DD258817A1 - PROCESS FOR PREPARING 2- (AMINOALKYL) -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 2- (aminoalkyl) -pyrimido & 4,5-5,4! Pyrrolo & 3,2-f! & 1,4! Thiazepines of the general formula I in which R 2, R 3 H, heteroalkylene, alkyl, aryl. These compounds are potential drugs and are also intermediates in the pharmaceutical industry. The aim of the invention is, starting from 5- (alkoxycarbonylalkylthio) -2-amino-3,4-dicarbamoyl-1H-pyrroles of the general formula IV in which R 1 is alkyl, 2- (aminoalkyl) -pyrimido & 4.5-5.4! pyrrolo & 3,2-f! & 1,4! thiazepines of general formula I. The synthesis of the compounds of general formula I is carried out by stepwise reaction of the compounds of general formula IV with a-Halogenacylhalogeniden and then with amines to the intermediates of the general formulas II or III, wherein R1, R2 and R3 have the above meaning, and the latter 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.

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the synthesis of 2- (aminoalkyl) pyrimido [4 ', 5'-5,4] pyrrolo [3,2-f] [1,4] thiazepine derivatives of general formula I,

wherein R ² , R ³ = H, heteroalkylene, alkyl, aryl

mean.

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 so far described neither in the patent nor in the specialist literature. For the first time, derivatives of pyrimido [4 ', 5'-5,4] -pyrrolo [3,2-f] [1,4] thiazepine with 2-aminoalkyl groups are shown.

Object of the invention

The aim of the invention is a simple and rapid production method for hitherto unknown 2- (aminoalkyl) -pyrimido [4 ', 5'-5.4] pyrrolo [3,2-f] [1,4] thiazepines of the general formula I with readily available starting materials to expand the range of potential drugs and / or interesting intermediates.

Presentation of the essence of the invention

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

wherein R ² , R ³ = H, heteroalkylene, alkyl, aryl

mean.

According to the invention the object is achieved in that 5- (alkoxycarbonylalkylthio) -2-amino-3,4-dicarbamoyl-1 Η-pyrroles of the general formula VII, wherein R ¹ = alkyl

means

be reacted with a-haloacyl halides in an organic solvent. The resulting 5- (alkoxycarbonylalkylthio) -2- (α-haloacylamino) -3,4-dicarbamoyl-1 Η -pyrroles of general formula II wherein R ¹ = alkyl

means

are reacted with amines in an organic solvent. The formed 5- (alkoxycarbonylalkylthio) -2- (aaminoacylamino) -3,4-dicarbamoyl-1 Η -pyrroles of the general formula III,

wherein R ¹ = alkyl,

R ² , R ³ = H, heteroalkylene, alkyl, aryl.

are cyclized under basic conditions to give both the pyrimidine and the 1,4-thiazepine rings, 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 3,4-dicarbamoyl-2-chloroacetyl-5-ethoxycarbonylmethylthio-1H-pyrrole

C ₁₂ H ₁₅ CIN ₄ O ₅ S (362.79)

0.01 mol of 2-amino-3,4-dicarb'amoyl-5-ethoxycarbonyl-methylthio-1 Η-pyrrole is dissolved in 25 ml of DMF. 0.01 mol of chloroacetyl chloride is added dropwise to this solution and stirred for 1 h at room temperature. Then you pour on water and sucks off the precipitate. The product is recrystallized from n-propanol. Melting point: 199-201 ⁰ C Yield: 86%

Example 2 Preparation of S, 1-dicarbamoyl-B-fethoxycarbonyl-methylthiol-1-morpholinoacetylamino J-i H-pyrrole

C ₁₆ H ₂₃ N ₅ O ₆ S (413.45)

To 0.01 mol of S -dicarbamoyl-chloroacetylamino-S-ethoxycarbonylmethylthio-i-pyrrole are added in 20 ml of dimethylformamide 0.02 mol of morpholine. Thereafter, it is heated under reflux for 2 h. After cooling, the reaction mixture is poured onto water and the precipitate is filtered off with suction. The product is recrystallized from n-propanol.

