DD297971A5 - PROCESS FOR THE PREPARATION OF CHINAZOLINE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of quinazoline derivatives of general formula I (wherein R exp 1 and R exp 2 are hydrogen or lower alkyl or R exp 1 and R exp 2 together form ethylene or trimethylene; and n is 2 or 3) which comprises a) reacting an isothiourea derivative (wherein R is lower alkyl or phenyl lower alkyl) with an amine at a temperature between 150 and 280 ° C; or b) cyclizing an N- (3-tetrahydro-2-furylamino) -propyl) -N-cyano-guanidine derivative, optionally in the presence of a catalyst. The compounds of general formula I are known hypotensive agents. The advantage of the method according to the invention is that the desired compounds of general formula I from the readily available new intermediates N- (3- (tetrahydro-2-furylamino) -propyl) -N-cyano-guanidinderivate for a simple, easy to carry out economic Method and in pure form can be produced. Formula I {method; quinazoline derivatives; Isothiourea derivative; Amine, between 150 degrees C and 280 degrees C; guanidine; Catalyst, cyclized}

Description

The invention relates to a novel process for the preparation of quinazoline derivatives.

The invention relates to a process for the preparation of quinazoline derivatives of the general formula I.

NH ₂

H ₃ CO

N-CO

(wherein

R ¹ and R ^{2 may be the} same or different and represent hydrogen or lower alkyl, or R ¹ and R ² together form ethylene (-CH ₂ -CHj-) or trimethylene (-CHr-CH ₂ -CHr-); and

η is 2 or 3)

and pharmaceutically acceptable acid addition salts thereof.

General Formula I includes all isomers and tautomers of these compounds. The invention extends to the manufacture of all isomers and tautomers of the compounds of general formula I.

The compounds of the general formula I are known pharmaceutical active ingredients and can be used in therapy because of their at-receptor blocking properties as antihypertensive agents.

The compounds of the general formula I can be prepared by known processes by reacting the 4-amino-6,7-dimethoxy-2-chloroquinazoline of the formula IX

IhCO

Nile 2

with an amine of general formula IV

R ¹

"CO '

or by reaction of the compound de ^r formula IX with the appropriate diamine, and subsequent acylation of the compound of general formula V thus obtained

Ί?

R I NII

(CII ₀ )

(wherein R ¹ , R ² and η are as defined above) (DOS No. 6466486, Belgian Patent Nos. 879730 and 873909, French Patent No. 2468595).

The disadvantage of the above known processes is that the starting material of formula IX Veratrumsäurealdehyd is prepared by means of a 7-step synthesis and some Schi itte the above synthetic route are feasible only with low yields (J. Med. Chem. 20.146 [1977]).

The object of the invention is the elaboration of a new method for producing the compounds of the general formula I which overcomes the above disadvantages of the known methods.

The process of the invention, the compounds of general formula I are prepared so that a) an isothiourea Deri'-at the general formula III

(wherein R is lower alkyl or phenyl lower alkyl, which phenyl ring of the latter group may optionally bear one or more lower alkyl and / or halogen substituents) with an amine of general formula IV (wherein R ¹ , R 'and η are as above Have meaning) at a temperature between 15O ⁰ C and 28O ⁰ C converts; or b) a compound of the general formula II

I ₂ I _n

N-CO-

(wherein R ¹ , R ^: and η have the above meaning) optionally cyclized in the presence of a catalyst; and, if desired, converting a compound of general formula I thus obtained into an acid addition salt. The present invention is based on the surprising finding that the compounds of the general formula I can be prepared simply and favorably from the novel compounds of the general formula II which are not described in the literature by thermal or catalytic cyclization.

