DD258013A1 - PROCESS FOR PREPARING 8,9,10,11-TETRAHYDRO-PYRIMIDO / 4 ', 5': 4,5 / THIENO / 2,3-C / ISOCHINOLIN-4 (3H) -ONE AND 7,8,9,10 -TETRAHYDRO-PYRIMIDO / 4 ', 5': 4,5 / THIENO / 2,3-B / CHINOLIN-4 (3H) -ONE, EACH WITH A (FUNCTIONALIZED) ALKYL REST IN 3-POSITION - Google Patents

Abstract

The invention relates to a process for preparing 8,9,10,11-tetrahydropyrimido / 4,5: 4,5 / thieno / 2,3-c / isoquinoline-4 (3H) -ones (I) and 7, 8,9,10-Tetrahydropyrimido / 4,5: 4,5 / thieno / 2,3-b / quinoline-4 (3H) -ones each with a (functionalized) alkyl radical in the 3-position (II). It is the object of the invention to represent such compounds from easily accessible starting compounds in a simple manner and in high yields. The task is to find a technically feasible synthetic route. The object is achieved by acylation of substituted 1-amino-6,7,8,9-tetrahydro-thieno / 2,3-c / -isoquinoline-2-carboxylic acid alkyl ester or 3-amino-5,6,7,8-tetrahydro -thieno / 2,3-b / quinoline-2-carboxylic acid alkyl esters in each case with carboxylic anhydrides or carboxylic acid chlorides and subsequent reaction of these separated, dry products with the primary amines H 2 N (CH 2) n R 2 (R 2 OH, NH 2, sec. amino, CH 3; n26) by heating. Formulas I and II

Description

, COOR ⁴ "

wherein R ³ and R ^{4 have} the following meanings:

R ³ = H, (un) substituted aryl, primary or secondary amino (optionally also aliphatic or heteroaliphatic bridged as eg.

Pyrrolidino or, preferably, morpholino); R ⁴ = lower alkyl (C ₁ -C ₃ ) or S-amino-B.ej.S-tetrahydro-thieno ^ .ab / quinoline ^ -carboxylic acid alkyl ester of general formula IV,

IV

where R ^{3 is} (un) substituted aryl and R ^{4 is} lower alkyl (C ₁ -C ₃ ),

in each case by refluxing with the carboxylic anhydrides (R ¹ CO) ₂ O or the carbonyl chlorides R ¹ COCI (R ¹ = lower alkyl [C ₁ -C ₃ ], [un] substituted aryl) in pyridine or aprotic solvents in the presence of an auxiliary base are reacted at room temperature, the resulting reaction product separated, dried and then by heating with primary amines of general formula V,

H ₂ N (CH ₂ J _n R ² V

wherein R ² = OH, NH ₂ , NR ⁵ R ⁶ (R ⁵ = R ⁶ = alkyl [C ₁ -C ₄ ] or NR ⁵ R ⁶ together form a cyclo or heterocycloaliphatic structural element) or CH ₃ and η = 2-6, to the compounds of general formula I,

- ύ - CiJO WJ

where R ¹ , R ² , R ³ and η have the meanings given above for the acylating agents and for the compounds of general formula I, or for the compounds of general formula II,

I and V)

where R ¹ , R ² , R ³ and η have the meanings given above (in the acylating agents and the compounds of the general formula IV and V).

embodiments

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

example 1

3- (3-Hydroxy-propyl) -2-methyl-7-morpholino-8,9,10,1-tetrahydro-pyrimidoM'jB'i ^ B / thieno ^^ - c / isoquinoline ^ OH) -one I ; R ¹ = CH ₃ , R ² = OH, R ³ = morpholino, η = 3

5.0 g of i-amino-δ-morpholino-e ^ S ^ -tetrahydro-thieno ^ Sc / isoquinoline ^ -carboxylic acid ethyl ester (III, R ³ = morpholino, R ⁴ = C ₂ H ₆ ) are mixed with 50 ml of acetic anhydride 3.5 h heated reflux. After cooling, the reaction mixture is mixed with 150 ml of 30% methanol and adjusted first with dilute sodium hydroxide solution and then with sodium carbonate to a pH of about 5. The precipitate formed after 6 hours standing is filtered off, washed with 50% methanol and dried. There are obtained 5.7 g of crude product.

40min to 5.0 g of dry crude product and 5.0 ml of 3-amino-propan-1-ol under reflux at 165 ⁰ C in the heated metal bath. After 15 hours of storage at 4 ⁰ C, the precipitate formed is filtered off with suction and washed with water.

