DD258234A1 - PROCESS FOR THE PREPARATION OF PYRIDO / 3 ', 2': 4,5 / THIENO / 2,3-E / IMIDAZO- / 1,2-C / PYRIMIDINES AND STRUCTURE ANALOGER -PYRIMIDO / 1,2-C / PYRIMIDINE BZW. -1,3-diazepino / 1.2-C / PYRIMIDINES - Google Patents

Abstract

The invention relates to a process for the preparation of pyrido / 3,2: 4,5 / thieno / 2,3-e / imidazo / 1,2-c / pyrimidines and structurally analogous pyrimido / 1,2-c / pyrimidines or 1,3-diazepino / 1,2-c / pyrimidines of general formula I. It is the object of the invention to easily prepare these compounds from readily available reactants in high yields. The task is to find a technically feasible synthetic route. The object is achieved by reacting 3- (2-chloroethyl) pyrido / 3,2: 4,5 / thieno / 3,2-d / pyrimidin-4 (3H) -ones with 1, v-diaminoalkanes with refluxing Reaction conditions, if necessary with the addition of further organic solvents, preferably DMF. The compounds obtained are biologically active and can, for. B. gain importance for the pharmaceutical industry due to their antianaphylactic effect. Formula I

Description

or their acid addition salts, preferably their hydrochlorides, are reacted, wherein

R ¹ = lower alkyl (C ₁ -C ₃ ), (un) substituted aryl;

R ² = H, CH ₃ , (un) substituted aryl;

R ³ = H, CH _3, benzyl;

R ⁴ = CH ₃ , (un) substituted Afyl;

or R ² R ³ together den- (CH ₂ ) ₄ -Strukturelement;

or R ³ R ⁴ together the - (CH ₂ ) ₄ structural element and

η = 2,3 or 4 mean.

2. The method according to item 1, characterized in that the diaminoalkanes of the general formula III organic solvents, preferably DMF, can be added.

3. The method according to item 1 and 2, characterized in that the reaction time in homogeneous solution is 15-30 min.

Field of application of the invention

The invention relates to a process for the preparation of tetracyclic and pentacyclic pyrimidines of the general formula I. Such compounds can be used as biologically active substances z. B. due to their antianaphylactic effect gain importance as pharmaceuticals or to find their use. The invention is also of interest to the chemical industry.

Characteristic of the known technical solutions

Pyrido [3 ', 2': 4,5] thieno [2,3-e] imidazo [1,2-c] pyrimidines, pyrido [3 ', 2': 4,5] thieno [2,3-e] pyrimido [1,2-c] pyrimidines, pyrido [3 ', 2': 4,5] thieno [2,3-e] 1,3-diazepino [1,2-c] pyrimidines, imidazo (or pyrimido) [1 ", 2": 3 ', 4'] pyrimido [5 ', 6': 5,4] thieno [2,3-b] quinolines are not yet described in the technical and patent literature.

Object of the invention

The aim of the invention is to produce such compounds from readily available reactants in a simple manner with high yields.

-2- ZÖ8Z34 Presentation of the essence of the invention

The object of the invention is to find a technically applicable synthesis route for the preparation of substituted tetra- and pentacyclic pyrimidines of the general formula I. According to the invention the object is achieved in that 3- (2-chloro-ethyl) pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidin-4 (3H) -ones of the general formula II,

_: O

where R ¹ , R ² , R ³ and R ^{4 have} the meanings given below:

R ¹ = lower alkyl (C ¹ -C ₃ ), (un) substituted aryl;

R ² = H, CH ₃ , (u η (substituted aryl;

R ³ = H, CH _3, benzyl;

R ⁴ = CH ₃ , (un) substituted aryl;

or R ² R ³ together den- (CH ₂ ) ₄ -Strukturelement;

or R ³ R ⁴ together den- (CH ₂ ) ₄ structural element, by refluxing with Ι, ω-diaminoalkanes of the general formula III,

H ₂ N (CH ₂ ) _n NH ₂ III

where η = 2,3 or 4,

if necessary. Also in the presence of conventional organic solvents such as dioxane, dimethyl sulfoxide, alkanols (Ci-C ₄ ) or preferably dimethylformamide to the tetra- or pentacyclic pyrimidines of general formula I,

where R ¹ , R ² , R ³ , R ⁴ and η have the abovementioned meanings, or their acid addition salts, preferably their hydrochlorides, are reacted.

