HU203342B - Process for producing quinazoline deivatives - Google Patents

Abstract

Prepn. of quinazoline derivs. of general formula (I) is claimed, where R1 and R2 may each = H, lower alkyl, or together (-CH2-CH2) or (-CH2-CH2-CH2-) and n = 2 or 3, and suitable acid addn. salts; comprising (a) reacting isothiourea deriv. (III) where R = lower alkyl or phenyl-lower alkyl (phenol opt. substd. with lower alkyl or halogen, pref. F, Cl, or Br. with an amine (IV) at 150-280 deg.C, or (b) cyclising cpd. (II) thermally or in presence of a catalyst. Pref. are (I) where R1 = CH3, R2 = H, and n = 3 and R1 + R2 = (CH2-CH2-) and n = 2.

Description

Scope of the description: 8 pages (including Figure 2)

EN 203 342 Β

The present invention relates to a novel process for the preparation of the quinazoline derivatives of the formula I and their acid addition salts.

The compounds of formula I are known as antihypertensive agents.

More specifically, the invention provides a quinazoline derivative of the formula (I)

- in which formula

R ¹ is C 1-4 alkyl and

R ² is hydrogen; or

R ¹ and R ² together form an ethylene or propylene group and n is 2 or 3 for the preparation of their pharmaceutically acceptable acid addition salts by:

a) an isothiourea of formula (I) wherein R is a C1-7 alkyl group or a phenyl (1-4C) alkyl group optionally substituted with one or more C1-C4 alkyl or halogen atoms; reacting with an amine of formula (R ¹ , R ² and n as defined above) at a temperature of from 150 ° C to 280 ° C; or

b) a compound of formula II wherein R ¹ , R ² and n are as defined above are thermally or catalytically ring-closed;

and, if desired, converting the compound of formula (I) prepared as above into a pharmaceutically acceptable acid addition salt.

The halogen is preferably fluorine, chlorine or bromine. C 1-4 alkyl can be straight or branched, for example methyl, ethyl, i-propyl or tert-butyl.

According to methods known in the art for the preparation of compounds of formula (I), 4-amino-6,7-dimethoxy-2-chloroquinazoline of formula (IX) is reacted with an amine of formula (IV) or a compound of formula (IX) with a suitable diamine. the compound of formula (V) is prepared and subsequently acylated (German Patent Nos. 2 646 186, Belgian Patent Nos. 879 730 and 873 909 and French Patent Nos. 2 468 595).

The disadvantage of these methods is that the starting material of formula (IX) can be prepared from the veratric acid aldehyde in step 7, many of which are very low yields [J. Med. Chem., 20, 146 (1977)].

The compound of formula (I) can thus be prepared from a total of 8 reaction steps of vanillin [Preparation of the compound of formula (IX) requires step 7 and the compound of formula (I) is formed in a further step]. the total yield of these 8 steps is extremely low, 3-4%.

Surprisingly, it has been found that all of these disadvantages can be easily eliminated if the compounds of formula (I) are prepared by thermal or catalytic ring closure of compounds of formula (I), which have not been known in the art.

The novel compounds of formula (II), which can be prepared by reacting the isothiourea of formula (I) with an amine of formula (IV), can be directly converted to the compounds of formula (I) without ringing.

According to the process of the present invention, the starting material of formula (III) can be prepared from veratrol in only 3 steps and can be converted into the final product of formula (I) by two further steps. The total yield of Step 5 is 40-60%.

The compounds of formula (I) are known [J. Heterocyclic. Chem. 23, 401 (1986)] or 181 743. can be prepared analogously to the method described in Hungarian Patent Application.

The compounds of formula (IV) are known from the literature (German Patent Publication No. 2 646 186, Belgian Patent Nos. 873,909 and 879,730 and French Patent Nos. 2,468,595).

In process a) of the present invention, an isothiourea derivative of formula (III) with an acylated amine of formula (IV) in a reaction-inert solvent at a temperature of 150 ° C or higher, for example dimethylformamide, dimethylacetamide, N methylpyrrolidone, hexamethylphosphoric triamide, dimethyl sulfoxide, sulfolane, dimethylene glycol dimethyl ether, diethylene glycol diethyl ether, diphenyl ether, nitrobenzene, dichlorobenzene, tetrahydronaphthalene, especially dimethylene glycol dimethyl ether or dimethyl formamide, preferably 150-220 ° C, particularly preferably 160 and 180 'Con.