Mp: 204-206 ° C (ethanol / water 7: 3 v / v). Yield: 85%

Example 2

3- (2-Amino-ethyl) -2-methyl-7-morpholino-8,9,10,11-tetrahydro-/ 4'5 ': 4,5 / thieno / 2,3-c / isoquinoline-4 (3H -on I; R ¹ = CH ₃ , R ² = NH ₂ , R ³ = morpholino, η = 2

1.0 g of the crude product mentioned in Example 1 and obtained by acylation are heated for 40 min with 5.0 ml of 1,2-diaminoethane hydrate at reflux condenser in a metal bath. After 12 hours of storage at -6 ° C, the precipitate formed is washed thoroughly with water, dried and dissolved in a mixture of 15 ml of methanol and chloroform. After filtration, the filtrate is treated with methanolic hydrochloric acid until acidic reaction. After overnight storage at -4 ° C, the hydrochloride formed is filtered off with suction and dissolved in aqueous methanol for conversion to the purified base. Sodium carbonate solution is then added until completion of the precipitate formation. The precipitate is filtered off with suction, washed with water and dried in air

M.p .: 182-184 ⁰ C (benzene / cyclohexane 1:10 v / v). Yield: 65%

Example 3

3- (3-amino-propyl) -2-methyl-7-morpholino-8,9,10,11-tetrahydro-/ 4 ', 5': 4,5 / thieno / 2,3-c / isoquinoline-4 ( 3H) -one I; R ¹ = CH ₃ , R ² = NH ₂ , R ³ = morpholino, η = 3

1.0 g of the product mentioned in Example 1 and obtained by acylation crude product are reacted with 1,3-diamino-propane analogously to Example 2 and worked up.

Mp:> 225 ° C (dec.) (Benzene / cyclohexane 1:10). Yield: 67%.

Example 4

3- (2-hydroxy-ethyl) -2-methyl 7-phenyl-8,9,10,11-tetrahydro-/ 4'5 ': 4,5 / thieno / 2,3-c / isoquinoline-4 (3H ) -onl; R ¹ = CH ₃ , R ² = OH, R ³ = C ₆ H ₆ , η = 2

2.0 g of ethyl 1-amino-5-phenyl-6,7,8,9-tetrahydro-thieno / 2,3-c / isoquinoline-2-carboxylate (III, R ³ = C ₆ H ₅ , R ⁴ = C ₂ H ₅ ) werderj refluxed with 20 ml of acetic anhydride for 2 h. After cooling, the reaction mixture is mixed with 20 ml of 90% methanol.

The precipitate formed after standing for a short time is washed with 30% methanol and then dried. 1.2 g of the dried crude product and 2.5 ml of 2-amino-ethanol are heated for 40 min at reflux condenser at 165 ° C in a metal bath. After 2 h storage at about -15 ° C, the precipitate formed is filtered off with suction and washed with water. Mp: 228-230 ° C (ethanol). Yield: 86%

Example 5

11- (4-chloro-phenyl) -3- (2-hydroxy-ethyl) -2-methyl-7,8,9,10-tetrahydro-pyrimido / 4 ', 5': _4/5 / thieno / 2, 3-b / quinolin-4 (3H) -onll;

R ¹ = CH ₃ , R ² = OH, R ³ = P-CI-C ₆ H ₄ , η = 2.

3.0 g of ethyl 3-amino-4- (4-chlorophenyl) -5,6,7,8-tetrahydro-thieno / 2,3-b / quinoline-2-carboxylate (IV; R ³ = P-Cl- C ₆ H _4, R ⁴ = C ₂ H _5; m.p .: 245-250 ⁰ C [ethanol]; yield: 78%) and 25 ml acetic anhydride are heated 2h back flowing, whereby a clear solution is obtained from which on cooling a Precipitate, which is filtered off, washed with methanol and dried. 2.0 g of the dry crude product and 10 ml of 2-aminoethanol are refluxed for 20 minutes. After cooling, 20 ml of methanol are added to the reaction mixture, the precipitate formed is filtered off with suction, washed with methanol and dried.

M.p .: 253X (ethanol); Yield: 70%.

