KR890004558B1 - Process for preparing 4-amino-6,7-dimethoxy quinazoline derivatives - Google Patents

Abstract

4-Amino-6,7-dimethoxy quinazoline derivs of formula (I) and their acid addn. salt are prepd. by reacting a cpd of formula (II) with a cpd. of formula (III) in the presence of C1-4 lower alcohol, formamide, dimethyl formamide, dimethylacetamide or dimethylsulfoxide at an elevated temperature. In the formulas, R is furyl, tetrahydrofuryl, 1,4-benzodioxan-2-yl or butanoyl; n is 2 or 3. (I) are useful as an antihyper tensive agent.

Description

Method for preparing 4-amino-6, 7-dimethoxy quinazoline derivative

The present invention relates to a 4-amino-6, 7-dimethoxy quinazoline derivative having structural formula (I) and a process for preparing acid addition salts thereof.

Here, R represents furyl, tetrahydrofuryl, 1,4-benzodioxan-2-yl, or an alkyl group having 5 or less carbon atoms, and n represents an integer of 2 or 3.

The compound has been introduced as a known compound with a high antihypertensive effect. Known methods for preparing the compounds of formula (I) include U.S. Pat. Bars described in Japanese Patent Laid-Open Nos. 75-140,474, 76-80,877, 76-82,285, 81-103,177, French Patent 2,475,548, Netherlands Patent 7,206,067, Belgium Patent 861,821, Canadian Patent 1,088,059, etc. The methods are classified as follows.

First, a method of obtaining the target compound (I) by reacting a quinazoline derivative of formula (II) with a piperazine derivative of formula (III), as shown in the following scheme, is introduced.

R is furyl, tetrahydrofuryl, 1, 4-benzodioxan-2-yl, or an alkyl group having 5 or less carbon atoms, n represents an integer of 2 or 3, and X represents a chlorine or methylthio group. do.

This method is not only high in yield, but also has a disadvantage in that it is not economical because the process for preparing the compound of formula (II) is long. Especially, when X is a methylthio group, the reaction process for obtaining the compound of formula (II) becomes longer and The yield of reaction with Ⅲ) was lower.

Second, the intermediate compound of formula (V) obtained by first reacting the quinazoline derivative of formula (II) with the piperazine compound of formula (IV) as described below was subjected to the acylation reaction of acid chloride RC-X 'with the structural formula (I). A method for obtaining the desired compound is introduced.

R is furyl, tetrahydrofuryl, 1,4-benzodioxan-2-yl, or an alkyl group having 5 or less carbon atoms, n is an integer of 2 or 3, and X represents a chlorine group. This method has lower yield and longer process than the first method.

Third, the intermediate compound of formula (V) obtained in the second method as described above is reacted with cyanide bromide and then reacted with the reaction intermediate of formula (VI) and MR corresponding to the carboon ion of the R group, A method for obtaining the target compound of I) is introduced.

Where R and n are the same as indicated in the first method and MR denotes the carbo-ionized light metal compound in which M is sodium and lithium.

This method is lower in yield than other methods and is not a practical production method.

Fourth, a method of obtaining the target compound of formula (I) by reacting 2-amino-4, 5-dimethoxy benzonitrile of formula (VII) with a piperazine derivative of formula (VII) in the presence of a base as follows: It is introduced.

Where R and n are the same as indicated in the first method, Y is H ₂ N-C-, N≡C-, R'ZC-, m represents an integer of 0 or 1, wherein R 'is methyl or Ethyl group, Z represents oxygen or sulfur. In addition, as the base used, a metal base such as a quaternary amine or MR ² , M represents lithium, sodium, and R ² represents phenyl, hydrogen, methoxy, ethoxy and the like.

The base used in this method is used in excess, poor yield, especially when using a metal base is not a practical method because a lot of impurities are generated by side reactions.

Fifth, the method of obtaining the target object (I) by carrying out the cyclization reaction from the 2-amino-4 and 5-dimethoxy benzonitrile of structural formula (V) through several processes is introduced as follows.

Where R and n are the same as indicated in the first method.

This method has good reaction yield in each process, but the reaction process from the structural formula, which is the main starting material, is long, and there are many inconveniences that require high temperature reaction and long time reaction in the final cyclization reaction.

Sixth, a method of obtaining the final target (I) by cyclization using a halogenated phosphate compound through several processes similar to the fifth method from 3,4-dimethoxyaniline of formula (VII) is introduced.

Where R and n are the same as indicated in the first method and X in POX ₃ , PX ₃ , PX ₅ is chlorine or bromine.

This method is similar to the fifth method in general, but the yield of obtaining intermediate (XI) through the reaction process (A) of iodine methane and cyanamide from reaction intermediate and structural formula (X) is low. There was no way.

In addition, a method of obtaining a target (I) through dehalogenation and hydrogenation under a metal catalyst has been published as follows. However, these methods are considerably bypassed compared to the above six methods, and the yield is also low. It cannot be said.