In the process (b) of the present invention, the above cyclization of the compounds of formula (I) to the desired compound of formula (I) can be carried out by simple heating or in the presence of a suitable catalyst.

The cyclization of the compounds of formula (I) by heating to the corresponding compound of formula (I) is carried out in the absence of a solvent or in a suitable reaction inert solvent in the range of 150 to 280 ° C, preferably 150 to 220 'C. The reaction may be carried out in a solvent having a boiling point of 150 ° C or higher, for example in dimethylformamide, dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoric triamide, dimethyl sulfoxide, sulfolane, dimethylene glycol dimethyl ether, diethylene glycol diethyl ether, diphenyl in ether, nitrobenzene, dichlorobenzene, tetrahydronaphthalene is particularly preferred in dimethylene glycol dimethyl ether or dimethylformamide.

The cyclization of the compounds of formula (I) in a solvent in the presence of a catalyst to the corresponding compound of formula (I) at 25-130 ° C, preferably 70-100 ° C, using phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride. using phosphorus tribromide or Lewis acid catalyst, preferably phosphorus oxychloride in a phosphorus trichloride catalyst. Lewis acid is preferably aluminum chloride, boron trifluoride, boron trifluoride etherate, zinc chloride, tin (II) chloride.

EN 203 342 Β

The starting materials of formula (b), compounds of formula (I), are prepared by reacting an isothiourea of formula (IH) with an amine of formula (IV) in a reaction inert solvent, preferably alcohols or polar. in an aprotic solvent, particularly preferably between 80 and 130 ° C, at a maximum temperature of 130 ° C.

The conversion of the compounds of formula (I) to the acid addition salt is carried out in a manner known per se. Preferably, it is reacted with a suitable inorganic or organic acid in a solvent such as hydrochloric acid, hydrobromic acid, sulfuric acid, maleic acid, fumaric acid.

An advantage of the present invention is that the compounds of formula (I) can be prepared simply, economically, in good quality.

The invention is illustrated by the following examples without limiting the invention to the examples.

Example 1

N-cyano-N '- (3,4-dimethoxyphenyl) -4- (2-tetrahydrofuroyl) piperazine-1-carboxamidine (starting material)

25.1 g (0.1 mol) of N-cyano-N '- (3,4-dimethoxyphenyl) -S-methylisothiourea and 27.6 g (0.15 mol) of N- (2-tetrahydrofuroyl) A solution of piperazine in 150 ml of isopropanol was refluxed for 6 hours. After cooling the reaction mixture, the isopropanol was evaporated and the remaining crude product (38.2 g) was recrystallized from ethanol. 35.7 g (92%) of product are obtained, m.p.

Example 2

N-cyano-N '- (3,4-dimethoxyphenyl) -4- (2-tetrahydrofur oil) homopiperazine-1-carboxamidine (starting material)

In all cases, as in Example 1, except that N- (2-tetrahydrofuroU) -homopiperazine (19.8 g, 0.1 mol) was used instead of N- (2-tetrahydrofuroyl) piperazine, and 50 was replaced by isopropanol. ml of dimethylformamide was used and stirred for 5 hours at 120 ° C. After cooling the reaction mixture, water (200 mL) was added. The precipitated crystalline material was filtered, washed with water (2 x 50 mL) and recrystallized from ethanol. 32.0 g (80%) of the title product are obtained, m.p.

Example 3

N-cyano-N '- (3,4-dimethoxyphenyl) -N' -methyl-N '- [3- (2-tetrahydrofuroylamino) propyl] guanidine (starting material)

In all cases, as in Example 1, except that N- [3- (methylamino) propyl] -2- (27.9 g, 0.15 mol) was used instead of N- (2-tetrahydrofuroyl) piperazine. tetrahydrofuran-carboxamide is used and the mixture is stirred at 60 ° C for 8 hours instead of 6 hours. Thus, 24.7 g (635%) of the title compound are obtained. 140-143 ° C.