Examples

3- (2-hydroxy-ethyl) -11- (4-methoxy-pheriyl) -2-methyl-7,8,9,10-tetrahydro-pyrimido / 4 ', 5': 4,5 / thieno / 2, 3-b / quinolin-4 (3H) -onll; R ¹ = CH ₃ , R ² = OH, R ³ = P-OCH ₃ -C ₆ H ₄ , η = 2

3.0 g of 3-amino-4- (4-methoxyphenyl) -5,6,7,8-tetrahydro-thieno / 2,3-b / quinoline-2-carboxylic acid methyl ester (IV; R ³ = P-OCH ₃ -C ₆ H ₄ , R ⁴ = CH ₃ , mp: 220-221 ° C [methanol], yield: 86%) and 30 ml of acetic anhydride are refluxed for 3 hours. Subsequently, the solvent is distilled off and the residue is brought to crystallization by trituration with methanol. After filtering off the solid product, it is washed with methanol and dried. 2.0 g of the dry crude product are reacted analogously to Example 5 with 10 ml of 2-amino-ethanol and worked up

 M.p .: 225-226X (methanol); Yield: 75%.

Claims (2)

claims: 1. A Process for the Preparation of 8,9,10,1-i-Tetrahydro-pyrimido-M'-S-thieno-Sc-isoquinoline-4 (3H) -ones and 7,8,9,10-Tetrahydropyrimido- ^ 5 ^ 4,5 / thieno / 2,3-b / quinoline-4 (3H) -ones each with a (functionalized) alkyl radical in the 3-position of the general formula I. or the general formula II characterized in that i-amino-ej ^ S-tetrahydrothieno / ^ S-c / isoquinoline- ^ -carboxylic acid alkyl ester of general formula III, III or S-amino-B ^ J ^ tetrahydro-thieno ^ S-b / quinoline ^ -carbonsäurealkylester of the general formula IV, COOR IV where R ^{4 is in} each case lower alkyl (C ₁ -C ₃ ), by refluxing with carboxylic anhydrides (R ¹ CO) ₂ O or carbonyl chlorides R ¹ COCI be reacted in pyridine oraprotischen organic solvents in the presence of an auxiliary base at room temperature, the resulting Reaction product separated, dried and then by heating with primary amines of general formula V H " ₂ N (CH ₂ ) _n R ² V to the compounds of general formula I, wherein
= Lower alkyl (C ₁ -Cs) ₁ (Un) SUbSti tUiEii: aryl;
= OH, NH ₂ , NR ⁵ R ⁶ , CH ₃ ;
= H, (un) substituted aryl, primary deoxidizer. Amino (optionally also aliphatic or heteroaliphatic bridged such. Pyrrolidino or, preferably, morpholino); = Alkyl (C ₁ -C ₄ ) or together represent a cyclo or heterocycloaliphatic structural element and η = 2-6, or to the compounds of general formula II, wherein R ^{3 is} an (un) substituted aryl radical R ₅ = R ⁶ R ⁵ R ⁶ corresponds to ^ jnd | _R \ R ³ , R ⁵ JJ ^ d R ⁶ as well as η denjDei len V ^ rbindungen ^ Fairgerneinen formula J given meanings reacted. 2. The method according to claim 1, characterized in that as auxiliary base tertiary amines, for. As triethylamine or conventional alkali or alkaline earth metal carbonates are used. Field of application of the invention The invention relates to a process for the preparation of 8,9,10,1-tetrahydro-pyrimido-M'B'-1, S-thieno-C-isoquinoline-OH) -ones and YAS.-O-tetrahydro-pyrimido-M ''. ^ .B / thieno ^ Sb / quinoline ^ OHJ-onene each with a (functionalized) alkyl radical in the 3-position of the general formula I or II. Such substances can be used as biologically active compounds, for. B. gain importance because of their antianaphylactic or anti-inflammatory or bacteriophage inhibitory effect. The invention is of interest to the chemical and pharmaceutical industries as well as to microbiological processes. Characteristic of the known technical solutions 8, 9, 10, 1-tetrahydro-pyrimidoM'jB'B, B, thieno ^^ c / isoquinoline ^ SHJ-one and 7, 8, 9, 10-tetrahydropyrimido / 4 ', 5': 4,5 / -thieno / 2,3-b / quinoline-4 (3H) -ones with a (functionalized) alkyl radical in the 3-position are unknown. Object of the invention The aim of the invention is to produce such compounds from readily available starting compounds in high yields. Explanation of the essence of the invention The object of the invention is to provide a technically applicable synthesis route for the preparation of 8,9,10,11-tetrahydropyrimido / each with a (functionalized) alkyl radical in the 3-position of the general formula I and II find. According to the invention the object is achieved in that 1-amino-6,7,8,9-tetrahydro-thieno / 2,3-c / isoquinoline-2-carboxylic acid alkyl ester of general formula I ^