Where R and n are the same as indicated in the first method, X is a halogen atom such as chlorine, bromine and iodine, and the metal catalysts used are heavy metals such as platinum, palladium, copper, cobalt and nickel.

The present invention provides a method for easily preparing a high purity target compound (I) with a simple process and a good yield as a new method to supplement the disadvantages of the preceding manufacturing methods.

When the method of the present invention is represented by the reaction scheme, it is as follows [reaction process chart I].

R represents furyl, tetrahydrofuryl, 1, 4-benzodioxan-2-yl, or an alkyl group having 5 or less carbon atoms, and n is an integer of 2 or 3.

In addition, the imide amido benzonitrile derivative of the structural formula (XII) used in the present invention is prepared from the piperazine compound in the following reaction process diagram II, and detailed preparation methods are specified in the examples.

Wherein R and n are the same as those shown in (Reaction Step I), and R ³ is an alkyl group, in particular methyl and ethyl, and in this process, the formimidate derivative of formula (XV) prepared from a known compound of formula (XIV) In reaction with 2-amino-4, 5-dimethoxy benzonitrile of the structural formula (Ⅶ) which is a well-known compound, C1-C4 lower alcohol, or aromatic organic solvent, such as benzene and toluene, or methylene chloride , Solvents of alkane chlorides such as ethylene chloride, chloroform or aprotic polar solvents such as acetone, ethyl acetate, acetonitrile, tetrahydrofuran, ether, formamide, dimethylformamide, between 40-180 ° C. The reaction is carried out under reflux, particularly in lower alcohols such as methyl alcohol and ethyl alcohol, to obtain an imide amido benzonitrile derivative of formula (XII), which is an intermediate of the present invention.

The present invention provides a compound of formula (I) by cyclization by adding a pyridine hydrochloride of formula (XIII) to a compound of formula (XII), which can be prepared from It is an easy method to obtain the target compound with good yield and high purity.

In this process, the solvent may be a lower alcohol or formamide having 1 to 4 carbon atoms, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide in the presence of a non-protic polar solvent or a mixed solvent therebetween or other The compound of formula (I), which is a target compound of high purity with good yield, is cyclized by heating at 60 ° to 150 ° C. using another organic solvent such as methylene chloride, chloroform, acetone, ethylene chloride, ethyl acetate, and ether. Get acid addition salts.

The present invention is compared with the preceding methods for the preparation of the target compound or similar methods for analogous derivatives of the target compound.

1. The reaction process is simple,

2. The reaction can be proceeded in good yield without using hard carboionized light metal compound,

3. It has the advantage of being able to separate the target compound with high purity by simple operation.

The method according to the present invention can yield various quinazoline derivatives which are therapeutic agents for hypertension.

In addition to the materials mentioned in the examples, in particular the following materials can be easily obtained by the method of the present invention.

Compounds that can be prepared of the present invention include 4-amino-2 [4- (1-oxobutyl) homopiperazin-1-yl] -6, 7-dimethoxy quinazoline and its hydrogen chloride, hydrogen bromide, iodide Hydrogen, alkyl or arylsulfonates and their hydrates and 4-amino-2- [4- (tetrahydro-2-furoyl-1-piperazinyl] -6, 7-dimethoxy quinazoline and its hydrogen chloride, brominated Hydrogen, hydrogen iodide, alkyl or arylsulfonate salts, and hydrates thereof.

In the following, embodiments are listed in order to explain the present invention in more detail, and the technical details of the present invention are not limited to these examples.

Example 1

Preparation of 1-cyano-4- (2-furoyl) piperazine

8.61 g (0.1 mol) of anhydrous piperazine was dissolved in 50 ml of anhydrous chloroform at room temperature, and 13.9 ml of triethylamine was added. Here, a solution of 10.6 g (0.1 mol) of cyanide in 50 ml of anhydrous chloroform was added dropwise at room temperature for 15 minutes, stirred at room temperature for 2 hours, adjusted to pH 10 with 2N-NaOH solution, and separated.

The water layer was extracted twice with 45 ml each of chloroform, mixed with the previously separated organic layer, dried over 15 g of potassium carbonate and filtered.

The filtrate was evaporated under reduced pressure, concentrated to 70 ml, 11.8 ml of triethylamine was added, cooled to 0-5 ° C., and 9.8 g (0.1 mol) of 2-furoyl chloride was added dropwise for 30 minutes and stirred at room temperature.

After completion of the reaction by tracking the reaction progress with thin layer chromatography (silica gel, acetic acid: normal butyl alcohol: water = 1: 4: 5), 30 ml of water was added to the reaction solution, and the organic layer was separated by adjusting to pH ₂ with 2N hydrochloric acid. do.

30 ml of water was added to the organic layer again, adjusted to pH 9 with 2N-NaOH solution, stirred sufficiently at room temperature, and dried by adding 10 g of forget-me-not to the separated organic layer, and evaporating the organic solvent of the filtrate layer under reduced pressure. Obtain 16.7 g of (2-furoyl) piperazine.

Yield: 81%

Melting Point: 63-65 ℃

In addition, according to the method of Example 1 it can be prepared a compound of formula (XIV) as follows.

