KR820001387B1 - Process for preparing oxadiyzolo pyrimidine derivatives - Google Patents

Abstract

Oxadiazolo pyrimidine derivs. (I; R1 = alkyl, alkoxyalkyl; R is alkyl or alkoxyalkyl which is different with R1), useful as hypotensive drug, were prepd. by trans-esterification of compd. (II) with R1-OH. Thus, methyl-5-[3,6-dihydro-1(2H)-pyridyl -2-oxo-2H-[1,2,4 oxadiazolo[2,3-a pyrimidine-7- carbamate 2 g was suspended in acetonitrile, treated with acetonitrile 20 ml and 3-azabicyclo[3,2,2 nonane 1.6 g soln. and then recrystallized to give pure 3-azabicyclo [3,2,2 nonane salt (m.p. 164-168≰C).

Description

Process for preparing oxadiazolo pyrimidine derivative

The present invention relates to a method for preparing oxadiazolo pyrimidine derivatives of the following general formula (IA) and salts thereof useful as vasodilators and blood pressure lowering agents.

In the above general formula

R 'is an alkyl or alkoxyalkyl group.

As used herein, "alkyl", alone or in combination with other groups, is a straight and branched chain saturated hydrocarbon having 1 to 8 carbon atoms, such as metel, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. By group and the term "alkoxy" is meant an alkyl ether group in which the "alkyl" moiety has the foregoing meanings.

The oxazolopyrimidine derivative of formula (IA) is transetherated to a compound of formula (I) with an alcohol of formula R'-OH (R 'is as described above), and the compound is salt Or by converting the salt to another salt.

In the above general formula

R is an alkyl or alkoxy alkyl group different from R '.

Preferred compounds of formula (I) are those wherein R is an alkyl group, especially an alkyl group having 1 to 4 carbon atoms. Formula (I), wherein R is a methyl group, ie methyl (5- [3,6-dihydro-1 (2H) -pyridyl] -2-oxo-2H- [1,2,4] oxadiazolo Particular preference is given to [2,3-a] pyrimidine-7-carbamates.

Trans-esterification of the compound of formula (I) is preferably carried out in the presence of a base by reacting the compound of formula (I) with an alcohol at a temperature of 25 to 150 ° C.

Suitable bases for this purpose are alkali alcoholates, alkali hydroxides, carbonates and the like. If alcoholates are used, they should correspond to the alcohols used in the reaction.

Trans-esterification is carried out in inert organic solvents such as aromatic hydrocarbons (eg benzene or xylene), ethers (eg dioxane, tetrahydrofuran or ethylene glycol dimethyl ether), dimethylformamide, dimethyl sulfoxide and the like. . If the alcohol used is a liquid at the reaction temperature, the excess alcohol may also act as the reaction medium.

The compound of general formula (I) to be used as a starting material is a novel substance and can be prepared, for example, by ring closing the compound of the following general formula (II).

R in the general formula is as described above.

The ring closure reaction of the compound of formula (II) is carried out by heating to a temperature of from 50 ° C. to 200 ° C., preferably from 100 ° C. to 150 ° C., in a known manner and in the presence or absence of a solvent or solvent mixture. When the ring closure reaction is carried out in a solvent or a mixture of solvents, as a solvent, an aromatic hydrocarbon such as benzene, toluene or xylene, a chlorinated hydrocarbon such as chloroform, an alcohol such as butanol or isobutanol, dibutyl ether, dioxane or diethylene glycol dimethyl ether Ethers such as dimethylformamide, dimethylsulfoxide and the like or mixtures thereof may be used. Of course, a solvent having a boiling point higher than the cyclocyclization temperature may be used and a solvent boiling at the reflux temperature in the above-mentioned range may be used. The ring closure reaction is preferably carried out using dimethylformamide or toluene as solvent and the time of the ring closure reaction depends on the temperature at which the reaction is carried out and is about 0.25 to 18 hours. When the ring-closure reaction is carried out at a preferred temperature of 100 ℃ to 150 ℃ the reaction time reaches about 0.25 to 12 hours, preferably 0.25 to 2 hours. To use alcohol as a solvent, the alcohol must be identical to the alcohol component in the starting materials used so that no trans-esterification occurs.

