DD240891A1 - PROCESS FOR PREPARING 3- (3,4-DIHYDRO-4-OXOTHIENO / 2,3-D / -PYRIMIDIN-2-YL) PROPIONE ACIDS - Google Patents

Abstract

The invention relates to a process for the preparation of 3- (3,4-dihydro-4-oxothieno / 2,3-d / -pyrimidin-2-yl) -propionic acids of the general formula I in which R1, R2H, alkyl, polymethylene, aryl, alkoxycarbonyl. These compounds are potential drugs and are also intermediates in the pharmaceutical industry. The aim of the invention is, starting from 3-carbamoyl or 3-alkoxycarbonylsubstituierten 2-Aminothiophenen of the general formula II, in which R1, R2H, alkyl, polymethylene, aryl, alkoxycarbonyl, R3amino, alkoxy mean, 3- (3,4- Dihydro-4-oxothieno / 2,3-d / -pyrimidin-2-yl) -propionic acids. The synthesis of the compounds of general formula I is carried out by reacting the compounds of general formula II with succinic anhydride in the melt, wherein the resulting N- (3-carbamoyl or 3-alkoxycarbonylthien-2-yl) -bernsteinsaeuremonoamide of general formula III either be cyclized with caustic or concentrated ammonia solution to the final products.

Description

Application of the invention

The invention relates to a process for the synthesis of 3- (3,4-dihydro-4-oxothieno / 2,3-d / pyrimidin-2-yl) -propionic acids of the general formula I,

R ¹ , R ² = H, alkyl, polymethylene, aryl, alkoxycarbonyl

mean.

These compounds are potential drugs and also intermediates of the pharmaceutical industry.

Characteristic of the known technical solutions

Compounds of the general formula I are so far described neither in the patent nor in the specialist literature. It is reported only via analogous thieno / 2,3-d / pyrimidin-2-ylcarboxylic acids and acetic acids or via some of their derivatives.

(DD 0152129, WP C 07 D 267719/7, WP C 07 D 267718/0, J. Heterocycl.Chem.1194497 [1980], J. Heterocycl Chem 21.375

Object of the invention

The aim of the invention is a simple and rapid production method for previously inaccessible 3- (3,4-dihydro-4-oxothieno- / 2,3-d / pyrimidin-2-yl) -propionic acids of general formula I with readily available starting materials, to expand the range of potential drugs or interesting intermediates.

Explanation of the essence of the invention

The object of the invention is a process for the synthesis of 3- (3,4-dihydro-4-oxothieno / 2,3-d / pyrimidin-2-yl) -propionic acids of the general formula I,

R ¹ , R ² = H, alkyl, polymethylene, aryl, alkoxycarbonyl

mean.

According to the invention the object is achieved in that 4,5-substituted 2-aminothiophene-3-carboxylic acid esters and amides of the general formula II,

R ¹ , R ² = H, alkyl, polymethylene, aryl, alkoxycarbonyl,

R ³ = amino, alkoxy

with succinic anhydride in the melt to give N- (thien-2-yl) -succinic acid monoamides of the general formula IN,

R ¹ , R ² = H, alkyl, polymethylene, aryl, alkoxycarbonyl,

R ³ = amino, alkoxy

mean, be implemented. The resulting N- (3-carbamoylthien-2-yl) -succinic acid monoamides can be prepared by treatment with medium-strength brine from both the above reaction melt and from the worked-up, pure succinic acid monoamide to the 3- (3,4-dihydro-4-oxothieno / 2,3-d / pyrimidin-2-yl) -propionic acids of the general formula I, wherein R ¹ and R ^{2 have the} above meaning, are cyclized. From the obtained in the acylation with succinic anhydride N- (3-alkoxycarbonylthien-2-yl) -bernsteinsäuremonoamiden the propionic acids of general formula I can also be synthesized by reaction with concentrated ammonia solution under mild conditions. The workup of the resulting products is carried out in a conventional manner.

The invention will be explained below with two examples:

Example 1 N - ^ - Carbamoyl-A-tetramethylenethienyl-succinic acid monoamide

0.01 mol of 2-amino-4,5-tetramethylenethiophene-3-carboxamide are mixed with 0.01 mol of succinic anhydride and heated to melt for 2 minutes. After cooling, the solidified mass is powdered and stirred with 50ml2% NaOH for 15 minutes. After filtration, the compound is precipitated by acidification with dilute HCl, washed with plenty of warm water, reprecipitated from alkalis and dried.

Melting point: 215-225 ° C (dec.), Yield: 27%

Succinic monoamides (corresponding to formula III) prepared in an analogous manner are summarized in Table 1.

