DD294485A5 - PROCESS FOR THE PREPARATION OF THIENO / 2,3-C / PYRAZOL-3,4-DIAMINES - Google Patents

Abstract

The invention relates to a process for the preparation of * I. It is the object of the invention to prepare these hitherto unknown compounds from readily available starting materials. The task is to find a technically feasible synthetic route. The object is achieved by reacting 3-amino-5-alkylsulfonyl-thiophene-4-carbonitriles with hydrazines. The compounds obtained are of pharmaceutical interest. Formula I {* * Intermediates for the Pharmaceutical Industry; Gastro therapeutics; biologically active preparations

Description

wherein R ^{1 represents} a hydrogen atom or a methyl group, to the thieno / 2,3-c / pyrazole-3,4-diamines of the formula I,

which may be present in the form shown here or as other tautomers, where R ¹ and R ^{2 have} the abovementioned meaning, are reacted.

2. The method according to claim 1, characterized in that the reaction using mineral or Lewis acids, such as. Hydrochloric acid, sulfuric acid or boron trifluoride is carried out, wherein the thieno / 2,3-c / pyrazole-3,4-diamines are obtained as salts which can be converted by conventional Met soil in the corresponding bases.

3. The method according to claim 1, characterized in that the reaction using an auxiliary base such. Eg Al! Dlialkoholat is performed.

4. The method according to claim 1-3, characterized in that the reaction is carried out in two stages, wherein in the first stage no Hiifsstoffe be used and in the second stage, acids and bases are used as Hiifsstoffe.

5. The method according to claim 1-4, characterized in that the intermediate hydrazinothiophenes IV,

IV

wherein R ¹ and R ^{2 have} the abovementioned meaning, be isolated in the meantime.

6. The method according to claim 1-5, characterized in that the reaction using a solvent such as. As alcohol, dimethylformamide, dioxane, acetonitrile, acetic acid or water is performed.

7. The method according to claim 1-6, characterized in that the reaction mixture is heated under reflux.

Field of application of the invention

The invention relates to a process for the preparation of thieno / 2,3-c / pyrazole-3,4-diamines. Such compounds may gain importance as pharmaceuticals, in particular as gastrotherapeutic agents as well as starting materials for the preparation of biologically active compounds.

-2- 294 485 Characteristic of the known state of the art

Thieno / 2,3-c / pyrazole-3,4-diamine are unknown. Thieno / 2,3-c / pyrazoles with other substituents in the 3- and 4-positions are accessible by five different methods.

1. Canceling the thiophene heterocycle starting from 4-functionalized pyrazole-3-thiones or their disulfones and CfRingschlußelementen such as chloroacetic acid, nitromethane or phenylacetic acid.

(I.Ya.Kvitko, A.A.Taresenko, Zh. Org.Khim.7 [1971] 1253, K.J. Brown, O. Meth.-Cohn, Tetrahedron Lett.46 (1974) 4069)

2. Construction of the thiophene heterocycle starting from unsubstituted in the 4-position dihydro-3-thione and C ₂ ring closure elements such. For example, acetophenone.

(Maquestiau, Y. van Haverbeke, J.C. Vanovervelt, Bull. Soc. Chim. BeIg. 86 [1977] 87)

3. Integration of thiophene heterocycle by reaction of 3-halo-pyrazole-4-carbatdehyden with thioglycolic acid or functionalized Thioglycolsäurederivaten as SC ring closure element.

(I.Ya.Kvitko, TMGalkina.Zh. Org. Khim.5 [1969] 1498; I.Ya.Kvitko, Khim. Geterosikl Soedin 1969, 760; BAPorai-Koshits, I. Ya. Kvitko, EA Shutkova Khim. Farm, Zh. 4 [1970] 19; Ya. N. Koshelev, I. Ya. Kvitko, CS Efros, Zh. Org. Khim. 8 [1972] 1750; Dong H. Kim.AASantilli, US 3,649 .641 [1969], ref. CA76 [1972] 140.803h; LNZakharov, I.Ya.Kvitko, AVEI'tsov, Zh. Org. Khim. 9 [1073] 2416)