By the term "lower alkyl" are meant straight-chain or branched saturated aliphatic hydrocarbon groups having 1-4 carbon atoms (for example, methyl, ethyl, n-propyl, isopropyl, η-butyl, tert-butyl, etc.). phenyl

Lower alkyl refers to the above alkyl groups which are substituted by a phenyl group (for example, benzyl, β-phenylethyl, etc.) The term "halogen" includes the fluorine, chlorine, bromine and iodine atoms and is advantageous for fluorine, chlorine or bromine.

The novel starting materials of general formula II can be prepared by reacting an isothiourea derivative of general formula III with an amine of general formula IV. The compounds of general formula II can either be isolated or cyclized in situ without isolation into the desired compounds of general formula I.

The starting materials of the general formula III are known compounds (J. Heterocycl.Chem., 23,401 [19861] or can be prepared analogously to the process described in Hungarian Patent No. 181743.

The starting materials of general IV are known compounds (DOS No. 2 646186, Belgian Patents No. 873909 and 879730, French Patent No. 2458595).

According to the process variant a) isothiourea derivative of the general formula III with the appropriate amine of the general formula IV in an inert, about 15O ⁰ C boiling solvent is reacted. As a solvent, for example

Dimethylformamide, dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoric triamide, dimethylsulfoxide, sulfolane, Dimethylonglykoldimethyläther, Diäthylenglykoldiäthyläther, diphenyl ether, nitrobenzene, dichlorobenzene or tetrahydronaphthalene can be used. It is particularly advantageous in Dimethylenglykoldimethyläther or dimethylformamide at a temperature between 15O ⁰ C and 220 ⁰ C - especially at 160-18O ⁰ C- work. As starting material of general formula III can advantageously be used the corresponding compound in which R is methyl.

According to the process variant b), a compound of the general formula II is cyclized either thermally or in the presence of a suitable catalyst to give the corresponding compound of the general formula I.

The thermal cyclisation of compounds of general formula II can be C-performed in the presence or absence of a solvent, at a temperature between 150 ° C and 28O ⁰ C-preferably at 150-220 ^0th As the reaction medium above 150 ° C boiling solvent -. For example, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone, hexamethylphosphoric triamide, dimethyl sulfoxide, sulfolane, Dimethylenglykoldimethyläther, Diäthylenglykoldiäthyläther, diphenyl ether, nitrobenzene, dichlorobenzene or tetrahydronaphthalene - Verwe. Find .dung. Dimethylenglykoldimethyläther and dimethylformamide have proved to be particularly advantageous as a solvent.

The catalytic cyclization of the compounds of the general formula Il can at a temperature between 25 ⁰ C and 13O ⁰ C, preferably at 70-100 ⁰ C - are carried out in the presence of a suitable catalyst. The solvent used may preferably be phosphorus oxychloride and, as catalyst, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide or a Lewis acid. Suitable Lewis acids are, for example, aluminum chloride, boron trifluoride, boron trifluoride etherate, zinc chloride or tin dichloride.

The compounds of the general formula I can be isolated from the reaction mixture in a manner known per se.

The compounds of the general formula I can be converted into their pharmaceutically suitable acid addition salts by methods known per se. The compound of general formula I can be reacted in a suitable solvent with the appropriate acid (e.g., hydrochloric, hydrobromic, sulfuric, maleic, fumaric, etc.).

According to an advantageous embodiment of the method according to the invention compounds of general formula I are prepared by applying the appropriate starting materials, in which R 'is methyl and R ^{2 is} hydrogen and

According to an advantageous embodiment of the process according to the invention, compounds of the general formula I are prepared by using the appropriate starting materials, in which R ¹ and R ² together are ethylene - (- CH ₂ -CH ₂ ) - meaning and η = 2.

The invention furthermore relates to novel compounds of the general formula II (in which R ', R ² and η have the above meaning).

The invention furthermore relates to a process for the preparation of novel intermediates of the general formula II by reacting an isothiourea derivative of the general formula III (in which R is lower alkyl or phenyl-lower alkyl, the phenyl ring of the latter group optionally having one or more lower alkyl groups. and / or halogen substituents) with an amine of general formula IV (wherein R ¹ , R 'and η dia have the above meaning) at a 13O ⁰ C not exceeding temperature.