Example 4

Preparation of Methyl [4- (2-furoyl) piperazin-1-yl] formamidate (XV)

16.7 g (0.08 mol) of 1-cyano-4- (2-furoyl) piperazine obtained in Example 1 was dissolved in 80 ml of anhydrous methyl alcohol at room temperature, and stirred while slowly injecting anhydrous hydrochloric acid gas at room temperature.

After completion of reaction by thin layer chromatography (silica gel, ethyl acetate: diethylamine = 95: 5), 400 ml of acetone was added to the white powder obtained by evaporation under reduced pressure, 12 ml (0.15 mole) of pyridine was added, and the mixture was stirred at room temperature for 1 hour and filtered. After evaporation of the solvent in the filtrate sufficiently under reduced pressure, the residue yielded 19.1 g of ethyl [4- (2-furoyl) piperazin-1-yl] formimidate.

Yield: 98%

Boiling Point: 84 ℃

In addition, according to the method of Example 4 it can be prepared a compound of the following structural formula (XV).

Example 7

Preparation of 3,4-dimethoxy-6- [4- (2-furoyl) piperazin-1-yl] formimide amido benzonitrile (XII).

12 g (0.05 mol) of methyl [4- (2-furoyl) piperazin-1-yl] formimidate obtained in Example 4 and 10.7 g (0.06 mol) of 2-amino-4,5-dimethoxy benzonitrile were prepared. After dissolving in 200 ml of anhydrous ethanol at room temperature and refluxing for 8 hours, the reaction was confirmed by thin layer chromatography (silica gel, ethyl acetate: diethylamine = 95: 5), and then the solvent was evaporated sufficiently under reduced pressure.

400 ml of methylene chloride and 100 ml of water were added to the residue, and the mixture was separated by adjusting to pH 2 with 2N-HC1. 200 ml of methylene chloride was added to the water layer and separated by adjusting to pH 10 with 2N-NaOH solution. 15 g of the separated methylene chloride layer was added with 15 g of forget-me-not, dried and filtered, and the organic solvent in the filtrate was evaporated under reduced pressure to give 3,4-dimethoxy-6- [4- (2-furoyl) piperazin-1-yl as a residue. ] 17.7 g of formimide amido benzonitrile is obtained.

Yield: 92%

Melting Point: 108-110 °

IR (KBr, Cm ^-1 ) 3400,3275,3095,2900,2215,1623,1587,1516,1409,1226,1212,862,836,745

In addition, according to the method of Example 7 it can be prepared a compound of formula (XII) as follows.

Example 10

Preparation of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6, 7-dimethoxy quinazoline hydrochloride

9.7 g (0.02 mol) of 3,4-dimethoxy-6- [4- (2-furoyl) piperazin-1-yl] formimamidobenzonitrile obtained in Example 7 was dried at room temperature with methyl alcohol. Dissolve in 200ml and add 6.9 g (0.06 mol) of pyridine hydrochloride and trace the reaction with thin layer chromatography (silica gel, acetic acid: normal butyl alcohol: water = 1: 4: 5) while stirring under reflux until no further reaction proceeds.

After evaporating the solvent under pressure, 120 ml of methylene chloride is added, and white powder is precipitated by slowly injecting anhydrous hydrogen chloride gas at room temperature over 2 hours. The solvent was evaporated under reduced pressure, 8 ml of water was added thereto, stirred for 30 minutes, filtered, and the mixture was washed twice with 40 ml of acetone and washed with 2- [4- (2-furoyl) piperazin-1-yl] -1-amino-6 , 8.1 g of hydrochloride of 7-dimethoxy quinazoline is obtained.

Yield: 76.3%

Melting Point: 278-280 ℃

IR (KBr, Cm ⁻¹ ): 3320, 3225, 3075, 2856, 1634, 1596, 1480, 1467, 1425, 1280, 795, 763, 750, 720, 717, 675.

In addition, according to the method of Example 10 it can be prepared a compound of formula (I) as follows.

Claims (5)

A process for preparing a compound of formula (I) and an acid addition salt thereof, wherein the compound of formula (XII) is cyclized with a compound of formula (XIII) in a warm state in the presence of an organic solvent.

Wherein R is furyl, tetrahydrofuryl, 1,4-benzodioxan-2-yl, or butanoyl group, n is an integer of 2 or 3. The organic solvent according to claim 1, selected from polar solvents such as lower alcohols having 1 to 4 carbon atoms, formamides, dimethylformamides, dimetalacetamides, dimethylsulfoxides, mixed solvents therebetween or other organic solvents therebetween. Method for producing a mixed solvent with. The method according to claim 2, wherein methyl alcohol or ethyl alcohol is used as the lower alcohol solvent having 1 to 4 carbon atoms. The process according to claim 2, wherein methylene chloride, chloroform, acetone, ethylene chloride, ethyl acetate, and ether are used as another organic solvent. The process according to claim 1, wherein the reaction temperature is carried out at 60-150 ° C.