4. Cancellation of the pyrazole cycle by reaction of thiophene derivatives with diazomethane as CNN ring closure element. (LM Korotaeva, AM Moiseenkov, VSBogdanov, VP Gul'tyai, Izv Akad Nauk SSSR, Ser Khim 1983, 2098, ref CA 100 [1984] 51.386w, LA Mukahamedova, MVKonoplev, SF Machmutova, BI Busuikin, WK Chairullin, Khim, Geterosikl Soedin 1976, 1426, HJ Backer, N. Dost, J. Knutnerus, Rac. Trav. Chim. 68 [1949] 237)

5. Preparation of thieno / 2,3-c / pyrazoles by ring conversion from other heterobicyclics; Photolytic ring contraction of Thieno / 2,3-c / diazepine.

(T.Tsuchiya, M.Enkaku, U.Sawanishi, J.Chem.Soc, Chom. Commun. 13 [1978], 568; T.Tsuchiya, M.Enkaku, U.Sawanishi, Chem. Pharm. Bull. 27 1979] 2188, T.Tsuchiya, M. Marazumi, U. Sawanishi, Jpn. Kokai Tokkyo Koho, 80-36.455 [1978], ref CA 93 [1980] 132.484r)

An analogous representation of thieno / 2,3-c / pyrazole-3,4-diamines is not possible because the corresponding starting compounds are not known.

The method claimed according to the invention describes, starting from easily accessible thiophene derivatives and N ₂ ring closure elements, a fundamentally novel access for the thieno / 2,3-c / pyrazole heterosystem.

Object of the invention

The aim of the invention is to produce such compounds in a simple manner.

Explanation of the essence of the invention

The object of the invention is to provide a technically feasible synthesis route for the preparation of thieno / 2,3-c / pyrazole-3,4-diamines of the formula I,

wherein R ^{1 represents} a hydrogen atom or a methyl group and R ^{2 represents} a CHaOOC- or a CjHbOOC- or a C ₈ HsCO-ReSt.

According to the invention this object is achieved in that 5-Alkylsulfonylthiophene of formula II,

where R ^{3 is} a lower alkyl radical (C ₁ -C ₆ ) and R ^{2 has} the abovementioned meaning, with reactants of the formula III,

R'-NH-NH ₂ VIII

wherein R ^{1 has} the meaning given above, are reacted. In this case, first, by substitution of the alkylsulfonyl group of II 5-hydrazino-thiophenes of the formula IV,

NC -ν

I 11 ^L

wherein R ¹ and R ^{2 have} the meaning given above formed. These intermediates, which may also be isolated, are subject to a cycloaddition reaction to the final products I. To achieve this cycloaddition, the use of basic auxiliaries, such. As alkali metal, or acidic auxiliaries, such as. As minuric or Lewis acids, advantageously, wherein using acidic auxiliaries, the thieno / 2,3-c / pyrazole-3,4-diamines firstly ils salts are obtained from which the corresponding bases can be released by conventional methods dio. The reactions are carried out using a solvent such. As alcohol, dimethylformamide, dioxane, acetonitrile, acetic acid or water. The starting compounds II with R ² = COOC ₂ H ₂ , COC ₈ H ₆ and R ³ = alkyl, which have not yet been described, were obtained analogously to the already known preparation of II with R ² = COOCH ₃ and R ³ = alkyl.

embodiments

example 1

Compound I with R ¹ = CH ₃ and R ² = C ₆ H ₆ CO

(meaning always parts by weight)

option A

1 part of Il (R ² = C ₆ H ₅ CO, R ³ = CH ₃ ) is mixed with 10 parts of methanol and 0.45 parts of methylhydrazine (III with R ¹ = CH ₃ ). The mixture is heated for 6 h under reflux and stirring, allowed to cool and mixed with 10 parts of methanol and 2 parts of concentrated methanolic hydrochloric acid. The batch is shaken for 2 h at room temperature and then filtered. From the filtrate, compound I is precipitated as the hydrochloride by the addition of ether. This gives 0.72 parts (60%) of the product, which has a melting range of 269-275 ⁰ C (water). 0.72 parts of the hydrochloride are mixed with 10 parts of 10% aqueous sodium carbonate solution and triturated. The precipitate was filtered off with suction after standing for one hour and washed with water. This gives 0.55 parts (91%) of the product, which has a melting range of 266-27O ⁰ C (methanol).