Example 4

2- [4- (2-tetrahydrofuroyl) piperazinyl] -4-amino-6,7-dimethoxyquinazoline hydrochloride

19.4 g (0.05 mol) of N-cyano-N '- (3,4-dimethoxyphenyl) 4- (2-tetrahydrofuroyl) piperazine-1-carboxamidine in 40 ml of diethylglycol diethyl ether for half an hour 180 Stir at C. After cooling the reaction mixture, dichloromethane (100 ml) was added, and the mixture was adjusted to 3-4 with ice-cold isopropanol under cooling with ice water and vigorous stirring. During the addition, crystallization begins. After stirring for an additional 1 hour at 05 ° C, the precipitated product is filtered off and recrystallized from isopropanol. Hy way

15.6 g (735%) of 2- [4- (2-tetrahydrofuroyl) piperazinyl] -4-amino-6,7-dimethoxyquinazoline hydrochloride are obtained, m.p.

Example 5

2- [4- (2-tetrahydrofuroyl) piperazinyl] -4-amino-6,7-dimethoxyquinazoline hydrochloride

In each case, the same procedure as in Example 4 was followed, except that instead of diethylene glycol diethyl ether, 40 ml of dimethylformamide was used and the reaction mixture was heated at 154 ° C for 15 hours. After cooling, 200 ml of water was added to precipitate the product, filtered, washed with water (2 x 100 ml), then suspended in 100 ml of methanol and acidified to pH 3-4 with hydrochloric acid isopropanol.

The precipitated crystalline product was filtered and recrystallized from isopropanol to give the title product (115 g, 54.2%).

Example 6

2- [4- (2-tetrahydrofuroyl) piperazinyl] -4-amino-6,7-dimethoxyquinazoline hydrochloride

In each case, as in Example 4, except that 30 ml of sulfolane was used instead of diethylene glycol diethyl ether, the reaction mixture was stirred at 280 ° C for 174 hours. This affords 12.29 (57.5%) of the title product

Example 7

N- {3 - [(4-Amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl} tetrahydro-2-furanecarboxamide hydrochloride

Phosphorus chloride (4.1 g, 0.03 mol) was added under cooling and stirring to 40 ml of phosphorus oxychloride, and after stirring for 10 minutes, 11.7 g (0.03 mol) of N-cyano-N 'was added slowly to the reaction mixture. 3,4-dimethoxy-phenyl) -N "-methyl-N" - [3- (2-tetrahydrofuroyl-amino) propyl] guanidine. The temperature is then slowly raised to 70 ° C for 25 hours. The excess phosphorus oxychloride was evaporated in vacuo and ice water was slowly added to the residue.

The precipitated crude product was recrystallized from ethanol

9.6 g (75%) of N- {3 - [(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] -propyl} -tetrahydro-2-furancarboxamide hydrochloride are obtained, m.p. 225 'C.

Example 8

N- {3 - [(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl} tetrahydro-2-furancarboxamide hydrochloride

EN 203 342 Β

In each case, the procedure of Example 7 was followed, except that phosphorus pentachloride (6.2 g, 0.03 mol) was used instead of phosphorus trichloride and the reaction was stirred at 25 ° C for 3 hours.

This gave 8.5 g (66.4%) of the title product.

Example 9

N- {3 - [(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl} tetrahydro-2-furancarboxamide hydrochloride

In each case, as in Example 7, the reaction was carried out with stirring with phosphorus tribromide (8.1 g, 0.03 mol) at 130 ° C for 1/2 hour instead of phosphorus trichloride.

This gave 7.8 g (61%) of the title product.

Example 10

N- {3 - [(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl} tetrahydro-2-furancarboxamide hydrochloride

In each case, as in Example 7, the mixture was saturated with hydrogen chloride gas and then stirred at 25-30 ° C for 15 minutes and finally at 70-75 ° C for 1 hour.

This gave 8.5 g (66.4%) of the title product.

Example 11

2- [4- (Tetrahydro-2-furoyl) piperazinyl] -4-amino-6,7-dimethoxyquinazoline hydrochloride

25.1 g (0.1 mol) of N-cyano-N '- (3,4-dimethoxyphenyl) -S-methylisothiourea and 27.6 g (0.15 mol) of N- (tetrahydro-2-carboxylic acid) furoyl) piperazine in 50 ml of dimethylformamide was heated at 155-160 ° C for 5 hours. After cooling the reaction mixture with water (200 mL), the product was precipitated, filtered, washed with water (2 x 100 mL) and then suspended in 100 mL of methanol and acidified to pH 3-4 with hydrochloric acid isopropanol.