Melting point: 248-251 ° C Yield: 73%

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

Table 1:

Compounds according to formula III

No. R ¹ R ² R ³

1 C ₂ H ₅ H mol C ₆ H ₅ enamel 2 C ₂ H ₅ H Dimensions 0-CH ₃ OC ₆ H ₄ point ( ⁰ C) 3 C ₂ H ₅ H 413.46 o, m- (CH ₃ ) ₂ C ₆ H ₃ 196-198 4 C ₂ H ₅ H 449.49 m-CIC ₆ H ₄ 147-150 5 C ₂ H ₅ H 447.51 P-COOHC ₆ H ₄ 201-203 No. to hum 453.90 yield 202-204 formula 463.47 (%) 147-149 1 . C ₁₈ H ₂₁ N ₅ O ₅ S 82 2 C ₁₉ H ₂₃ N ₅ O ₆ S 79 3 C ₂₀ H ₂₅ N ₅ O ₅ S 85 4 C ₁₈ H ₂ oCln ₆ 0 ₅ S 75 5 C ₁₉ H ₂₁ N ₅ O ₇ S 52

In an analogous manner, the following compound was also shown:

3,4-Dicarbamoyl-5-ethoxycarbonylmethylthio-2- (1,2,3,4-tetrahydroisoquinolinoacetylamino) -1H-pyrrole C ₂₁ H ₂₅ N ₅ O ₅ S (459.52)

Melting point: 174-175 ⁰ C Yield: 79%

Example 3 Preparation of 2-morpholinomethyl-4,5,6,7,8,10-hexahydro-3H-pyrimido [4 ', 5'-5,4] pyrrolo [3,2-f] [1,4] thiazepine-4 , 5,7-trione

C ₁₄ H ₁₅ IM ₅ O ₄ S (349.37)

0.01 mol of 3,4-dicarbamoyl-5- (ethoxycarbonylmethylthio) -2- (morpholinoacetylamino) -1H-pyrror is dissolved in 25 ml of sodium hydroxide solution (4 mol / l) and boiled for 2 minutes. After the solution has cooled, it is neutralized with HCl (2 mol / l) and the precipitate is filtered off with suction.

Melting point: 203-203 ° C Yield: 72%

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

Table 2: according to Formula I links R ² R ³ No. H C ₆ H ₅ 1 H _0-CH3 OCC ₆ H ₄ 2 H o, m- (CH ₃ ) ₂ C ₆ H ₃ 3 H ID-CIC ₆ H ₄ 4 H P-HOOCC ₆ H ₄ 5

No. to hum mol yield Sch'melz- formula Dimensions (%) punktfC) 1 C ₁₆ H ₁₃ N ₅ O ₃ S 355.37 69 > 36D 2 C ₁₇ H ₁₅ N ₅ O ₄ S 385.40 73 > 360 3 C ₁₈ H ₁₇ N ₅ O ₃ S 383.43 74 > 360 4 C ₁₆ H ₁₂ CIN ₅ O ₃ S 389.81 70 > 360 5 C ₁₇ H ₁₃ N ₅ O ₅ S 399.38 65 > 360

In an analogous manner, the following compound according to formula I was furthermore shown:

2- (1,2,3,4-Tetrahydroisochinolinomethyl) -4,5,6,7,8,10-hexahydro-3H-pyrimido [4 ', 5'-5,4] pyrrolo [3,2-f] [1,4] -thiazepine-4,5,7-trione C ₁₉ H ₁₇ N ₅ O ₃ S (395.44)

Melting point: 250-252 ⁰ C Yield: 72%

formula sheet

f?

HN

NH

H ^M 2 R,

= H, hetero-

alkylene, alkyl, aryl

Formula I

H ₂ NOC ^.

ClCH ₂ CONH

_ CONH,

N Ή

^J - SCHO COOR

Formula II

H ₂ NOC 2 ⁽

__ CONH.

N H

SCH ₂ COOR '

Formula III R ¹ = alkyl

R ¹ = alkyl

R ² , R ³ = H, heteroalkyl, alkyl, aryl

O ₂ NOC - H ₉ N

ι-CONH,

SC

H ₂ COOR ¹ R ¹ = alkyl

Formula IV

19.1.87- 402148

Claims (1)

Process for the preparation of 2- (aminoalkyl) -pyrimido [4 ', 5'-5,4] pyrrolo [3,2-f] [1,4] thiazepine derivatives of general formula I, wherein R ² , R ³ = H, heteroalkylene, alkyl, aryl, characterized in that B-falkoxycarbonylalkylthio ^ -amino-S ^ -dicarbamoyl-i-pyrroles of the general formula IV, wherein R ¹ = alkyl means with α-haloacyl halides in an organic solvent to give 5- (alkoxycarbonylalkylthio) -2- (α-haloacylamino) -3,4-dicarbamoyl-1H-pyrroles of general formula II wherein R ¹ = alkyl means which are subsequently reacted in a reaction with amines in an organic solvent to give 5- (alkoxycarbonylalkylthio) -2- (α-aminoacylamino) -3,4-dicarbamoyl-1H-pyrroles of the general formula III wherein R ¹ = alkyl, R ² , R ³ = H, heteroalkylene, alkyl, aryl
mean, which are cyclized after purification by recrystallization in a final stage under basic conditions, wherein both the pyrimidine and the 1,4-thiazepine ring are formed and the compounds of general formula I are obtained.