DD258015A1 - PROCESS FOR THE MANUFACTURE, IF APPLICABLE, IN 7,8-BZW. 8,9-POSITION CYCLOALIPHATICALLY-CRACKED 4-ALKOXY-PYRIDO- / 3 ', 2': 4,5 / THIENO / 3,2-D / PYRIMIDIN-2-CARBONSAEURES - Google Patents

Abstract

The invention relates to a process for the preparation of 4-alkoxy-pyrido / 3,2: 4,5 / thieno / 3,2-d / pyrimidine-2-carboxylic acids having different substituents on the pyridine ring of the tricycle or of 4-alkoxy-8 , 9,10,11-tetrahydro-pyrimido / 4,5: 4,5 / thieno / 2,3-c / isoquinoline-2-carboxylic acids with optionally substituents in the 7-position or 4-alkoxy-7,8, 9,10-tetrahydro-pyrimido / 4,5: 4,5 / thieno / 2,3-b / quinoline-2-carboxylic acids having an (un) substituted aryl radical in the 11-position from corresponding 3-amino-thieno / 2, 3-b / pyridine-2-carbonitriles or in the 5-position optionally substituted 1-amino-6,7,8,9-tetrahydro-thieno / 2,3-c / isoquinoline-2-carbonitriles or 3-amino -4- (un) substituted aryl-5,6,7,8-tetrahydro-thieno / 2,3-b / quinoline-2-carbonitriles. The preparation of the compounds, which are potential drugs or can gain importance as intermediates for the chemical and pharmaceutical industries, can be carried out both in one-step and two-step synthesis. formula

Description

Field of application of the invention,

The invention relates to a process for the preparation of 4-alkoxy-pyrido / 3 ', 2': 4,5 / thieno / 3,2-d / pyrimidine-2-carboxylic acids, 4-alkoxy-8,9,10,11- tetrahydro-pyrimido / ^ 5 ': 4,5 / thieno / 2,3-c / isoquinoline-2-carboxylic acids and 4-alkoxy-7,8,9,10-tetrahydropyrimido / 4', 5 ': 4,5 / thieno / 2,3-b / quinoline-2-carboxylic acids of the general formulas I, II and III. Such substances are potential drugs and can also gain importance as intermediates for the chemical and pharmaceutical industries.

Characteristic of the known technical solutions

Compounds of general formulas I, II and III are described neither in the patent nor in the chemical literature.

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 4-alkoxy-pyrido / 3 ', 2': 4,5 / thieno / 3,2-d / pyrimidine-2-carboxylic acids of the general formula I or 4- Alkoxy-8,9,10,11-tetrahydropyrimido / 4 ', 5': 4,5 / thieno / 2,3-c / isoquinoline-2-carboxylic acids of the general formula II or 4-alkoxy-7,8 , 9,10-tetrahydro-pyrimido / 4 ', 5': 4,5 / thieno / 2 _/ 3-b / quinoline-2-carboxylic acids of the general formula IM find.

According to the invention, the object of preparing the compounds of the general formula I is achieved by reacting 3-aminothieno / 2,3-b / pyridine-2-carbonitriles of the general formula IV

IV

in which

R ³ = H, CH ₃ , CH ₃ , (un) substituted aryl; R ⁴ = H, CH ₃ , benzyl and R ⁵ = H, CH ₃ , mean (un) substituted aryl

or for the preparation of the compounds of the general formula II-i-amino-ejAS-metronidro-thieno / ^ S-c / isoquinoline-carbonitriles of the general formula V,

R ⁶ = H, (un) substituted aryl, primary or secondary amino (possibly also aliphatic or heteroaliphatic bridged as eg.

Pyrrolidino or preferably morpholino) or, for the preparation of the compounds of the general formula III, carbonitriles of the general formula VI,

Vl

where R ⁷ = R ⁷ = (un) substituted aryl,

in each case by refluxing with oxalic acid of the general formula VII

• R ¹ OCOCOOR ¹

VII

in alkanolic sodium alkoxide solution R ² OH / R ² ONa, wherein R ¹ and R ^{2 may be the} same or different and each is lower alkyl (Ci-C ₃ ), brought to reaction and by adding water and then storing the reaction solution in Temperature range of> 30 ° C to the boiling point of the reaction mixture and subsequent acidification of the cooled reaction mixture with dilute acids, preferably hydrochloric acid or acetic acid, to the 4-alkoxypyrido / 3 ', 2': 4,5 / thieno / 3,2-d / pyrimidine-2-carboxylic acids of general formula I.

R *

or the 4-alkoxy-8,9,10,11-tetrahydro-pyrimido / 4 ', 5': 4,5 / thieno / 2,3-c / isoquinoline-2-carboxylic acids of the general formula I.

HOCC

or the 4-alkoxy-7,8,9,10-tetrahydro-pyrimido / 4 ', 5': 4,5 / thieno / 2,3-b / quinoline-2-carboxylic acids of the general formula I.

wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given above, are reacted.

