DD226893A1 - PROCESS FOR PREPARING ARYLAMINOSUBSTITUTED THIENO 2,3-D PYRIMIDINES - Google Patents

Abstract

The invention relates to a process for the preparation of aryl-substituted thieno (2,3-d) pyrimidines of the general formula III in which R 1 is R 2 methyl, R 1 R 2 tetramethylene R 3 HR 4 aryl R 5 HR 6 aryl or -NR 5 R 6 monocyclic heterocyclic saturated ring meanings. The aim of the invention is starting from the 2,4-dichlorothieno (2,3) pryrimidines of the general formula I in which R 1 is R 2methyl, R 1 is tetramethylene, thieno (2,3) represent pryrimidine derivatives of the general formula III. The synthesis of compounds of general formula III, wherein -NR3R4 are other than -NR5R6, is carried out once in a multistage process by boiling an amine of general formula HNR3R4 under reflux in ethanolic or propanolic solution with compounds of general formula I. Under these conditions are primary compounds of general formula II. From these compounds of the general formula III could be obtained in a subsequent reaction with an amine of the general formula HNR5R6. Compounds of the general formula III with -NR3R4-NR5R6 are prepared by boiling at the reflux of the 2,4-dichlorothieno (2,3-d) pyrimidine of the general formula III in excess of the amine. Compounds of these structural classes are potential drugs with antiplatelet activity.

Description

wherein R ¹ = R ² = methyl, R ', R ² = tetramethylene, either first in ethanblischer and propanolic solution with aniline or an aniline derivative with refluxing to give compounds of general formula II

IX

reacted, optionally isolated and then reacted with saturated N-heterocycles in the amine as a reaction partner and solvent to non-identical in 2- and 4-position thieno [2 ', 3-d] pyrimidines or by boiling at reflux with aniline as a reactant and solvent in the 2- and 4-position similarly substituted thieno [2,3-d] pyrimidines are reacted.

Field of application of the invention

The invention relates to a multistage process for the preparation of 2,4,5,6-tetrasubstituted thieno [2,3-d] pyrimidines according to the general formula III.

Ill

wherein R ¹ = R ² -methyl, R \ R ² = tetramethylene R ³ = HR ⁴ = aryl R ⁶ = HR ⁶ = aryl or

-NR ⁵ R ⁶ = monocyclic, heterocyclic, saturated ring.

Structural class compounds of general formula III are potential drugs of antiplatelet activity.

Characteristic of the known technical solution

Compounds of the general formulas II and III have hitherto been prepared by reacting corresponding 2,4-dichlorothieno [2,3-d] pyrimidines I with alkylamines, dialkylamines and cycloalkylamines, where likewise identical or dissimilarly substituted derivatives are obtained in the 2- and 4-positions were.

Object of the invention

The aim of the invention is to develop a process for the synthesis of arylamino-substituted thieno [2,3-d] pyrimidines.

The presentation of a series of N-aryl derivatives of these known aminothieno [2,3-d] pyrimidines expands the range of antiplatelet drugs.

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Explanation of the essence of the invention

The invention has for its object to introduce arylamino groups both in the 4-position and in the 2- and 4-position of thieno [2,3-d] pyrimidine.

The essence of the invention consists in the preparation arylaminosubstituierter thieno [2,3-d] pyrimidines of the general formula III

Ill

wherein R ¹ = R ² = methyl, R ¹ , R ² = tetramethylene

R ³ = H

R ⁴ = aryl

R ⁵ = H

R ⁶ = aryl or

-NR ⁵ R ⁶ = monocyclic, heterocyclic, saturated ring

mean that the respective amino-substituted in the 2- or 4-position can either be dissimilar or similar. The synthesis of the compounds of the general formula III in the case of dissimilar substitution is carried out by reacting the 2,4-dichlorothieno [2,3-d] pyrimidines of the formula I.

with the corresponding amine HNR ³ R ⁴ , wherein R ³ = H and R ⁴ = aryl. The solvent used is ethanol or propanol. As intermediates compounds of general formula II are obtained.

II

which are either isolated or reacted immediately with an amine of the formula HNR ⁵ R ⁶ , wherein the amine is the reaction partner and solvent. There are obtained compounds of general formula III, wherein NR ³ R ^{4 are} not equal to NR ⁵ R ⁶ . Compounds of the general formula III with NR ³ R ⁴ = NR ⁵ R ⁶ are prepared by refluxing the 2,4-dichlorothieno [2,3-d] pyrimidine of the general formula I in excess of the amine HNR ³ R ⁴ = HNR ⁵ R ⁶ , wherein R ³ = R ⁵ = H and R "= R ⁶ = aryl.

embodiments

The invention will be explained below with reference to three embodiments.

example 1

Preparation of 2-chloro-4- (o-toluidino) -5,6,7,8-tetrahydrobenzothieno (2,3-d) pyrimidine, C ₁₇ H ₁₆ CIN ₃ S (329.87) 1.3 g (ca. 10 mmol) of 2,4-dichloro-5,6,7,8-tetrahydrobenzothieno [2,3-d] pyrimidine are treated with 1.2 g (6.3 mmol) of freshly distilled o-toluidine in 50 ml of propanol for 6 hours Reflux heated to boiling. The precipitated after cooling crystals are filtered off, suspended in water, again filtered with suction and recrystallized several times.

