HK1054742A - Method for producing thienopyrimidines - Google Patents

Description

Preparation method of thienopyrimidine compound

The invention relates to a preparation method of a compound of formula IWherein R is¹Is that

Straight-chain or branched alkyl having 1 to 10 carbon atoms, in which one or two CH groups₂Radical (I)

May be replaced by-CH ═ CH-, or

Cycloalkyl or cycloalkylalkylene having 5 to 12 carbon atoms, or

Phenyl or phenylmethyl, and the radicals being substituted by-COOH, -COOA, -CONH₂、-CONHA、-CON(A)₂or-CN-substituted, wherein A has an alkyl group of 1 to 6 carbon atoms.

The compound of formula I is an effective raw material for synthesizing medicaments, because the carbonyl group of pyrimidine can be connected with various groups, thereby laying a way for synthesizing new medicaments, and the properties of the compounds can be changed by modifying the connecting groups.

Medicaments containing heterocyclic systems of compounds of the formula I have been disclosed, for example, in DE-19819023A 1. These compounds and their salts show good tolerability while having very valuable pharmacological properties. In particular, they exhibit a specific inhibition of cGMP phosphodiesterase (PDE V). The compounds are therefore suitable for the treatment of diseases of the cardiovascular system, in particular cardiac myoinsufficiency, and for the treatment and/or therapy of sexual dysfunction (erectile dysfunction).

For widespread use of these pharmaceutical substances, it is necessary to be able to provide adequate amounts of the appropriate starting compounds. Due to the stringent requirements placed on the purity of the drug, these starting compounds should have a high purity. In addition, the reaction should produce high yields to reduce costs and prevent waste disposal problems.

Houben-Weyl, E9b/2, pp.29-30, describes the preparation of 2-substituted quinazolin-4 (3H) -ones. In this process anthranilic acid or anthranilate is reacted with a nitrile.

In J.heterocyclic Chem.17, 1497(1980) K.G.Dave et al describe a process for preparing fused pyrimidines. In particular, the synthesis of benzothieno [3, 2-d ] pyrimidines and the synthesis of substituted 4-ethoxy-5, 6, 7, 8-tetrahydrobenzo [ b ] thieno [2, 3-d ] pyrimidines is also described.

It is an object of the present invention to provide a process for the preparation of compounds of formula I which is simple to operate and provides compounds of formula I in high yields and high purity.

This object is achieved by a process for the preparation of compounds of the formula I, in which 2-aminobenzothiophene-3-carboxylic acid esters of the formula IIWherein R is²Is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, in particular methyl, with a nitrile of the formula III

N≡C-R₁III wherein R¹Having the above meaning, in solution or suspension in a solvent in the presence of an acid.

Methyl, ethyl or propyl is preferred, and isopropyl, butyl, isobutyl, sec-butyl are further preferredOr tert-butyl, and n-pentyl, neopentyl, isopentyl or hexyl as radicals R of formic esters of the formula II². Radical R for nitriles of the formula III¹Straight or branched chain alkyl groups having 1 to 10 carbon atoms, wherein one or two CH may be used₂May be replaced by-CH ═ CH-. Alkyl radicals used are preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 1-, 2-or 3-methylbutyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1-, 1, 2-, 1, 3-, 2, 2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-3-methylpropyl, 1, 2-or 1, 2, 2-trimethylpropyl, a straight-chain or branched heptyl, octyl, nonyl or decyl group. Furthermore R¹Can be but-2-enyl or hex-3-enyl.

As the cycloalkyl group or cycloalkylalkylene group having 5 to 12 carbon atoms, a cyclopentylmethylene group, a cyclohexylmethylene group, a cyclohexylethylene group, a cyclohexylpropylene group or a cyclohexylbutylene group can be used. The cycloalkyl group preferably contains 5 to 7 carbon atoms. Examples are cyclopentyl, cyclohexyl or cycloheptyl. Furthermore, R¹It may be phenyl or phenylmethyl.

The various radicals being substituted by-COOH, -COOA, -CONH₂、-CONHA、-CON(A)₂or-CN-substitution. Wherein A is an alkyl group having 1 to 6 carbon atoms. Examples of suitable radicals are methyl, ethyl or propyl, and also isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and also n-pentyl, neopentyl, isopentyl or hexyl.

In the process of the present invention, the compounds of formula I may be obtained as salts. These salts are generally precipitated from the reaction solution as crystalline precipitates, and sufficient purity can be obtained by simple filtration.

The synthesis of the compounds of the formula I is generally carried out by initially introducing the formic ester of the formula II and the nitrile of the formula III into a suitable solvent and subsequently adding the acid, for example by passing it as a gas into the solution. However, if an excess of acid is initially dissolved in the solvent, it is preferred that the solvent is saturated with acid and that the subsequent addition of the 2-aminobenzothiophene-3-carboxylic acid ester of the formula II and the nitrile of the formula III can significantly improve the reaction yield and the purity of the reaction product of the formula I and can significantly shorten the reaction time.

