DD258816A1 - PROCESS FOR PREPARING PYRIMIDO 4 ', 5'-5,4-PYRROLO 3,2-F 1,4 THIAZEPINE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of pyrimido & 4,5-5,4! Pyrrolo & 3,2-f! & 1,4! Thiazepine derivatives of general formula I, wherein R 1 is H, alkyl, R 2 alkyl, carboxyalkyl, arylalkyl, hydroxy. These compounds are potential drugs and are also intermediates in the pharmaceutical industry. The object of the invention is, starting from 5- (alkoxycarbonylalkylthio) -2-amino-3,4-dicarbamoyl-1H-pyrroles of the general formula II, in which R 1 is H, alkyl, R 3 is alkyl, pyrimido & 4,5-5,4! Pyrrolo & 3, 2-f! & 1,4! Thiazepinderivate the general formula I represent. The synthesis of the compounds of general formula I is carried out by reacting the compounds of general formula II either with nitriles under the action of dry HCl gas or with acyl halides in organic solvents to the compounds of general formula III, wherein R 1 is H, alkyl, R 2 is alkyl, carboxyalkyl , arylalkyl, alkoxy, R3 alkyl, XO, NH mean, which are cyclized after purification by recrystallization under basic conditions to form both the pyrimidine and the 1,4-thiazepine ring and the compounds of formula I are obtained.

Description

For this 1 page formulas

Field of application of the invention .

The invention relates to a process for the synthesis of pyrimido [4 ', 5'-5,4] pyrrolo [3,2-f] [1,4] thiazepines of the general formula I in which R ^{1 is} H, alkyl,

R ² = alkyl, carboxyalkyl, arylalkyl, hydroxy

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

Characteristic of the known technical solutions

Compounds of the general formula I are described neither in the patent nor in the specialist literature. For the first time, compounds with pyrimido [4 ', 5'-5,4 "] pyrrolo [3,2-f] [1,4] thiazepine are shown as the main body.

Object of the invention

The aim of the invention is a simple and rapid production method for hitherto inaccessible pyrimido [4 ', 5'-5.4] pyrrolo [3,2-f] [1,4] thiazepine derivatives of general formula I with readily available starting materials to the Range of potential drugs or interesting intermediates.

Presentation of the essence of the invention

The object of the invention is a process for the synthesis of pyrimido [4 ', 5'-5,4] pyrrolo [3,2-f] [1,4] thiazepines of the general formula I,

wherein R ¹ = H, alkyl,

R ² = alkyl, carboxyalkyl, arylalkyl, hydroxy.

According to the invention the object is achieved in that S-fAlkoxycarbonylalkylthiol ^ amino-SAdicarbamoyl-i Η-pyrroles of the general formula II, wherein R ¹ = H, alkyl,

R ³ = alkyl,

either reacted with nitriles under the action of dry HCI gas or with acyl halides in organic solvents. The resulting compounds of general formula III, wherein R ¹ = H, alkyl

R ² = alkyl, carboxyalkyl, arylalkyl, alkoxy,

R ³ = alkyl,

X = O, NH mean,

are cyclized after purification by recrystallization under basic conditions to form both the pyrimidine and the 1,4-thiazepine ring, and the compounds of formula I are obtained. The work-up of the intermediate and end products takes place in a manner known per se.

embodiments

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

example 1 Preparation of N- (3,4-dicarbamoyl-5-ethoxycarbonyl-methylthio-1H-pyrrol-2-yl) -phenylacetamidine

C ₁₈ H ₂₁ N ₅ O ₄ S (403.46)

By a solution of 0.01 mol of 2-amino-3,4-dicarbamoyl-5- (ethoxycarbonylmethylthio) -1 Η-pyrrole in 25 ml of benzyl cyanide is introduced with stirring at room temperature for 2 h dry HCl gas. The resulting amidine hydrochloride is filtered off with suction. After dissolving in water, it is neutralized with NaOH and the precipitate is filtered off with suction. The product is recrystallized from n-propanol.