The precipitated crystalline product was filtered, recrystallized from isopropanol to give 19.5 g (46%) of the title product, m.p.

Example 12

2- [4- (tetrahydro-2-furoyl) piperazinyl] -4-amino-6,7-dimethoxyquinazoline hydrochloride

All in all. EXAMPLE 1 Dimethylformamide diethyl ether (100 ml) was used in place of dimethylformamide and the reaction mixture was heated at 180 ° C for 2 hours. After cooling, 100 ml of dichloroethane was added to the reaction mixture, followed by cooling with ice water and vigorous stirring to adjust the pH to 3-4 with hydrochloric acid isopropanol. After stirring for 1 hour at 0-5, the precipitated product is filtered off and recrystallized from isopropanol. 20.8 g (49%) of the title compound are obtained, m.p.

Example 13

N-3 - [(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl-tetrahydro-2-furancarboxamide hydrochloride

5.2 g (0.02 mol) of N-cyano-N '- (3,4-dimethoxyphenyl) -S-methylisothiourea and 4.1 g (0.022 mol) of N- [3- (methylamino) ) -propyl] -2-tetrahydro-furanecarboxamide is melted at 180 ° C. The cooled melt is taken up in 30 ml of chloroform and 30 ml of water, the phases are separated, the chloroform phase is dried over sodium sulfate, the residue is taken up in 30 ml of acetone, 5 ml of 20% hydrochloric acid ether is added.

As a result of this solution, 3.9 g (45.8%) of the solution is obtained, m.p. 222-225 'C.

Example 14

N-3 - [(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl-tetrahydro-2-furancarboxamide hydrochloride

7.8 g (0.02 mol) of N-cyano-N '- (3,4-dimethoxyphenyl) N' -methyl-N '- [3- (2-tetrahydrofuroylamino) propyl] guanidine 180 At -90 ° C, it is fused for 10 minutes. All of the reaction mixture was treated as in Example 13. Hy, 4.5 g (53%) of product is obtained, m.p. 223-225 'C.

Claims (9)

PATENT CLAIMS A process for the preparation of quinazoline derivatives of the formula (I) - in the formula R ¹ is C 1 -C 4 alkyl and R ² is hydrogen; obsession R ¹ and R ² together form ethylene or propylene and n is 2 or 3 and pharmaceutically acceptable acid addition salts thereof. (a) an isothiourea number of formula (ΙΠ) (wherein R is C 1 -C 7 alkyl or phenyl-C 1 -C 4 alkyl optionally substituted with one or more C 1 -C 4 alkyl or halogen atoms) in the general formula (I); with an amine of formula (wherein R ¹ , R ² and n are as defined above) at a temperature of from 150 ° C to 280 ° C; obsession b) thermally or catalytically cycling a compound of formula II wherein R ¹ , R ² and n are as defined above; and optionally converting the compound of formula (I) prepared above into a pharmaceutically acceptable acid addition salt. Process (a) according to claim 1, characterized in that the reaction is carried out in a solvent having a boiling point higher than 150 ° C, preferably in dimethylformamide or diethylene glycol diethyl ether. Process (a) according to claim 1, characterized in that the reaction is carried out at 150 to 220 ° C. HU 203 342 Β Process b) according to claim 1, characterized in that the thermal ring closure is carried out at 150-280 'C, preferably 150-220' C. Process b) according to claim 1, characterized in that the reaction is carried out without the use of a solvent. Process b) according to claim 1, characterized in that the reaction is carried out in a solvent. Process b) according to claim 1, characterized in that the reaction is carried out in the presence of an acidic catalyst. Process according to claim 7, characterized in that the reaction is carried out at 25-130 'C, preferably at 70-100' C. Method b) according to claim 1, or method 7 and 7 The process of claim 8, wherein the acid-catalyzed ring closure is selected from the group consisting of phosphorus oxychloride, the catalyst being phosphorus trichloride, phosphorus tribromide, and Lewis acid.