Variant B

1 part of Il (R ² = C ₆ H ₅ CO, R ³ = CH ₃ ) are mixed with 10 parts of methanol and 0.45 parts of methylhydrazine (III with R ¹ = CH ₃ ). The mixture is refluxed for 6 h and stirred, allowed to cool, filtered off and washed with water and a little methanol. This gives 0.8 parts (90%) of the intermediate IV (R ¹ = CH ₃ , R ² = C ₆ H ₆ CO) of the melting range of 218-223T (methanol). 0.8 parts of IV (R ¹ = CH ₃ , R ² = C ₆ H ₈ CO) are mixed with 80 parts of absolute methanol and 0.8 parts of sodium. The batch is heated under reflux for 3 h. After cooling, the mixture is allowed to stand for 12 h, the precipitate is filtered off with suction and washed with dilute acetic acid and a little methanol. 0.3 part (40%) of compound I (with R ¹ = CH ₃ and R ² = C ₆ H ₆ CO) is obtained.

Variant C

0.8 parts of IV (R ¹ = CH ₃ , R ² = C ₆ H ₆ CO) prepared according to Variant B are dissolved in 160 parts of concentrated acetic acid and admixed with 0.1 part of boron trifluoride ethyl etherate. The mixture is shaken for 8 h at room temperature and then allowed to stand for 12 h. The precipitate is filtered off with suction and triturated with 10 parts of a 10% sodium carbonate solution. The precipitate is sucked off after standing for one hour. This gives 0.2 part (20%) of compound I (with R ¹ = CH ₃ and R ² = C ₆ H ₆ CO).

Variant D

According to variant B prepared 0.8 parts of IV (R ¹ = CH ₃ , R ² = C ₆ H ₆ CO) are mixed with 40 parts of concentrated hydrochloric acid. The batch is shaken for 2 h at room temperature and allowed to stand for 8 h at room temperature. The resulting precipitate is filtered off and washed with a little water. This gives 0.8 parts (90%) of compound I (with R '= CH ₃ and R ² = C ₆ H ₆ CO x HCI, x H ₂ O) with the melting range of 269-275 ⁰ C (water).

Variant E

According to variant B prepared 0.8 parts of IV (R ¹ = CH ₃ , R ² = C ₆ H ₆ CO) are mixed with 15 parts of methanol and 0.8 parts of concentrated methanolic hydrochloric acid. The batch is shaken for 15 min at room temperature and filtered. From the filtrate, after addition of ether, compound I precipitates as the hydrochloride. This gives 0.65 parts (70%) of compound I (with R ¹ = CH ₃ and R ² = C ₈ H ₆ CO X HCI, XH ₂ O).

Example 2

Compound I with R ¹ = H and R ₂ = C ₆ H ₆ CO

(meaning always parts by weight)

1 part of Il (R ² = C ₆ H ₆ CO, R ³ = CH ₃ ) is mixed with 25 parts of methanol and 1 part of 80% hydrazine solution (III with R ¹ = H). The batch is refluxed for 30 min. After cooling, the precipitate formed is filtered off with suction and washed with methanol and water.

This gives 0.68 parts (81%) of the intermediate IV (R '= H, R ² = C ₆ H ₅ CO), which has a melting range of 209-215 ⁰ C (toluene / acetone). 0.68 parts of IV (R ¹ = H, R ² = C ₆ H ₆ CO) are mixed with 10 parts of methanol and 2 parts of concentrated methanolic hydrochloric acid. The mixture is shaken for 15 min at room temperature and then filtered. From the filtrate compound I is precipitated by addition of ether as the hydrochloride. This gives 0.75 parts (91%) of the product (I with R ¹ = H and R ² = C ₈ H ₆ CO x HCI, χ H ₂ O), which has a melting range of 167-171 ⁰ C (water.