Another particularly preferred method is to carry out the ring closure reaction in the presence of a base, in which case the reaction temperature can actually be carried out at a lower temperature. The ring closure reaction in this process is preferably carried out at 0 ° C to 80 ° C, conveniently at room temperature. Suitable bases include inorganic bases such as alkali hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g. barium hydroxide, calcium hydroxide), carbonates (e.g. potassium carbonate and sodium carbonate), and bicarbonates (e.g. sodium bicarbonate); Organic bases such as dimethylamine, triethylamineethyldiisopropylamine and the like. When a base is used, the ring closure reaction is carried out in a suitable inert solvent or solvent mixture, and as the solvent, the above-mentioned solvent can be used. When inorganic bases are used, the ring closure reaction is conveniently carried out in the presence of water in a solvent mixture containing water or in a two-phase system such as methylene chloride / water. When intentionally causing trans-esterification, the ring closure reaction is preferably carried out in the presence of a base.

Compound of formula (II) is a novel substance

This compound is, for example, 2,4-diamino-6- [3,6-dihydro-1 (2H) -pyridyl] -pyrimidine- of the following general formulas (II), (IV) and (V) 3-oxide or tautomeric 6-amino-4- [3,6-dihydro-1 (2H) -pyridyl] -1,2-dihydro-1-hydroxy-2-imino pyrimidine and 2-amid-4- [3,6-dihydro-1 (2H) -pyridyl] -1,6-dihydro-1-hydroxy-6-imino-pyrimidinol of formula (VI) Prepared by reaction with chloroform acid ester.

(Where R is the same as above)

The reaction proceeds in an inert solvent or solvent mixture in the presence of an acid binder. Suitable solvents for this purpose are chlorinated hydrocarbons such as methylene chloride and chloroform, ethers such as diethyl ether, tetrahydrofuran and dioxane, dimethylformamide and the like or mixtures thereof. The reaction is also carried out in the presence of water in a solvent containing water or in an ideal system such as methylene chloride / water.

Examples of acid binders are bases such as triethylamine, ethyldiisopropylamine, dimethylamine, pyridine, alkali hydroxide and the like. If the reaction is carried out in the presence of a liquid base, this base also acts as a solvent. The reaction is conveniently carried out at -10 ° C to room temperature, preferably at 0 ° C to 10 ° C.

In contrast, starting materials of the general formula (II) are prepared by dialkyl 6-chloro-2,4-pyridinedidine-dicarbamate-3-oxide of the following general formula (II): 1,2,5,6-tetrahydro Prepared by reaction with pyridine.

R in the general formula is as described above.

The reaction is carried out in an inert solvent or solvent mixture and suitable solvents for this purpose are chlorinated hydrogen carbonates such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, xylene and the like or mixtures thereof. The reaction is also preferably carried out at room temperature, preferably in an inert gas, preferably 0 to 50 ° C. under an argon or nitrogen stream. Excess 1,2,5,6-tetrahydropyridine can also be used in place of an inert solvent.

Compounds of formula (III) or their tautomers of formulas (IV) and (V) can be prepared in a similar manner to the preparation of known compounds. Two processes are described in the following general formula diagram. The exact reaction conditions are described in detail in the Examples.

Dialkyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxides of general formula are novel and belong to the present invention. This compound is prepared by reacting 2,4-diamino-6-chloropyrimidine-3-oxide of formula (XIII) with chloroformic ester of formula (VI). This reaction is carried out under the reaction conditions given for reacting the above-described compound of formula (III) or their tautomer of formula (IV) or (V) with chloroformate ester of formula (VI).

Compounds of formula (I) may be converted to salts. Treated with an inorganic base such as, for example, alkali hydroxides (e.g. sodium or potassium hydroxide) or alkaline earth metal hydroxides (e.g. calcium hydroxide) or mono alkylamines (e.g. methylamine) dialkylamines (e.g. dimethylamine), trialkyl Amines (e.g. triethylamine), basic amino acids (e.g. arginine), piperidine, azabicyclooctanetan or -nonane (e.g. 3-azabicyclo [3,2,1] octane or 3-azabi Treated with an organic base such as cyclo [3,2,2] nonane). Salts of compounds of formula (I) are also prepared by double decomposition of the appropriate salt. Among the salts of the compound of formula (I), pharmaceutically unfavorable salts are preferred.

Oxadiazolo pyrimidine provided by the present invention has useful long-lasting vasodilating action and / or hypotensive action and thus can be used for the treatment of hypertension caused by blood vessels or as a vasodilator in the case of abnormal peripheral blood supply.

Blood pressure drop is measured by the following method in conscious natural hypertension rats.

Systolic blood pressure and heart rate are measured twice before administration of the test substance. The test substance is administered daily in the morning and at the afternoon of two meals. Measures 1, 3, 6 and 24 hours after administration of these two variables and calculate the percent change for the control. Systolic blood pressure is indirectly measured in rat tail arteries by Gerold et al. (Helv. Physio. Acta 24 58-69, 1966: Arzneimittelforschung 18: 1285-1287 1968).