In a further embodiment of the invention, the object can also be achieved by separating the intermediates obtained in the reaction of the aminocarbonitriles of the general formulas IV, V and VI with oxalic acid dialkyl esters of the general formula VII in alkanolic sodium alkoxide solution R ² OH / R ² ONa and in aqueous polar protic solvents, preferably alkanols (C 1 -C 3), acetone, dioxane and the like. Ä. With alkali metal hydroxide, preferably sodium hydroxide, by heating to the compounds of general formula I, II and III, wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given above, are reacted.

embodiments

The invention will be explained in more detail below on 5 exemplary embodiments.

example 1

4-methoxy-9-methyl-7-phenylpyrido / 3 ', 2': 4,5 / thieno / 3,2-d / pyrimidine-2-carboxylic acid I; R ² = R ⁵ = CH ₃ , R ³ = C ₆ H ₅ , R ⁴ = H Method A

1.4 g of S-amino-1-methyl-1-phenylthieno ^ Sb / pyridine-1-carbonitrile (IV; R ³ = C ₆ H ₅ , R ⁴ = H, R ⁵ = CH ₃ ) are dissolved in 60 ml of sodium methoxide solution ( 60 ml of abs. Methanol / 0.36 g of sodium), briefly boiled up, treated with 0.8 g of diethyl oxalate and heated at reflux for 3 hours, during which time a solid separates out. Then 20 ml of water are added and refluxed for a further 30 min, filtered off from a little undissolved residue and the reaction mixture acidified with dilute acetic acid. The precipitate formed is filtered off with suction, washed with water and methanol and dried.

Mp: 245-246 ° C (propan-1-ol); Yield: 64%.

Method B

1.1 g of the solid formed and isolated according to Method A are refluxed in 55 ml of methanol and 15 ml of NaOH (0.5 mol / l) for 30 min to give a nearly clear solution. The mixture is then filtered off from a little undissolved residue and worked up as described under method A.

Mp: 245-246 ° C (propan-1-ol); Yield: 90%.

Example 2

4-methoxy-7-methyl-9-phenyl-pyrido / 3 ', 2': 4,5 / thieno / 3,2-d / pyrimidine-2-carboxylic acid i; R ² = R ³ = CH ₃ , R ⁴ = H, R ⁵ = C ₆ H ₅ Method B

1.4 g of 3-amino-6-methyl-4-phenylthieno / 2,3-b / pyridine-2-carbonitrile (IV; R ³ = CH ₃ , R ⁴ = H, R ⁵ = C ₆ H ₅ ) are suspended in 60 ml of sodium methoxide solution (60 ml of absolute methanol / 0.36 g of sodium), boiled briefly, treated with 2.0 g of diethyl oxalate and heated under reflux for 3 h, whereby a solid precipitates, which is filtered off with suction, washed with methanol and dried becomes.

1.2 g of the dry solid are refluxed in 54 ml of methanol and 6 ml of KOH (1 mol / l) for 15 min to give a clear solution. The reaction solution is then acidified with dilute acetic acid, the precipitate formed is filtered off with suction, washed with water and methanol and dried.

Mp: 231-233 ° C (propan-1-ol); Yield: 81%.

Example 3

4-methoxy-7,8,9-trimethyl-pyrido / 3 ', 2': 4,5 / thieno / 3,2-d / pyrimidine-2-carboxylic acid L; R ² = R ³ = R ⁴ = R ^B = CH ₃ Method B

6.0 g of S-amino-ae-trimethyl-thieno ^^ - b / pyridine ^ -carbonitrile (IV; R ³ = R ⁴ = R ^B = CH ₃ ) are dissolved in 300 ml of sodium methoxide solution (300 ml of absolute methanol / 2.1 g Sodium), briefly boiled up, mixed with 12 g of diethyl oxalate and refluxed for 3 hours, during which time a solid precipitates, which is filtered off with suction after cooling, washed with methanol and dried.

3.0 g of the dry solid are dissolved in 120 ml of 1.0 g sodium hydroxide containing 50% aq. Ethanol heated for 30 min under reflux to give a clear solution. Then the reaction solution is mixed with 60 ml of water, acidified with acetic acid, the precipitate formed is filtered off with suction, washed with water and methanol and dried.

M .: from 27O ⁰ C (Zers.); Yield: 82%.

Example 4

4-ethoxy-7-morpholino-8,9,10,11-tetrahydropyrimido / 4 ', 5': 4,5 / thieno / 2,3-c / isoquinoline-2-carboxylic acid II; R ² = C ₂ H ₅ , R ⁶ = morpholino

Method B

4.8 g of 1-amino-5-morpholino-6,7,8,9-tetrahydrothieno / 2,3-c / isoquinoline-2-carbonitrile (V; R ⁶ = morpholino) are dissolved in 180 ml of sodium ethoxide solution (180 ml of abs. Ethanol / 1.08 g sodium), briefly boiled up, treated with 6.5 g of diethyl oxalate and refluxed for 3 h, where a solid precipitates, which is filtered off with suction after cooling, washed with water and ethanol and dried. 4.4 g of the dry solid are refluxed for 30 min in 100 ml of a 90% strength aqueous ethanolic solution containing 1.2 g of potassium hydroxide. It is then filtered, the cold reaction solution acidified with dil. Acetic acid, the precipitate formed is filtered off, washed with aq. Washed methanol and dried at about 40 ⁰ C.