Melting point: 178-8O ⁰ C

Yield: 83%

In an analogous manner, the compounds summarized in Table 1 are prepared:

Table 1: Compounds no. according to formula III R ¹ R ² R ³ yield X Melting point ( ⁰ C) 1 2 no. HC ₆ HH CH ₂ molecular formula 5 C ₂ H ₅ COOH C ₂ H ₅ molecular weight 67 78 NH NH 272-73 150-52 1 2 C ₁₇ H ₁₉ N ₅ O ₄ SC ₁₃ H ₁₇ N ₅ O ₆ S 389.43 371.37

Example 2

Preparation of 2-acetylamino-3,4-dicarbamoyl-5- (ethoxycarbonylmethylthio) -1H-pyrrole C ₁₂ H ₁₆ N ₄ O ₅ S (328.92)

To a solution of 0.01 mol of 2-amino-3,4-dicarbamoyl-5- (ethoxycarbonylmethylthio) -1-pyrrole in 20 ml of pyridine is added dropwise "0.01 mol of acetyl chloride and the solution is stirred for 1 h at room temperature The reaction mixture is added to water and the resulting precipitate is filtered off with suction and the product is recrystallized from methanol.

Melting point: 204-206 ° C

Yield: 87%

In an analogous manner, the compounds summarized in Table 2 are prepared:

Table 2: Compounds no. according to formula III R ¹ R ² OCH ₃ CH ₃ - Molar mass R ³ Yield (%) X Melting point ( ⁰ C) 3 4 no. H CH ₃ sums formula 344.34 342.37 C2H5 C ₂ H ₅ 75 86 O O 192-95 113-15 3 4 C ₁₂ H ₁₆ N ₄ O ₆ SC ₁₃ H ₁₈ N ₄ O ₅ S

Example 3 Preparation of pyrimido [4 ', 5'-5,4] pyrrolo [3,2-fl- [1,4] thiazepine derivatives

General rule:

0.01 mol of the compounds of the general formula III is dissolved in 25 ml of sodium hydroxide solution (4 mol / l) and brought to the boil for 2 minutes. After the solution has cooled, it is neutralized with HCl (2 mol / l) and the precipitate is filtered off with suction. The products are recrystallized from DMF or n-propanol.

The substances produced according to this regulation are summarized in Table 3:

Table 3:

Compounds according to Formulation No. R ¹ R ²

5 H CH ₂ C6H5 yield enamel 6 H C ₆ H 5 (%) point (° C) 7 H CH ₂ COOH 79 > 360 8th H CH ₃ 67 > 360 9 H OH 55 > 360 10 , CH ₃ CH ₃ 87 > 360 No. to hum mol 89 > 360 formula Dimensions 85 > 360 5 C ₁₆ H ₁₂ N ₄ O ₃ S 340.36 6 C ₁₅ H ₁₀ N ₄ O ₃ S 326.33 7 C ₁₁ H ₈ N ₄ O ₆ S 308.27 8th C ₁₀ H ₈ N ₄ O ₃ S. 264.25 9 C ₉ H ₆ N ₄ O ₄ S 266,22 10 C ₁₁ H ₁₀ N ₄ O ₃ S 278.29

formula sheet

Formula IR ¹ = H, alkyl,

R ^ = alkyl, carboxyalkyl, arylalkyl, hydroxy

H ₂ NOC - ii 1 CONH ₂ ^H 2 ⁿ⁴ -NH X S-CHCOOR formula II H ₂ NOC - P ir RC-NH- " CONH ₂ S-CHCOOR 4- i ^ N - ff III formula

R ¹ = H, alkyl, R ³ = alkyl

R ¹ = H, alkyl,

R ³ = alkyl, ρ

R = alkyl, carboxyalkyl, arylalkyl, alkoxy, = O, NH

19.187 · 402147-

Claims (1)

Process for the preparation of pyrimido [4 ', 5'-5.4] -pyrrolo [3,2-f] [1,4] thiazepine derivatives of general formula I,
wherein R ¹ = H, alkyl, R ² = alkyl, carboxyalkyl, arylalkyl, hydroxy
mean, characterized in that 5- (alkoxycarbonylalkylthio) -2-amino-3,4-dicarbamoyl-1 Η-pyrroles of general formula II,
wherein R ¹ = H, alkyl, R ³ = alkyl
mean ' are reacted either with nitriles under the action of dry HCl gas or with acyl halides in organic solvents and the resulting compounds of general formula III,
wherein R ¹ = H, alkyl, R ² = alkyl, carboxyalkyl, arylalkyl, alkoxy, R ³ = alkyl, X = O, NH
mean, after purification by recrystallization under basic conditions, whereby both the pyrimidine and 1,4-thiazepine rings are formed and the compounds of formula I are obtained.