Vasodilation is measured by the following method in conscious, chronically implanted dogs.

Hybrid female babies weighing about 25 kg are implanted around the abdominal aorta with an electron flow reporter and a vasocompressor under aseptic conditions. Zero-blood flow is measured by tightening blood vessels using an obturator. The heart rate and aortic blood flow starting from the pulsating blood flow were recorded continuously for the first 3 hours after oral administration of the test substance, while the dogs in the test box were lying quietly in each case while measuring 6, 24, 48 and 72 hours later. It is not. The test substance is orally administered by gelatin capsules. The results obtained here are shown in the following table. In each case the maximum percent deviation from the control and the duration of action (calculated as average from 5 experimental mice or 3 experimental dogs) are shown.

A = ethyl 5- [3,6-dihydro-1 (2H) pyridyl] -2-oxo-2H- [1,2,4-oxadiazolo [2,3-a] pyrimidine-7-carba Mate

B = isobutyl 5- [3,6-dihydro-1 (2H) -pyridyl] -2-oxo-2H- [1,2,4] -oxadiazolo [2,3-a] pyrimidine- 7-carbamate

C = methyl 5- [3,6-dihydro-1 (2H) -pyridyl] -2-oxo-2H- [1,2,4] oxadiazolo [2,3-a] pyrimidine-7- Carbamate

AABF = abdominal aortic blood flow

Compounds of formula (I) and their pharmaceutically harmless salts can be used as medicaments: for example in the form of pharmaceutical preparations containing the compound together with pharmaceutically suitable carriers. Such carrier materials are organic or inorganic inert carrier materials suitable for enteral or parenteral administration, for example water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, waselin and the like. Pharmaceutical preparations may be made in solid form (eg tablets, dragees or capsules) or in liquid form (eg liquids, suspensions or emulsions). The pharmaceutical preparations may be sterilized and / or may contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts or buffers which change the osmotic pressure, and may also contain other therapeutically useful substances. .

For oral administration, the daily dose is 10 to 500 mg and for intravenous administration is 1 to 50 mg. The above dosages are given by way of example and may be varied depending on the severity of the condition being treated and the judgment of the attending physician.

The following examples illustrate the manufacturing method of the present invention. Melting point is not corrected.

Example 1

2. g (6.9 mmol) methyl 5- [3,6-dihydro-1 (2H) -pyridyl] -2-oxo-2H- [1,2,4] oxadiazolo [2,3-a ] Pyrimidine-7-carbamate is heated to reflux with 50 mg of sodium in 100 ml of n-butanol under an argon stream. After 6 hours the solution is acidified with hydrochloric acid and evaporated. Chromatographic separation of dibutyl 6- [3,6-dihydro-1 (2H) -pyridyl] 2,4-pyrimidine-dicarbamate-3-oxide with a melting point of 126-128 ° C. and melting point Butyl 5- [3,6-dihydro-1 (2H) -pyridyl] -2-2H- [1,2,4] oxadiazolo [2,3-a] pyrimidine-7 at 183 to 187 ° C Carbamate is obtained.

Methyl 5- [3,6-dihydro-1 (2H) -pyridyl] -2-oxo-2H- [1,2,4] oxadiazolo [2,3-a] pyrimidine used as starting material -7-carbamate is prepared according to the following method.

A) 144.5 g (1 mol) of 2,4-diamino-6-chloropyrimidine is suspended in 2000 ml of ethanol. When the suspension is warmed to 35 ° C. with stirring (about 15 minutes) most of the material is in solution. The mixture is cooled to 6-8 ° C. and at this temperature 175 mL (about 1 mole) of 40% peracetic acid in glacial acetic acid is added dropwise within 40 minutes. After the addition is completed, the mixture is further stirred at 6 to 8 ° C for 30 minutes. The mixture is left to warm to room temperature and then stirred for another 3 hours at room temperature. 2000 ml of petroleum ether is added and stirred for 1 hour before being prevented overnight. The separated precipitate was filtered off with back washing with 200 ml of petroleum ether and then dried under reduced pressure to give 2,4-diamino-6-chloropyrimidine-3-oxide. Recrystallization gives a pure product having a melting point of 193 ° C.

The 2,4-diamino-6-chloropyrimidine-3-oxides described above can also be prepared as follows.

75 g (0.52 mole) of 2,4-diacetyl-6-chloropyrimidine is dissolved in 1500 ml of ethanol at 35 ° C. After cooling the solution to −10 ° C., 100 g of 3-chloro-perbenzoic acid (0.57 mol) in 500 ml ethanol was slowly added dropwise over 1 hour. The suspension is then stirred for 7 hours at -10 ° C-, left overnight at 5 ° C and the suspension is neutralized with 24 g of sodium hydroxide in 100 ml water. The solid material was filtered off and recrystallized from ethanol to give pure 2,4-diamino-6-chloropyrimidine-3-oxide.