The preparation of the novel compounds of the formula II is carried out by the action of preferably phosphorus oxychloride or other inorganic acid chlorides such as thionyl or sulfuryl chloride on 3- (2-hydroxyethyl) pyrido [3 ', 2': 4,5] thieno [3,2- d] pyrimidin-4 (3H) -ones of general formula IV,

₂ CH ₂ OH O

wherein R ¹ , R ² , R ³ and R ^{4 have} the meanings given above.

embodiments

The invention will be explained in more detail below to 8 exemplary embodiments.

example 1

5,7-dimethyl-9-phenyl-2,3-dihydro-pyrido [3 ', 2': 4,5] thieno [2,3-e] imidazo [1,2-c] pyrimidine I; R ¹ = R ² = CH ₃ , R ³ = H, R ⁴ = C ₆ H ₅ ,

6.0 g of 3- (2-chloroethyl) -2,9-dimethyl-7-phenylpyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidin-4 (3H) - on (II; R ¹ = R ² = CH _3i R ³ = H, R ⁴ = C ₆ H ₅ ; mp: 254-256 ° C [toluene]; yield: 75%) are dissolved in a 75 ml 1,2-diamino-ethanmonohydrat

and DMF refluxed for 30 minutes. After cooling, the precipitate formed is filtered off with suction, washed with methanol and then with water and dried

 Mp: 323-325 ° C (dioxane / DMF9: 1 v / v); Yield: 78%.

Example 2 *

6,8-dimethyl-10-phenyl-3,4-dihydro-2H-pyrido [3 ', 2': 4,5] thieno [2,3-e] pyrimido [1,2-c] pyrimidine I; R ¹ = R ² = CH ₃ , R ³ = H, R ⁴ = C ₆ H ₆ , η = 3

6.0 g of the chloro-ethyl compound of the general formula II mentioned in Example 1 are reacted with 60 ml of 1,3-diaminopropane, but without DMF, analogously to Example 1 and worked up.

Mp: 295-299 ° C (dioxane); Yield: 70%.

Example 3

7,9-dimethyl-11-phenyl-1,3,4,5-tetrahydropyrido [3 ', 2': 4,5] thieno [2,3-e] 1,3-diazepino [1,2- c] pyrimidine I; R ¹ = R ² = CH ₃ , R ³ = H, R ⁴ = C ₆ H ₆ , η = 4

0.5 g of the chloro-ethyl compound of the general formula II mentioned in Example 1 are refluxed with 3.0 ml of 1,4-diaminobutane for 60 min. After cooling, water is added to the reaction mixture until cloudy. After storage of the reaction mixture at 4 ⁰ C, the precipitate is filtered off with suction, washed with water and dried.

Mp: 232-238 ° C (DMF / water); Yield: 25%.

Example 4

7-methyl-5,9-diphenyl-2,3-dihydro-pyrido / 3 ', 2': 4,5] thieno [2,3-e] imidazo [1,2-c] pyrimidine I; R ¹ = R ⁴ = C ₆ H ₅ , R ³ = H, R ² = CH ₃ ,

6.0 g of 3- (2-chloro-ethyl) -9-methyl-2,7-diphenyl-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-4 (3H) - on (II; R ¹ = R ⁴ = C ₆ H ₅ , R ³ = H, R ² = CH ₃ , mp: 252-254 ° C [chloroform / methanol]; yield: 92%) and 1,2- Diamino-ethane monohydrate are reacted and worked up analogously to Example 1.

M.p .: 273-278 ° C (dioxane); Yield: 74%.