Excess acid means that the amount of acid is so large that unbound acid is still present in the solution after the compounds of formula I and II have reacted quantitatively and precipitated out as salts. The amount of acid should be present in the reaction mixture already at the start of the reaction.

The reaction may be carried out by: first a solution, preferably a saturated solution, of the acid in a solvent is prepared and separately a solution containing the compounds of formula I and formula II is prepared. The two solutions can then be introduced simultaneously into the reaction vessel in which the reaction is carried out, or an acid solution can be added first and then a solution of the compounds of the formulae I and II. However, it is also possible to add a solution of the compounds of the formulae I and II first and then an acid solution. However, in this case the acid solution should be added to the solution of the compounds of formula I and formula II as quickly as possible.

It has proven suitable for the solvent to be selected from the group consisting of ethers, alcohols, esters, water, carboxamides, amines, carboxylic acids, chlorinated hydrocarbons and mixtures thereof. A particularly suitable solvent is dioxane.

Suitable ethers are, for example, diethyl ether, isopropyl ether, tetrahydrofuran or dioxane. Suitable alcohols are, for example, methanol, ethanol, isopropanol, n-propanol, n-butanol and tert-butanol. Glycol ethers are also suitable, such as ethylene glycol monomethyl or monoethyl glycol ether (methyl or ethyl glycol), diglyme. Suitable amides are, for example, acetamide, dimethylacetamide, N-methylpyrrolidone or dimethylformamide. Suitable carboxylic acids are, for example, glacial acetic acid. Esters which may be used are, for example, ethyl acetate. Suitable chlorinated hydrocarbons are, for example, trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane. Mixtures of the above solvents may also be used.

The acid is selected from the group consisting of Bronsted acids and Lewis acids, in particular hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, polyphosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, aluminum trichloride and boron trifluoride. Particularly suitable are gaseous acids, especially hydrogen chloride.

The reaction is suitably carried out at from-10 ℃ to 100 ℃, preferably from 0 ℃ to 60 ℃, especially from 10 ℃ to 50 ℃.

In a particularly preferred embodiment of the process according to the invention, the acid is added to the mixture continuously during the reaction. Quantitative precipitation of the compound of formula I as the salt of the acid can thereby be achieved.

The compounds of formula I are valuable starting materials for further syntheses. If in the next step the compound of formula I is converted to a compound of formula IV in the presence of a chlorinating agent, the compound of formula I may be further activated.Chlorine can be directly replaced by a suitable nucleophile.

The chlorinating agent is suitably selected from SOCl₂、POCl₃、PCl₅、ClCOCOCl。

The compounds of formulae II and III are either known or prepared by those skilled in the art using known synthetic routes. Examples of the synthesis of the compounds of formulae II and III are described below in the context of particularly preferred compounds. For other R¹And R²The reaction can be carried out in a similar manner.

From thiosalicylic acids1Initial Synthesis of methyl 2-aminobenzothiophene-3-carboxylate7And (4) synthesizing. The carboxyl is reduced under the action of lithium aluminum hydride to obtain alcohol2. Thereafter the thiol group is reacted with benzyl chloride to give a thioether3. Subsequent compound3Reacting the hydroxyl group with hydrochloric acid to obtain chloride4Which in turn reacts with sodium cyanide to give nitriles5. The compound reacts with dimethyl carbonate to obtain a compound 6Which is finally cyclized to the compound7。

From trans-cyclohexane-1, 4-dicarboxylic acid esters8The preferred trans-4-cyanocyclohexanecarboxylic acid methyl ester was initially synthesized,8first hydrolysis with KOH to give the monomethyl ester9. The compound is first converted to the acid chloride with thionyl chloride and subsequently to the amide with ammonia10. From amides10Finally obtaining the nitrile11。

According to the invention, the compounds are7And11cyclization to aminoketones (Imidon)12. By reaction with thionyl chloride, a compound can be obtained13The chlorine thereof can be nucleophilically substituted and thus used as a starting compound for the synthesis of a variety of pharmacologically active substances.

Hereinafter, the present invention is illustrated by examples.

Example 1

4- (benzothieno [2, 3-d)]3H-4-oxo-pyrimidin-2-yl) cyclohexanecarboxylic acid methyl ester12Preparation of (scheme A)

9079g of methyl 2-aminobenzothiophene-3-carboxylate7And 8600g of methyl trans-4-cyanocyclohexanecarboxylate11Dissolved in 501 parts of 1, 4-dioxane. The mixture was heated to 45 ℃ and HCl gas was passed through the mixture for 15 hours. The reaction was monitored by thin layer chromatography (methanol/dichloromethane ═ 1: 1). After 10 days the precipitate was removed by filtration and dried, yield 79.1%. HPLC (acetonitrile/H)₂O60: 40(v/v) and containing 0.1% trifluoroacetic acid) showed 86% purity. This was found to be 68% in terms of the content.