The reaction is carried out in an inert solvent, preferably in an alcohol or a polar aprotic solvent. The reaction can be carried out particularly advantageously in isopropanol or dimethylformamide as the reaction medium. The reaction is carried out at a temperature not exceeding 13O ⁰ C. It can be advantageous to work at a temperature between 25 ⁰ C and 13O ⁰ C.

The compounds of general formula II can be isolated from the reaction mixture by methods known per se. It is advantageous to evaporate the solvent and recrystallize the residue.

The advantage of the process according to the invention is that the desired compounds of the general formula I can be prepared in pure form by a simple and economical method, using readily available starting materials.

Further details of the method according to the invention can be found in the following examples, without limiting the scope of protection to these examples.

example 1

4- (2-Tetrahydrofuroyl) -piperazine-1- [N -cyano-N '- (3,4-dimethoxy-phenyl)] -carboxyamine A solution of 25.1 g (0.1 mole) of N-cyano-N '- | 3,4-dimethoxyphenyl) -S-methyl-isothiourea and 27.6 g (0.15 mol) of N-tetrahydro-2-furoyl-pipe / azine in 150 ml of isopropanol are heated to boiling for 6 hours. The reaction mixture is cooled, the isopropanol removed and the zurückgebliebende crude product (38.2 g) recrystallized from ethanol. There are obtained 35.7 g of the title compound, yield 92%, mp .: 182-184 ⁰ C.

Example 2

4- (2-tetrahydrofuroyl) -homopipurazin-1- [N-cyano-N '- (3,4-dlmothoxy-phenyl)] - earboxamldln

The procedure is as in Example 1, with the difference that instead of N- (tetrahydro-2-furoyl) -piperazine 19.8 g (0.1 mol) N- (tetrahydro-2-furoyl) -homopiperazine and used as solvent instead of isoprpanol 50ml dimethylformamide. The Reaction mixture is stirred for 5 hours at 120 ° C, then cooled abgc. After adding 200 ml of water, the

filtered crystals, washed twice with each SOmI water and recrystallized from ethanol. There are obtained 32.0 g of the title compounds, yield 80%, mp. 166-168 ⁰ C.

Example 3 N-O ^ dimethoxy-phenyD-N-methyl-N-lS-lteirahydro ^ -furoylamlnol-propyll-N-cyano-guanldin The procedure is as in Example 1, with the difference that instead of N- (tetrahydro-2-furoyl) -piperazine 27.9 g (0.15 mol) Tetrahydro-N- [3- (methylamino) -propyl] -2-furan-carboxamide used. The reaction mixture for 8 hours at 6O ⁰ C

24.7 g of the title compound are obtained, yield 63.5%, m.p .: 160-163 ° C.

Bel ^ .eu

2- [4- (Tetrahydro-2-furoyl) -piperazinyl) -4-amino-6,7-dimethoxy-quinazoline hydrochloride 19.4 g (0.05 mol) of 4- (2-tetrahydro-2-furoyl) -piperazine 1-IN-cyano-N '- (3,4-dimethylmethoxy-phenyl)] -carboxamidine are stirred in 40 ml diethylene glycol diethyl ether at 180 ° C for half an hour. After the reaction mixture has cooled, 100 ml of dichloromethane are added. The pH of the reaction mixture is adjusted to 3-4 with vigorous stirring and cooling with ice-cold water by addition of hydrochloric isopropanol. During car addition of the acid a crystal formation begins. The mixture is stirred at 0-5 "C for a further hour. The precipitated product is filtered and recrystallized from isopropanol. There are 15.6 g of the compound named in the title, yield 73.5%, m.p .: 277-279 ⁰ C.