Example 5

8-methyl-6,10-diphenyl-3,4-dihydro-2H-pyrido [3 ', 2': 4,5] thieno [2,3-e] pyrimido [1,2-c] pyrimidine I; R ¹ = R ⁴ = C ₆ H ₅ , R ³ = H, R ² = CH ₃ , η = 3

6.0 g of the chloroethyl compound of the general formula II mentioned in Example 4 are reacted and worked up analogously to Example 1 in a mixture of 60 ml each of 1,3-diamino-propane and DMF.

M.p .: 278-281 ⁰ C (dioxane / water); Yield: 54%.

Examples

5,7,8,9-tetramethyl-2,3-dihydro-pyrido [3 ', 2': 4,5] thieno [2,3-e] imidazole [1,2-c] pyrimidine I; R ¹ = R ² = R ³ = R ⁴ = CH ₃ , η = 2 6.0 g 3- (2-chloroethyl) -2,7,8,9-tetramethylpyrido [3 ', 2': 4 , 5] thieno [3,2-d] pyrimidin-4 (3H) -one (II; R ¹ = R ² = R ³ = R ⁴ = CH _3, m.p .: 218-221 ⁰ C [chloroform / ethanol] Yield: 60%) are reacted and worked up in a mixture of 40 ml of 1,2-diarhinoethane monohydrate and DMF analogously to Example 1. M.p .: 286-287 ⁰ C (DMF / water); Yield: 68%.

Example 7

6,8,9,10-tetramethyl-3,4-dihydro-2H-pyrido [3 ', 2': 4,5] thieno [2,3-e] pyrimido [1,2-c] pyrimidine I; R ¹ = R ² = R ³ = R ⁴ = CH ₃ , η = 6.0 g of the chloro-ethyl compound of the general formula II mentioned in Example 6 are analogous in a mixture of 40 ml each of 1,3-diamino-propane and DMF Example 1 implemented and worked up. M.p .: 286-290 ⁰ C (DMF / water); Yield: 46%.

Example 8

7- (4-chloro-phenyl) -5-methyl-2,3,8,9,10,11-hexahydroimidazo [1 ", 2": 3 ', 4'] pyrimido [5 ', 6': 5, 4] thieno [2,3-b] quinoline = 'VW-chloro-phenyD-S-methyl-S ^ -tetramethylene ^ S-dihydro-pyridoxy', 2 ': 4,5] thieno [2,3-e] imidazole [1,2-c] pyrimidine "I; R ¹ = CH ₃ , R ² = P-CI-C ₆ H ₄ , R ³ R ⁴ = - (CH ₂ J ₄ -, η = 2

0,9g3- (2-chloro-ethyl) -11- (4-chloro-phenyl) -2-methyl-7,8,9,10-tetrahydropyrimido [4 ', 5': 4,5] thieno [ 2,3-b] quinoline-4 (3H) -one = "3- (2-chloro-ethyl) -9- (4-chloro-phenyl) -2-methyl-7,8-tetramethylene-pyrido [3 ' , 2 ': 4,5] thieno [3,2-d] pyrimidin-4 (3H) -one "(II; R ¹ = CH ₃ , R ² = P-CI-C ₆ H ₄ , R ³ R ⁴ = - [CH ₂ I ₄ -; mp: 247-255 ° C [chloroform / methanol]; yield: 88%), 8 ml of 1,2-diaminoethane monohydrate and 8 ml of DMF are refluxed for 30 minutes. After cooling, the precipitate formed is filtered off with suction, washed with aqueous methanol and dried

M.p .: 285-287 ⁰ C (methanol / water); Yield: 61%.

Furthermore, the following compounds of the general formula I were synthesized from the chloroethyl compounds of the general formula II listed below in analogy to the abovementioned examples:

5-methyl-9-phenyl-2,3-dihydro-pyrido [3 ', 2': 4,5] thieno [2,3-e] imidazo [1,2-c] pyrimidinl; R ¹ = CH ₃ , R ² = R ³ = H, R ⁴ = C ₆ H ₅ , η = 2; M.p .: 285-290 ⁰ C (ethanol); Yield: 43%.

5,7,9-trimethyl-2,3-dihydro-pyrido [3 ', 2': 4,5] thieno [2,3-e] imidazo [1,2-c] pyrimidine I; R ¹ = R ² = R ⁴ = CH ₃ , R ³ = H, η = 2; Mp: 241-247 ° C (ethanol / water); Yield: 80%.