Table 1 R ³ Molecular formula molar mass Fp- ( ⁰ C) Yield (%) R ¹ R ² NH ₂ C ₁₁ H ₁₄ N ₂ O ₄ S 270.3 200-205 (Zers.) 37 CH ₃ CH ₃ NH ₂ C ₁₅ H ₁₄ N ₂ O ₄ S 318.3 220-225 (Zers.) 56 HC ₆ H ₆ OC ₂ H ₅ C ₁₃ H ₁₇ NO ₅ S 299.3 144-146 47 CH ₃ CH ₃ OC ₂ H ₅ C ₁₅ H ₁₉ NO ₅ S 325.4 154-156 42 - (CHa) ₄ - OC ₂ H ₅ C ₁₆ H ₂₁ NO ₅ S 135-137 135-137 69 - (CHa) ₅ - OC ₂ H ₆ C ₁₆ H ₂₁ NOS C ₆ H ₆ H OC ₂ H ₅ C ₁₈ H ₁₉ NO ₅ S 361.4 104-106 36 CßHö CH3 OC ₂ H ₅ C ₁₅ H ₁₉ NO ₇ S 357.4 163-165 11 CH3 C2H5O2C OCH ₃ C ₁₄ H ₁₇ NO ₅ S 311.4 149-153 54 - (CHa) ₄ -

Example 2

3- (3,4-dihydro-4-oxothieno / 2,3-d / pyrimidin-2-yl) -propionic acids (corresponding to formula I) Method A

1 g of the corresponding succinic acid monoamide (according to formula III) obtained from 2-aminothiophene-3-carboxylic acid amides and succinic anhydride is refluxed in 30 ml of 2% sodium hydroxide solution. After cooling and filtration, the propionic acid formed is precipitated with dilute hydrochloric acid. The product is then reprecipitated several times from lye, washed with plenty of warm water and dried.

Method B

The product obtained in the preparation of the succinic acid monoamides (according to formula III) from 2-aminothiophene-3-carboxamides and succinic anhydride by melting (see example 1) is taken up after solidification without purification or isolation in 2% sodium hydroxide solution and after filtering off the insoluble constituents heated to reflux for one hour. The work-up is analogous to method A.

Method C

The mass obtained after the melting of 2-aminothiophene-3-carboxylic acid esters and succinic anhydride (see Example 1) is allowed to stand for a longer time after cooling and solidification in a sealed vessel with 30 ml of concentrated ammonia. The reaction is monitored by thin-layer chromatography. After complete reaction is filtered and neutralized with dilute hydrochloric acid. The resulting precipitate is worked up analogously to method A.

The obtained according to the methods A, B or C 3- (3,4-dihydro-4-oxothieno / 2,3-d / pyrimidin-2-ylj-propionic acids (corresponding to formula I) are summarized in Table 2.

Table 2 Molecular formula molar mass Mp CC) method Yield (%) R ¹ R ² C ₁₁ H ₁₂ N ₂ O ₃ S 252.3 225 (Zers.) A 75 CH ₃ CH ₃ C 60 C ₁₃ H ₁₄ N ₂ O ₃ S 278.3 225 (Zers.) A 90 - (CH ₂ ) ₄ - B 36 C 60 C ₁₄ H ₁₆ N ₂ O ₃ S 292.3 220 (Zers.) C 68 - (Ch ₂ J ₅ - Ci ₅ H ₁₂ N ₂ O ₃ S 300.3 220 (Zers.) A 80 HC ₆ H ₅ C ₁₆ H ₁₄ N ₂ O ₃ S 314.4 215 (Zers.) C 63 C ₆ H ₅ CH ₃

1 ^ Λ. R ¹ , R ² = E, alkyl, polymethylene,

μ j] T ³ - aryl, alkoxycarbonyl

Pormel I

R ¹ , R ² = H, alkyl, polyethylene

aryl, alkoxycarbonyl, R 1 = aimino, alkoxy II

Jl Η - R ¹ , R ² = H, alkyl,

_R 2-i JLmCOCH ₀ CH ₀ CO ₀ H ^ _{} alkoxycartoriyl }}

R · = amino, alkoxy

Preamble III

Claims (2)

Claim: Process for the preparation of 3- (3,4-dihydro-4-oxothieno / 2,3-d / -pyrimidin-2-yl) -propionic acids of general formula I, R ¹ , R ² = H, alkyl, polymethylene, aryl, alkoxycarbonyl mean, characterized in that 3-carbamoyl or 3-alkoxycarbonyl-substituted 2-aminothiophenes of the general formula II, R ¹ , R ² = H, alkyl, polymethylene, aryl, alkoxycarbonyl, R ³ = amino, alkoxy mean, with succinic anhydride in a melt to N- (3-carbamoyl or S-alkoxycarbonylthien ^ -yl) -memsteinsäuremonoamiden the general formula III, wherein R ¹ , R ² and R ^{3 have the} above meaning, reacted and then either with Lye or be cyclized with concentrated ammonia solution.