Example 2

4- (benzothieno [2, 3-d)]3H-4-oxo-pyrimidin-2-yl) -cyclohexanecarboxylic acid methyl ester12Preparation of (scheme B)

First 501 parts of 1, 4-dioxane were added to the first reaction vessel and the temperature was adjusted to 10 ℃. 14.8kg of HCl gas were subsequently introduced over a period of 15.5 hours.

First 501 g of 1, 4-dioxane was added to the second reaction vessel and then 9079g of methyl 2-aminobenzothiophene-3-carboxylate was added7And 8600g of methyl trans-4-cyanocyclohexanecarboxylate11. The reaction mixture was heated to 45 ℃ and then a HCl saturated 1, 4-dioxane solution was added over 20 minutes. During the addition, an off-white precipitate crystallized. 6kg of HCl gas were then introduced at an internal temperature of 34 ℃ to 45 ℃ over a period of 4.75 hours. The reaction mixture was stirred at 34 ℃ overnight. The following day 10kg of HCl gas was added over a period of 8 hours and the reaction mixture was stirred overnight. The precipitate is separated and resuspended in 601 deionized water. The pH was adjusted to 9 by addition of 121% ammonia (13% by weight). After the addition was complete, stirring was continued for 45 minutes and the crystalline precipitate was filtered off through a suction filter funnel. The filter cake was washed 2 times with 121 deg.c of deionized water and the product was subsequently dried under reduced pressure at 50 deg.c.

The yield of white crystals was 10.75kg, melting point > 300 deg.C

Example 3

4- (4-chloro-benzothieno [2, 3-d)]Pyrimidin-2-yl) -cyclohexanecarboxylic acid methyl ester13Preparation of

12.51 thionyl chloride was first added and cooled to 25 ℃ with stirring. 2320g of12And 1100ml of dimethylformamide are added dropwise. After stirring overnight, the solution was extracted under reduced pressure. The crystallization residue was dissolved in dichloromethane and then slowly added to ice/water. The organic phase was separated off. The aqueous phase was extracted 3 times with dichloromethane. The combined organic phases were extracted with water, aqueous sodium hydroxide solution and again with water and dried over sodium sulfate.After filtration, the solvent was distilled off under reduced pressure. The crystalline residue was washed with cold isopropyl ether and the crystals were separated by filtration. The crystals were dried at 50 ℃ to constant weight.

Yield: 1420g of yellow crystals

Melting point: 127 DEG C

Claims (8)

1. Process for preparing compounds of formula IWherein R is¹Is that

Straight-chain or branched alkyl having 1 to 10 carbon atoms, where one or two CH groups₂The radicals may be replaced by-CH ═ CH-, or

-cycloalkyl or cycloalkylalkylene having 5 to 12 carbon atoms, or

-phenyl or phenylmethyl, and the radicals being COOH, COOA, CONH₂、CONHA、CON(A)₂Or CN is taken at onceWherein A is an alkyl group having 1 to 6 carbon atoms,

by 2-aminobenzothiophene-3-formic ester of formula IIWherein R is²Is a linear or branched alkyl radical having 1 to 6 carbon atoms, in particular methyl, with a nitrile of the formula III in solution or suspension in a solvent in the presence of an acid

N≡C-R₁III wherein R¹Have the above-mentioned meanings.

2. A process according to claim 1, wherein an excess of the acid is first dissolved in a solvent, preferably saturated with said acid, and the 2-aminobenzothiophene-3-carboxylic acid ester of formula II and the nitrile of formula III are subsequently added.

3. A process according to claim 1 or 2 wherein said solvent is selected from the group consisting of ethers, alcohols, esters, water, amides, carboxylic acids, chlorinated hydrocarbons and mixtures thereof.

4. A process according to any one of claims 1 to 3, wherein the acid is selected from the group consisting of bronsted and lewis acids, in particular hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, polyphosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, aluminum trichloride and boron trifluoride.

5. The process of any of claims 1 to 4, wherein the reaction is carried out at a temperature of-10 ℃ to 100 ℃, preferably 0 ℃ to 60 ℃, in particular 10 ℃ to 50 ℃.

6. A process according to any one of claims 1 to 5 wherein the acid is added to the mixture continuously during the reaction.

7. A process according to any one of claims 1 to 6, wherein in additionIn an additional step the compound of formula I is converted to a compound of formula IV using a chlorinating agent

8. The process of claim 7 wherein said chlorinating agent is selected from the group consisting of SOCl₂、POCl₃、PCl₅、ClCOCOCl。