HU189946B - Process for preparing substituted 2-imino-3,4,6,7-tetrahydro-/4h/-pyrimido/6,1-a/isoquinolin4-one derivatives - Google Patents

Abstract

The present invention relates to a novel process for the preparation of substituted 2-imino-3,4,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-ones of the formula I <IMAGE> Compared with the known preparation process, the process according to the invention is shorter and gives a higher total yield.

Description

The present invention relates to a novel process for the preparation of substituted 2-imino-3,4,6,7-tetrahydro-4 (4H) -pyrimido [6,1-a] isoquinolin-4-one having the pharmacological properties of tetrachloride. for the preparation of derivatives. In the general formula (I)

R ¹ and R ^J are C 1-4 alkyl and

R 'is phenyl substituted with polysubstituted C 1-4 alkyl groups.

The compounds of formula (I) are prepared according to the invention by:

1) a 2- (3,4-dialkoxyphenyl) ethylamine of formula II - wherein R ^{1 in} formula II is a) an isocyanate of formula III - in formula III 'has the meaning given above - in hydrocarbons, chlorinated hydrocarbons, ketones, ethers or esters at temperatures between -10 ° C and + 100 ° C, or

b) reacting a phenyl ester of the urea of formula V, wherein R a in ^the formula V is as defined above, with lower alkanol, toluene or ethyl acetate at 50-150 ° C,

2) the resulting carbaroid derivative of formula (IV) - wherein R ¹ and R ^{a in} formula (IV) are as defined above, with a maloneave ester of formula (VI) - in formula (VI) R ^s is C 1-4 alkyl - is reacted with inert hydrocarbon or lower alkanol for 10-30 hours in the presence of a basic catalyst and

3) reacting the barbyluric acid derivative of the formula (VII) thus obtained - in the general formula (VII), R ¹ and R ^a are reacted with a phosphorus halide in boiling in an optionally inert organic solvent, and

4) reacting (VIII) with an intermediate of formula - in the formula (VIII) R ¹ and R ^J are as defined above and X is chlorine or bromine, and Y * is halogen or foszforhalogenid anion - an amine of general formula (IX) - in formula (IX), R 'is reacted in the above organic solvent with a pyridine, triethylamine or 1,5-diazabicyclo (5,4,4 OJundecane) as an auxiliary base.

In contrast to the production method described in German Patent Publication No. 2,847,693, the process according to the invention has the advantage of being one and two steps more rusty and having a higher overall yield; furthermore, the process of the present invention does not involve the difficulty of liberating the compounds of formula (I) from the unwanted isomers. According to the above-mentioned publication, when the presence of a substituent at the 3-position of the compounds of the formula I is required, the compounds of the formula I in which R ^a is hydrogen are alkylated in the final step of the process. ), wherein R ^a is alkyl. This reaction also partially alkylates the exocyclic nitrogen to form a non-selective isomer of the compound of formula I, which must be removed in a separate purification step. The process of the present invention excludes the formation of such an isomer in Borane.

In the first step of the process of the invention, a 2- (3,4-dialkoxyphenyl) ethylamine of general formula (II) is converted to a urea derivative of general formula (IV) using an isocyanate of formula (III). This interaction occurs in an inert solvent. Suitable solvents include hydrocarbons such as toluene or petroleum ether; chlorinated hydrocarbons such as dichloromethane; ketones such as acetone; ethers such as diisopropyl ether, di-tert-butyl ether, tetrahydrofuran or 1,2-dimethoxyethane; or esters, such as ethyl acetate; and acetonitrile. It is preferable to use solvents which directly crystallize the resulting urea of formula (IV). The reaction is carried out at a temperature in the range of -10 'C to + 100' C, preferably at a temperature of 0-50 'C. A preferred embodiment of the process according to the invention is to dissolve 2- (3,4-dialkoxyphenyl) ethylamine (II) in toluene and optionally dropwise mole of alkyl isocyanate (III) under ice-cooling. added. After completion of the reaction, the resulting urea derivative (IV) is filtered off with suction or isolated after distilling off the solvent.

Alternatively, the urea of formula (IV) may be prepared from a base by reacting an amine of formula (II) with an alkyl carbamic acid ester of formula (V). Any common organic solvent can be used for this reaction, preferably low molecular weight alcohols such as methanol or isopropanol or tolucyl or ethyl acetate. The reaction is carried out at a temperature in the range of 50 ° C to 150 ° C. In a preferred embodiment of the process of the present invention, a phenyl carboxylic acid ester of formula (V), wherein R ⁴ is phenyl, is reacted in hot isopropanol with a phenylethylamine of formula (II). After completion of the reaction, the solvent and the phenol formed are distilled off in vacuo and the remaining urea derivative (IV) is purified by recrystallization.