Melting point: 145-148 ° C (ethanol)

In an analogous way are shown:

4-anilino-2-chloro-5,6,7,8-tetrahydrobenzothieno [2,3-d] pyrimidine, C ₁₆ H ₁₄ CIN ₃ S (315.84) Melting point: 156-158 ° C (ethanol)

2-Chloro-4- (m-toluidino) -5,6,7,8-tetrahydrobenzothieno (2,3-d] pyrimidine, C ₁₇ H ₁₆ CIN ₃ S (329.87) Melting point: 166-168 ° C (ethanol)

2-chloro-5,6-dimethyl-4-pyrimidine (o-toluidino) thieno [2,3-d],

C ₁₆ H ₁₄ CIN ₃ S (303.83)

Melting point: 218-221 ⁰ C (isopropanol)

Example 2

Preparation of 2-morpholino-4- (o-toluidino) -5,6,7,8-tetrahydrobenzothieno [2,3-d] pyrimidine, C ₂₁ H ₂₄ N ₄ OS (380.55) 1.0 g (ca. 3.0 mmol) of 2-chloro-4- (o-toluidino) -5,6,7,8-tetrahydrobenzothieno [2,3-d] pyrirnidine are refluxed with 10 ml (about 0.11 mol) of morpholine for 2 hours cooked. If no precipitate crystallizes on cooling, the solution is stirred into 50 to 70 ml of water. The precipitate is filtered off and recrystallized.

The final product falls already on cooling, the working up is as in Example Melting point: 118-122 ⁰ C (ethanol) In an analogous manner are presented:

5,6-dimethyl-2-morpholino-4- (o-toluidino) thieno [2,3-d] pyrimidine, C ₁₉ H ₂₂ N ₄ OS (354.51) Melting point: 204-206 ⁰ C (ethanol ) 4-Anilino-2-morpholino-5,6,7,8-tetrahydrobenzothieno [2,3-d] pyrimidine, C ₂₀ H ₂₂ N ₄ OS (366.53) Melting point: 164-166 ° C (acetone) 2-morpholino-4- (m-toluidino) -5,6,7,8-tetrahydrobenzothieno [2,3-d] pyrimidine, C ₂₁ H ₂₄ N ₄ OS (380.55) melting point: 198-201 ⁰ C ( ethanol)

Example 3

Preparation of 2,4-di (m-toluidino) -5,6,7,8-tetrahydrobenzothieno [2,3-d] pyrimidine, C ₂₄ H ₂₄ N ₄ S 4.0 g (about 15.4 mmol) 2,4-Dichloro-5,6,7,8-tetrahydrobenzothieno [2,3-d] pyrimidine are brought to the boil in 50 ml of freshly distilled m-toluidine for hours.

If, after cooling, the end product does not precipitate, the excess m-toluidine is distilled off under reduced pressure.

The substance is taken up in about 50 ml of water, filtered off and washed with a little cold ethanol and recrystallized.

If the substance precipitates immediately after cooling, it is filtered off with suction, suspended in water, again filtered off with suction and recrystallized.

Melting point: 179-181 ⁰ C (ethanol / acetone mixture 50:50) in an analogous manner are presented:

2,4-dianilino-5,6,7,8-tetrahydrobenzothieno [2,3-d] pyrimidine, C ₂₂ H ₂₀ N ₄ S (372.52) Melting point: 196-198 ⁰ C (ethanol / acetone mixture, 50:50) 2,4-di- (o-toluidino) -5,6,7,8-tetrahydrobenzothieno [2,3-d] pyrimidine, C ₂₄ H ₂₄ N ₄ S (400.58) Melting point: 184- 186 ° C (ethanol)

Claims (1)

Invention claim: Process for the preparation of arylamino-substituted thieno [2,3-d] pyrimidines of the general formula I III wherein R ¹ = R ² = methyl, R ', R ² = tetramethylene R ³ = HR ⁴ = aryl R ⁵ = HR ^e = aryl or -NR ⁵ R ⁶ = monocyclic, heterocyclic, saturated ring, characterized in that the starting compound of the general formula I