M.p .: 222-224 ⁰ C (ethanol); Yield: 83%.

Example 5

4-Ethoxy-11- (4-methoxyphenyl) -7,8,9,10-tetrahydropyrimido / 4 ', 5': 4,5 / thieno / 2,3-b / quinoline-2-carboxylic acid III ; R ² = C ₂ H ₅ , R ⁷ = P-OCH ₃ -C ₆ H ₄

Method A

2.7 g of 3-amino-4- (4-methoxyphenyl) -5,6,7,8-tetrahydrothieno / 2,3-b / quinoline-2-carbonitrile (VI; R ⁷ = D-OCH ₃ -C ₆ H ₄ ) are suspended in 90 ml of sodium ethoxide solution (90 ml of absolute ethanol / 0.54 g of sodium), boiled briefly, treated with 1.3 g of diethyl oxalate and heated under reflux for 3 h, during which a solid separates out. Then 45 ml of water are added and continue as in Example 1 method Averfahren.

Mp: 214 ° C (methanol); Yield: 56%.

Method B

1.5 g of the solid formed and isolated according to Method A are reacted in 55 ml of methanol and 15 ml of NaOH (0.5 mol / l) analogously to Example 1, Method B and worked up.

Mp: 214 ° C (methanol); Yield: 89% '.

Claims (2)

claims: 1. A process for the preparation of ^ alkoxy-pyrido / S '^' i ^ ö / thieno / S ^ -d / pyridimidin ^ -carboxylic acids of general formula I, wherein R ³ = H, CH ₃ , (un) substituted aryl; R ⁴ = H, CH ₃ , benzyl and R ⁵ = H, CH ₃ , (un) substituted aryl or 4-alkoxy-8,9,10,11-tetrahydro-pyrimidoM '^' ^ S / thieno ^ S-c / isoquinoline ^ -carboxylic acids the general formula II, HQOC in which R ⁶ = H, (un) substituted aryl, primary or secondary amino (if appropriate also aliphatic or heteroaliphatic bridged such. B. pyrrolidino or preferably morpholino) or ^ alkoxy-y ^^ iO-tetrahydro-pyrimidoM '^' i ^ B / thieno ^^ - b / quinoline ^ -carboxylic acids of the general formula III, COOH wherein R ⁷ = (un) substituted aryl, characterized in that for the preparation of the compounds of the general formula I 3-amino-thieno / 2,3-b / pyridine-2-carbonitriles of the general formula IV IV or for the preparation of the compounds of general formula II 1-amino-6,7,8,9-tetrahydrothieno ^^ - c / isoquinoline ^ carbonitriles of the general formula V or for the preparation of the compounds of general formula III 3-amino-5,6,7,8-tetrahydrothieno / ^ S-b / quinoline ^ carbonitriles of the general formula VL wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given above, by refluxing with Oxalsäuredialkylestem of the general formula VII R ¹ OCOCOOR ¹ VII in alkanolic sodium alkoxide solution R ² OH / R ² ONa, wherein R ¹ and R ^{2 may be the} same or different and each is lower alkyl (C ₁ -C ₃ ), reacted and by adding water and then storing the reaction solution in the temperature range of> 30 ° C to the boiling temperature of the reaction mixture and subsequent acidification of the cooled reaction mixture with dilute acids, preferably hydrochloric acid or acetic acid, to the 4-alkoxy-pyrido ^ 2 ': 4,5 / thieno / 3,2-d / pyrimidine 2-carboxylic acids of general formula I or the 4-alkoxy-8,9,10,11-tetrahydro-pyrimido / 4 ', 5': 4,5 / thieno / 2,3-c / isoquinoline-2-carboxylic acids of the general formula II or the 4-alkoxy-7,8,9,10-tetrahydro-pyrimido / 4 ', 5': 4,5 / _< thieno / 2,3-b / quinoline-2-carboxylic acids of general formula III, wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ denote * have the meanings given above, are reacted. 2. The method according to item 1, characterized in that in the reaction of the aminocarbonitriles of the general formulas IV, V and Vl with Oxalsäuredialkylestem the general formula VII in alkanolic sodium alkoxide solution R ² OH / R ² ONa resulting intermediates and separated in aqueous polar protic solvents, preferably alkanols (C ₁ -C ₃ ), acetone, dioxane and the like. Ä. With alkali metal hydroxide, preferably sodium hydroxide, by heating to the compounds of general formula I, II and III, wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given above, are reacted.