Subsequently, the urea derivative (IV) is cyclized with a malonic acid ester (VI) in the presence of a basic catalyst to a substituted barbituric acid (VII). Examples of the basic catalyst include alkanolates such as sodium melanolate, sodium ethanolate or potassium tert-butanolate, as well as sodium hydride or sodium amide. Sodium methanolate is particularly preferred. The reaction may be carried out in an inert organic solvent, for example, toluene, tetrahydrofuran, 1,2-dimethoxyethane, methyl tert-butyl ether or low molecular weight alcohols such as methanol. According to a preferred embodiment of the process of the invention, the urea derivative (IV) is added to a 1.2-1.8 molar solution of sodium methanol in methanol, followed by the dropwise addition of the malonic acid (VI). The mixture is then refluxed for 10-30 hours and, after completion of the reaction, acidified with mineral acid with cooling, whereupon the barbituric acid derivative of formula VII crystallizes.

According to the process of the present invention, the compound (VII) thus obtained is heated with a phosphorus halide, such as dichloromethane or phosphorus tribromide. The use of phosphorus chloride is particularly preferred for this reaction. This reaction may be carried out in the absence of a solvent or in the presence of an inert organic solvent. Preferred organic solvents are, for example, toluene, chlorobenzene or 1,2-dichloroelane. In a preferred embodiment of the process of the invention, the compound of formula (VII) is heated in a toluene solution with phosphorous chloride and, upon completion of the reaction, the volatile components are evaporated in vacuo. The crude intermediate (VIII) thus formed may be directly reacted with an amine (IX); however, the crude product VIII may be crystallized by addition of a suitable solvent such as tetrahydrofuran, toluene or 1,2-dimethoxyethane and isolated by filtration.

Preferably, the crude product of formula VIII is reacted with an amine of formula IX without drying and further purification. This reaction is conveniently carried out in the presence of an excess of an amine of formula IX, optionally in the presence of an organic solvent and an additional base such as pyridine, triethylamine or 1,5-diazabicyclo (5,4,0) undecane-5 (DBU). The use of excess amine or an additional base is required to bind the hydrogen halide formed during the reaction.

Reaction Compounds of formula (I) formed on the borane are isolated in the form of the bases by conventional methods, such as fractional crystallization or chromatography, preferably after removal of the volatile components by vacuum distillation.

In a preferred embodiment of the process according to the invention, after completion of the reaction of the compounds of general formulas (VIII) and (IX), boric acid gas is added to the reaction mixture to a strongly acidic reaction. Thus, a mixture of hydrochlorides is precipitated.

In order to further purify the compounds of formula (I) thus obtained, a separate mixture of hydrochlorides can be processed in two ways. The first method involves treating the salt mixture with sodium hydroxide solution, preferably in the presence of an organic, water-immiscible solvent such as dichloromethane. After isolation and concentration of the organic phase, the compounds of formula (I) are obtained which may be further purified by recrystallization from a suitable organic solvent.

In a second method of purifying the compounds of formula I, the separated salt mixture is extracted with a suitable solvent, such as acetone, in which the hydrochloride of the resulting compound of formula I is dissolved. At this time, most of the hydrochloride of the other amines remains insoluble. After distilling off the solvent, the crude hydrochloride of the compound of formula (I) is obtained, which can then be further purified by conversion to the base of formula (I).

The invention ezerinti method the overall yield relative to the general> amine of formula (II) used in the theoretical yield of 40-45% of / in the case where in formula (I), R ^{1 and} R is methyl, and R is mesityl / .

The compounds of the formula I have valuable pharmacological properties: they are predominantly antihypertensive and can therefore be used as medicaments.

The present invention is illustrated in detail in the following examples.

Example 1

Preparation of N- (2- (3,4-Dimethoxyphenyl) ethyl) -N-methylurea (Step 1 (a))

To a solution of 186 g of 2- (3,4-dimethoxyphenyl) ethylamine (97% yield) and 920 ml of toluene in ice-water is added dropwise 57 g of methyl isocyanate at an internal temperature of 20-30 ° C. After stirring at room temperature, the precipitated crystals were filtered off with suction, washed with 60 ml of toluene and dried to give 220 g (93% yield) of the title crystalline product, m.p.

(Step 1 (b))

To a solution of 174.4 g of 86.6% methylcarbamic acid phenyl ester in 1 liter of isopropanol refluxed with 200 g of 2- (3,4-dimethoxyphenyl) ethylamine and 530 g of A mixture of isopropanol (ml) was added dropwise, the mixture was refluxed for 3 hours, and the isopropanol and phenol formed were evaporated in vacuo. The viscous residue was taken up in tetrahydrofuran (460 mL) and diisopropyl ether (280 mL) was added slowly dropwise. The product precipitates out. After stirring for an additional 30 minutes at 0 ° C, the solid was filtered off with suction, washed with diisopropyl ether (140 mL) and dried in vacuo. 226 g (93%) of the title compound are obtained, m.p. 120-121 ° C.