Compound II (R ² = C ₆ H ₆ CO, R ³ = CH ₃ ) was obtained as follows: 1 part of 4-amino-5-benzoyl-3-cyanothiophene-2-thiol are mixed with 5 parts of methanol and 1, 2 parts Methyliodld added, shaken vigorously for 30 min and then allowed to stand for 2 h. The mixture is mixed with a few drops of water and the precipitate is filtered off with suction. This gives 0.67 parts (60%) of the intermediate compound 4-amino-5-benzoyl-3-cyano-2-methylthio-thiophene with the melting range of 140-148 ⁰ C (methanol), which is mixed with a mixture of 3 parts Acetic acid and 1.5 parts ca, 30% hydrogen peroxide solution is added. The mixture is heated for 2 h at 100 ⁰ C and then cooled to room temperature. After standing for 2 h, the precipitate is filtered off, washed with a little methanol and water. This gives 0.64 part of the compound II (with R ² = C ₆ H ₆ CO and R ³ = Cl-I ₃ ), which has a melting range of 177-184 ° C (methanol).

Example 3

Compound I with R ¹ = H and R ² = COOCH ₃

option A

1 part of Ii (R ² = COOCH ₃ , R ³ = CH ₃ ) are mixed with 20 parts of methanol and 1 part of 80% hydrazine hydrate solution (III with R ¹ = H). The mixture is heated for 45 min under reflux, allowed to cool and mixed with 5 parts of concentrated methanolic hydrochloric acid. The batch is shaken at room temperature and then filtered. From the Fittrat compound I is precipitated by addition of ether as the hydrochloride. This gives 0.3 parts (30%) of the product, which has a melting range of 206-208 ⁰ C (methanol / water) uesiut.

Variant B

1 part of Il (R ² = COOCH ₃ , R ³ = CH ₃ ) is mixed with 20 parts of methanol and 2 parts of 70% hydrazine hydrate solution (III with R ¹ = H). The mixture is refluxed for 1 h and the precipitate is filtered off with suction. This gives 0.7 parts (89%) of Zwischenstcffos IV (Ri = H, R ² = COOCH ₃ ) of the melting range 204-209 ° C (methyl glycol).

0.7 part of ethylene (R '= H, R ² = COOCH ₃ ) are mixed with 7 parts of 10% strength methanolic sulfuric acid. The batch is stirred for 15 min at room temperature, the precipitate is filtered off with suction. This gives 0.63 parts (72%) of the sulfate of the compound I (with R ¹ = H, R ² = COOCH ₃ x ¹ / 2H ₂ SO ₄ ) of the melting range from 211 ⁰ C decomposition (ethanol).

0.63 parts of this sulfate are mixed with 13 parts of 10% sodium bicarbonate solution. After completion of the evolution of gas, the precipitate is filtered off with suction and washed with water. This gives 0.5 parts (95%) of the product, which has a melting range of 254-245 ° C decomposition (acetonitrile).

Example 4

Compound I with R '= CH ₃ and R ² = COOCH ₃

1 part of Il (R ² = COOCH ₃ , R ³ - CH ₃ ) is mixed with 10 parts of methanol and 0.35 parts of methylhydrazine (III with R ¹ = CH ₃ ). The mixture is heated under reflux for 6 h and allowed to cool. The resulting precipitate is filtered off with suction and washed with methanol and water. This gives O, 73 parts (84%) of Intermediate IV (with R '= CH _{3 and} R ² = COOCH ₃ ) having a melting range of 204-205 ° C (methyl glycol).

0.73 parts of IV (R ¹ = CH ₃ , R ² = COOCH ₃ ) are mixed with 14 parts of methanol and 0.7 part of concentrated methanolic hydrochloric acid and shaken for 1 h at room temperature.

After filtration, compound I is precipitated from the filtrate with ether as the hydrochloride. This gives 0.88 parts (98%) of the product (I with R ¹ = CH ₃ , R ² = COOCH ₃ x HCI χ H ₂ O), which has a melting range of 267-268 ⁰ C (methanol / ether).