9- (4-Bromo-phenyl) -5,7-dimethyl-2,3-dihydro-pyrido [3 ', 2': 4,5] thieno [2,3-e] imidazole [1,2-c] pyrimidine I; R ¹ = R ² = CH ₃ , R ³ = H, R ⁴ = P-Br-C ₆ H ₄ , η = 2; M.p .: 306-308 ⁰ C (ethanol / dioxane); Yield: 73%.

7- (4-Bromo-phenyl) -5,9-dimethyl-2,3-dihydro-pyrido [3 ', 2': 4,5 / thieno [2,3-e] imidazo! [1,2-c ] pyrimidine I; R ¹ = R ⁴ = CH ₃ , R ³ = H, R ² = P-Br-C ₆ H ₄ , η = 2; M.p .: 279-280 ⁰ C (chloroform / methanol); Yield: 73%.

8-Benzyl-5,7,9-trimethyl-2,3-dihydro-pyrido [3 ', 2': 4,5] thieno [2,3-e] imidazo [1,2-c] pyrimidine I; R ¹ = R ² = R ⁴ = CH ₃ , R ³ = CH ₂ C ₆ H ₅ , η = 2;

The compounds of general formula I were prepared from the following compounds of general formula II:

3- (2-Chloroethyl) -2-methyl-7-phenyl-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidin-4 (3H) -one II; R ¹ = CH ₃ , R ² = R ³ = H, R ⁴ = C ₆ H ₅ ; Mp: 235-24O ⁰ C (chloroform / methanol); Yield: 95%.

3- (2-Chloro-ethyl) -2,7,9-trimethyl-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidin-4 (3) -one II; R ¹ = R ² = R ⁴ = CH ₃ , R ³ = H; M.p .: 230-233 ⁰ C (chloroform / methanol); Yield: 95%.

7- (4-Bromo-phenyl) -3- (2-chloro-ethyl) -2,9-dimethyl-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidine-4 ( 3H) -one II; R ¹ = R ² = Ch ₃ , R ³ = H, R ⁴ = P-Br-C ₆ H ₄ ;

Mp: 291-293 ° C (chloroform / methanol); Yield: 70%.

9- (4-bromo-phenyl) -3- (2-chloro-ethyl) -2,7-dimethyl-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidin-4 ( 3H) -one II; R ¹ = R ⁴ = CH ₃ , R ² = p-Br-C ₆ H ₄ , R ³ = H;

Mp: 230 ° C (chloroform / methanol); Yield: 75%.

8-Benzyl-3- (2-chloroethyl) -2,7,9-trimethyl-pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidin-4 (3H) -one II; R ¹ = R ² = R ⁴ = CH ₃ , R ⁼ CH ₂ C 6 H 5;

M.p .: 191-193 ⁰ C (chloroform / ethanol); Yield: 78%.

General procedure for the preparation of the compounds of the general formula II

2.5 g of the correspondingly substituted 3- (2-hydroxyethyl) pyrido [3 ', 2': 4,5] thieno [3,2-d] pyrimidin-4 (3H) -one and 30 ml of POCl ₃ are allowed to stand for 30 min Refluxed, whereby clear solutions are obtained. After distilling off the excess phosphorus oxychloride, the residue is worked up with ice-water, the remaining solid product is filtered off with suction, washed with water and methanol and dried.

Claims (1)

1. A process for the preparation of pyrido [3 ', 2': 4,5] thieno [2,3-e] imidazo [1,2-c] pyrimidines and
structurally analogous pyrimido [1,2-c] pyrimidines or 1,3-diazepino [1,2-c] pyrimidines of the general formula I, characterized in that 3- (2-chloroethyl) pyrido [3 ', 2 ': 4,5] thieno [3,2-d] pyrimidin-4 (3H) -ones of the general formula II by refluxing with Ι, ω-diaminoalkanes of the general formula III, H ₂ N (CH 2) _n NH ₂ III to the tetracyclic or pentacyclic pyrimidines of the general formula I