Example 5

2- [4- (tetrahydro-2-furoyl) -plperazlnyl] -4-amino-6,7-dimethoxy-quinazolin-hydrochlofici

The procedure is as in Example 4, with the difference that instead vijj Diäthylengiy: oldiäii'vl3thur RJW \) dimethylformamide

used. The reaction mixture is stirred at 154 ° C for one and a half hours! After cooling ν i.-d the product by

Excreted addition of 200 ml of water, filtered, washed twice with \ t iGüml water washed, in OCm I! Methanol suspended

and the pH is adjusted to 3/4 by the addition of hydrochloric isopropanol. The precipitated crystalline product is filtered and recrystallized from isopropanol. There will be 11.5g of the compound called ici title, yield / ⁹ £ 4.2%.

Example 6

2- [4- (Totrahydro-2-furoyl) -piperazlnyl] -4-amlno-6,7-dlmethoxy-chlnazciin-hydrochlorld

The procedure is as in Example 4 with the difference that instead of diethylenglykoldiäthyläther 30 m 'oulfolan related. The reaction mixture is stirred at 28O ⁰ C 15 minutes. There will be 12.29g of the Vk rbintU: ng jtoaiien mentioned in the title,

Yield 57.5%.

Example 7

N- [3 - [(4-Amino-6,7-dimethoxy-2-chloroazolinyl) -methylamino] -propyl] -tetrahydro-2-furancarboxamide hydrochloride 4.1 g (0.03 mol) of phosphorus trichloride are added with stirring and Cool to 40ml phosphorus oxychloride added. The mixture is stirred for 10 minutes, after which 11.7 g (0.03 mol) of N- (3,4-dimethoxyphenyl) -N-methyl-N- | 3- (tetrahydro-2-furylamino) -propyl) - N-cyano-guanidine are added. The temperature is slowly increased to 70 ⁰ C and the reaction mixture is held for 2.5 hours at this temperature. The excess phosphorus oxychloride is removed under reduced pressure. Ice-cold water is added slowly to the residue. The precipitated crude product is recrystallized from ethanol. There are obtained 9.6 g of the title compound, yield 75%, mp 223-225 ⁰ C.

Examples

N- [3- [4-Amino-e, 7-methoxy-2-chloro-nacollyl) -methyl-amino] -propyl-tetrahydro-2-furanecarboxamide hydrochloride The procedure is as in Example 7, with the difference that, instead of phosphorus trichloride, 6.2 g (0.03 mol) of phosphorus pentachloride used. The reaction mixture is stirred at 25.degree. C. for 3 hours. There are obtained 8.5 g of the title compound, yield 66.4%.

Example 9 N- [3- [4-Amlno-6.7-dlmethoxy-2-chinazollnyl) methylamino] propyl] tetrahydro-2-furan-carboxamide hydrochloride The procedure is as in Example 7, with the difference that instead of phosphorus trichloride 8.1 g (0.03 mol) of phosphorus tribromide

used and the reaction mixture stirred at 13O ⁰ C for half an hour. There are obtained 7.8 g of the title compound, yield 61%.

Example 10 N-tS ^ -Amlno-ej-dimethoxy ^ -chinazolinyO-methylaminoI-propyU-tetrahydro ^ -furancarboxamid hydrochloride The procedure is as in Example 7, with the difference that the mixture is saturated by introducing hydrogen chloride gas,

then for 15 minutes at 25-3O ⁰ C and finally for one hour at 70-75 ⁰ C stirred. It will be 8.5 g of those mentioned in the title

Compound obtained, yield 66.4%. Example 11

2- [4- (tetrahydro-2-furoyl) -piperanzinyl] -4-amino-6,7-dimethoxy-quinazoline hydrochloride

A solution of 25.1 g (0.1 mol) of N-cyano-N '- (3,4-dimethoxyphenyl) -S-methyl-isothiourea and 27.6 g (0.15 mol) N- (tetrahydro-2-furoyl) -piperazine in 50 ml of dimethylformamide is heated at 155-16O ⁰ C for 5 hours to boiling. The

Reaction mixture is cooled. By adding 200 ml of water, the product is precipitated, filtered, washed twice with 100 ml of water and suspended in 100 ml of methanol. The pH is adjusted to 3-4 by addition of hydrochloric isopropanol. The precipitated product is filtered and recrystallized from isopropanol. There are 19.5 g of the title compound are obtained, yield 46%, m.p .: 277-279 ⁰ C.