Example 5

Compound I with R ¹ = H and R ² = COOCjH ₆

1 part of Il (R ² = COOC ₂ H ₆ , R ³ = CH ₃ ) is mixed with 5 parts of ethanol, heated to boiling and treated with boiling 1 part of 80% hydrazine hydrate solution (III with R ¹ = H).

Thereafter, the batch is heated for 5 min under reflux. The mixture is then poured into ice-water, the resulting precipitate is filtered off with suction and washed with a little ethanol and water. This gives 0.78 parts (90%) of the intermediate IV (with R ¹ = H and R ² = COOC ₂ H ₆ ), which has a melting range of 210-212 ⁰ C (ethanol / water).

To 0.78 part (R ¹ = H, R ² = COOC ₂ H ₆ ) are added 3 parts of absolute ethanol and 0.8 part of concentrated ethanolic hydrochloric acid and shaken for 1 h at room temperature. After filtration, compound I is precipitated as the hydrochloride from the filtrate by treatment with ether and subsequent standing for 24 hours. This gives 1 part (90%) of the product (I with R ¹ = H, R ² = COOC ₂ H ₅ x HCI, χ H ₂ O), which has a melting range of 208-211 ⁰ C (ethanol / ether).

Examples

Compound I with R ¹ = CH ₃ and R ² = COOC ₂ H ₆

1 part (R ² = COOC ₂ H ₆ , R ³ = CH ₃ ) is mixed with 8 parts of ethanol and 0.4 part of methylhydrazine (III with R ¹ = CH ₃ ) and heated for 3 hours under reflux. After cooling, the precipitate is filtered off with suction and washed with a little ethanol and water. This gives 0.74 parts (80%) of the intermediate IV (with R '= CH ₃ and R ² = COOC ₂ H ₆ ), which has a melting range of 182-186 ⁰ C (ethanol).

0.74 parts of IV (R '= CH ₃ , R ² = COOC ₂ H ₆ ) are mixed with 5 parts of ethanol and 0.75 parts of concentrated ethanolic hydrochloric acid and shaken for 1 h at room temperature.

After addition of ether, compound I is precipitated as the hydrochloride. This gives 0.94 parts (98%) of the product (I with R '= CH ₃ , R ² = COOC ₂ H ₆ x HCI, χ H ₂ O), which has a melting range of 208-260 ° C (methanol / ether ) owns.

Compound II (R ² = COOC ₂ H ₆₁ R ³ = CH ₃ ) was obtained as follows: To 12.8 parts of sodium hydroxide in 120 parts of ethanol was added 10.6 parts of malononitrile with stirring. Thereafter, C12 portions of carbon disulfide in 150 parts of dioxane are added dropwise with stirring at a temperature of 15-20 ⁰ in portions. Obtained after sucking the precipitate 30 parts of

2,2-dicyanothendithiolate as disodium salt. To 12 Tollen of this compound in 100 parts of ethanol are added dropwise 6.13 parts of ethyl chloroacetate with stirring at a temperature of 0-5 "C within 2h. Subsequently, the batch is stirred for 1 h at 0-5 ⁰ C and then left to warm to room temperature. This gives a solution of 4-amino-3cyan-5-ethoxycarbonyl-thiophene-2-thlol, which after distilling off 100 parts of the ethanol in analogy to the preparation of Il (with R ² = COC ₆ H ₆ and R ³ = CH ₃ ), only with the use of concentrated formic acid and Perchlorsäuro instead of acetic acid and at 0-5 ⁰ C instead of at 100 ⁰ C, are reacted. This gives 4.8 parts (53%) of the compound II (with R ^J = COOC ₂ H ₆ and R ³ = CH ₃ ), which has a melting range of 170-177 ⁰ C.

Claims (1)

1. A process for the preparation of thieno / 2,3-c / pyrazole-3,4-diamines, characterized in that 5-Alkylsulfonylthiophene of formula II, NC Wherein R ^{2 is} a CH ₃ OOC- or C ₂ H ₀ OOC- or a C ₈ H ₅ CO-ReSt and R ^{3 is} a lower alkyl radical (C ₁ -C ₆ ), with compounds of the formula III, R ¹ -NH-NH ₂ III