Example 2

Preparation of N- (2- (3,4-Dimethoxyphenyl) ethyl) -N-melyl-barbituric acid (Step 2 of the procedure)

Sodium methanolate (56.5 g) was added with stirring to 710 ml of methanol, the suspension was heated to 30 ° C and 143 g of N- (2- (3,4-dimethoxyphenyl) ethyl) -N'- methylurea is added. The solution was then heated to 45 ° C, treated with 112 g of malonic acid diethyl ester and refluxed for 24 hours. At this time, the solution was cooled to 0-10 ° C and the pH was adjusted to 1-2 by addition of a solution of concentrated sulfuric acid (65 g) in water (560 ml), followed by stirring at 0 ° C for an additional hour. The precipitate was filtered off with suction and washed with ice water and dried. This gave 160 g (80%) of the title compound, 91.9%, m.p. 173-176 ° C.

Example 3

2- (Mesityl imino) -3-methyl-9,10-dimethoxy-3,

Preparation of 4,6,7-tetrahydro- (4H) -pyrimido (6,1-a) isoquinolin-4-one (Steps 3 and 4 of the procedure)

A mixture of 68.1 g of N- (2- (3,4-dimethoxyphenyl) ethyl) -N'-methyl-barbituric acid, 200 ml of toluene and 245 g of phosphoryl chloride was removed under reflux for 3.5 hours. boil. Thereafter, about 200 ml of a mixture of phosphoryl chloride and toluene was distilled off in vacuo, 100 ml of toluene were added to the residue and 160 ml of the mixture was distilled off again. To the still-stirring residue was added tetrahydrofuran (280 mL), stirred for 1 hour at 0 ° C, the yellow precipitate was filtered off with suction, washed with tetrahydrofuran (60 mL) and the crude wet product was returned to the apparatus. A mixture of 230 ml of toluene and 50 g of 2,6,4-trimethylaniline is added, the mixture is heated to 60 ° C and the pH is adjusted to 9 by the addition of about 60 g of triethylamine. thereafter

The mixture is refluxed for 2.5 hours and optionally maintained at pH 9 by addition of triethylamine (about 5 g). After completion of the reaction, the mixture was cooled to 5-10 ° C and adjusted to pH 1 with about 30 g of hydrochloric acid gas. The precipitated salt mixture was suction filtered, washed with 25 mL of toluene and the precipitate was boiled twice with successively 630 mL of acetone. The insoluble material is filtered off with suction and washed with 130 ml of acetone. The acetone solutions were combined, evaporated and the residue was stirred with a mixture of 450 ml of dichloromethane, 200 ml of water and 25 g of concentrated sodium hydroxide solution. The organic layer was washed with water (200 mL), and the aqueous layers were combined and extracted with dichloromethane (80 mL). The thousands of aqueous phases were combined and evaporated. The oily residue (70 g) was dissolved in methanol (250 ml) at 50 ° C, cooled to 0 ° C, stirred at this temperature for 2 hours and then filtered off with suction. The filtered precipitate was washed with cold methanol (40 mL) and dried in vacuo at 40 ° C. Yield: 48.9 g (57.9%), m.p. 157 DEG C., 96% active ingredient.

Claims (3)

Claims 1) a 2- (3,4-dialkoxyphenyl) ethylamine of formula (II) - wherein R ^{1 in} formula (II) is ^a ) an isocyanate of formula (III) - in formula (III) R ^J is as defined above in hydrocarbons, chlorinated hydrocarbons, ketones, ethers or esters at temperatures between -10 ° C and + 100 ° C, or b) reacting with a phenyl ester of carbamate V of formula V wherein R 'is as defined above in lower alkanol, toluene or ethyl acetate at 50-150 ° C, A process for the preparation of the 2-imino-3,4,6,6,7-tetrahydro-4H-pyrimido [6,1-a] isoquinolin-4-one derivatives of the general formula (I) in the general formula (I) R ¹ and R ^J are C 1 -C 4 alkyl and R ¹ is phenyl substituted with C 1 -C 4 alkyl groups, characterized in that 2) the urea derivative (IV) obtained in the formula (IV) R ¹ and R * are as defined above, with one of the tnalonic acid esters of formula VI in formula VI, R 4 being C 1 -C 4 alkyl, in an inert hydrogen or lower alkanol boiling for 10-30 hours. and in the presence of a catalyst 3) reacting the bar-bituric acid derivative of formula (VII) - in formula (VII) - with a phosphorus halide in refluxing an optionally inert organic solvent and reacting the resulting compound of formula (VIII) intermediate - (VIII), ^R¹ and R in the general formula above and X is chlorine or bromine and Y * halogónvagy does foezfor halide anion with an amine (IX) - in the formula (IX) R is as hereinbefore defined in an organic solvent and as a base in the presence of pyridine, triethylamine or 1,5-diazabicyclo (5.4.0) undecane.