Examples

2- [4- (Tetrahydro-2-furoyl) -plperazlnyl] -4-amlno-6,7-dlmethoxychlnazolln hydrochloride The procedure is as in Example 11, with the difference that instead of dimethylformamide 100 ml Äthylenglykoldiäthyläther used. The reaction mixture is heated at 18O ⁰ C for 2 hours to boiling. After cooling, 100 ml of dichloroethane are added. The pH of the mixture is adjusted to 3-4 by adding hydrochloric isopropanol while cooling with ice-cold water and stirring vigorously. The mixture is stirred for one hour at 0-5 ⁰ C, the precipitated product is filtered and recrystallized from isopropanol. There are obtained 20.8 g of the titled compound / yield 49%, F .: 277-279 ⁰ C.

Claims (11)

claims: 1. A process for the preparation of quinazoline derivatives of the general formula NI I ₂ . H ₃ CO '\ ^ "N' ^S N, .N-CO (wherein R ¹ and R ^{2 may be the} same or different and are hydrogen or lower alkyl or R ¹ and R ² together form ethylene (-CH ₂ -CH ₂ -) or trimethylene (-CH ₂ -CH ₂ -CH ₂ -); and η is 2 or 3) and pharmaceutically acceptable acid addition salts thereof, characterized in that a) an isothiourea derivative of the general formula III (wherein R is lower alkyl or phenyl lower alkyl, which phenyl ring of the latter group may optionally bear one or more lower alkyl and / or halogen substituents) with an amine of general formula IV R ¹ H' CO (wherein R ¹ , R ² and η have the above meaning) at a temperature between 150 ⁰ C and 280 ⁰ C, or
b) a compound of the general formula II CO (wherein R ¹ , R ² and η have the above meaning) optionally in the presence of a Catalyst cyclized, and, if desired, converting a compound of general formula I thus obtained into an acid addition salt. 2. The method according to claim ia), characterized in that one carries out the reaction in a boiling above 15O ⁰ C solvent-preferably dimethylformamide, dimethylacetamide or sulfolane τ -. 3. The method according to claim 1 b), characterized in that one carries out the reaction at 150-220 ⁰ C. 4. The method according to claim 1 b), characterized in that one carries out the reaction at a temperature between 15O ⁰ C and 280 ⁰ C - preferably at 150-220 ⁰ C - performs. 5. The method according to claim 1 b) or 4, characterized in that one carries out the reaction in the absence of a solvent. 6. The method according to claim 1 b) or 4, characterized in that one carries out the reaction in the presence of a solvent. 7. The method according to claim 1 b), characterized in that one carries out the reaction in the presence of a catalyst. 8. The method according to claim 7, characterized in that one carries out the reaction at a temperature between 25 ⁰ C and 130 ⁰ C-preferably at 70-100 ⁰ C-performs. 9. The method according to any one of claims 7 or 8, characterized in that one uses as solvent phosphorus oxychloride and as a catalyst, phosphorus trichloride, phosphorus tribromide or a Lewis acid. 10. The method according to any one of claims 1-9 for the preparation of a compound of general formula I ₁ wherein R ^{1 is} methyl and R ^{2 is} hydrogen and η = 3, characterized in that one uses the corresponding starting materials. 11. The method according to any one of claims 1-9 for the preparation of a compound of general formula I, wherein R ¹ and R ² together form ethylene (-CH ₂ -CH ₂ -) and η = 2, characterized in that the corresponding Starting materials used.