (R ² = COOCH ₃ , R ³ = CH ₃ ) are spiked with 90 parts of acetonitrile and 4.6 parts of sodium cyanoacetamide. The batch is shaken overnight. The precipitate is filtered off with suction and dissolved in 150 parts of water. The aqueous solution is filtered and acidified by the addition of hydrochloric acid (3 mol / L). The precipitate is filtered off with suction and washed with a little methanol.

This gives 3.7 parts (79%) of the beige product, which has a melting range of 219-222 ° C (acetic acid).

Claims (1)

1. A process for the preparation of 5-position variously substituted 3-aminothiophene-4-carbonitriles, characterized in that S-alkylsulfonyl-S-aminothiophene-carbonitriles of the general formula II, wherein R ^{2 is} an aroyl or acyl radical or another carboxyl derivative, such as. B. CN, CC ^ alkyl, CONH ₂ - and R ^{3 is} a lower alkyl radical (C ₁ -C ₆ ), with nucleophilic reactants of the general formula ill, R'-H III, wherein R ^{1 represents} an alkoxy, aralkoxy, a primary or secondary aliphatic ^ amino group or a hydrazino radical or a substituted cyanomethylene group (CH (CN) R with R = CN, CONH ₂ , CO aryl), to those in the 5-position variously substituted 3-aminothiophene-4-carbonitriles of the general formula I,