155 g (0.967 mole) of 2,4-diamino-6-chloro pyrimidine-3-oxide was added to 640 ml of 0-xylene and 260 ml (2.83 mole) of 1,2,5,6-tetra under argon stream. Stir and mix with hydropyridine. The mixture was heated to reflux for 30 minutes to raise the internal temperature from 115 ° C to 123 ° C. The mixture is cooled to 5 ° C., treated with 40 g of sodium hydroxide in 40 ml water and stirred at 5 ° C. for 1 hour. The precipitate formed was separated by filtration, washed with 200 ml of water and recrystallized with 3000 ml of water to obtain pure 2,4-diamino-6- [3,6-dihydro-1 (2H) having a melting point of 263 to 26 ° C (decomposition). ) Pyridyl] pyrimidine-3-oxide is obtained.

45 g (0.218 mole) of 2,4-diamino-6- [3,6-dihydro-1 (2H) -pyridyl] pyrimidine-3-oxide in 90 ml of tree in 600 ml of methylene chloride After mixing with ethylamine, it is cooled to 5 ° C. 90 mL (1.14 mol) of chloroformic acid methyl ester is added dropwise while stirring. The mixture is stirred at 5 ° C. for 30 minutes at room temperature for 18 hours. The mixture is treated with 100 ml of methanol and then extracted with 400 ml of methylene chloride, washed with water, dried over potassium carbonate and evaporated under reduced pressure. Recrystallization of the residue from methanol gives dimethyl 6- [3,6-dihydro-1 (2H) -pyridyl] -2,4-pyrimidine-dicarbamate-3-oxide having a melting point of 202 to 203 캜. .

The last mentioned 3-oxides can also be prepared as follows.

20 g (0.0965 mol) of 2,4-diamino-6- [3,6dihydro-1 (2H) -pyridyl] pyrimidine-3-oxide is suspended in 100 ml of methylene chloride and 200 ml of water. And stir. While stirring, 25 ml (0.317 mol) of chloroformic acid methyl ester and 30 ml of 28% sodium hydroxide in 50 ml methylene chloride were added dropwise simultaneously so as to have a pH of 7.5 to 8.5. After completion of the dropwise addition, the suspension is stirred for an additional hour and the precipitate formed is subsequently filtered off. The filtrate is washed with methylene chloride and mixed with the precipitate. When the mixture was recrystallized from methylene chloride / methanol, dimethyl-6- [3,6-dihydro-1 (2H) -pyridyl] -2,4-pyrimidine-dicarb having a melting point of 202 to 206 캜 (decomposition). Mate-3-oxide is obtained.

B) 56 g of 2,4-diamino-6-chloropyrimidine-3-oxide and 100 ml of triethylamine in 500 ml dimethylformamide were cooled to 0 deg. 80 ml (1.015 mol) of chloroformic acid methyl ester is added dropwise within 1 hour with stirring. After the addition, the mixture is stirred for 48 hours. The precipitate was separated by filtration, suspended in a mixed solution of 2500 ml of methylene chloride and 500 ml of methanol, followed by stirring for 80 minutes. The insoluble residue was filtered off and dried to give pure dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide having a melting point of 204 ° C. (decomposition). The organic layer is washed with water and concentrated to give a higher amount of pure material.

A suspension of 10 g (0.036 mol) of dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 40 ml methylene chloride was added to 20 ml (0.22 mol) of 1,2,5,6-tetra Treat with hydropyridine and stir at room temperature under argon for 16 hours. The resulting precipitate was filtered off and recrystallized from a mixture of methylene chloride and methanol and purified with pure dimethyl 6- [3,6-dihydro-1 (2H) -pyridyl] -2,4-pyrimidine-dicarba at a melting point of 203 ° C. Mate-3-oxide is obtained.

50 g (0.171 mol) of dimethyl 6- [3,6-dihydro-1 (2H) -pyridyl] -2,4-pyrimidine-dicarbamate-3-oxide was stirred in 300 ml of dimethylformamide for 30 minutes. Heating to 140 ° C. under argon. The dimethylformamide was decanted under reduced pressure and the residue was recrystallized from methanol / methylene chloride to give methyl 5- [3,6-dihydro-1 (2H) -pyridyl] -2- having a melting point of 213 ° C. to 215 ° C. (decomposition). [2,3-a] pyrimidine-7-carbamate is obtained with oxo-2H- [1,2,4]] oxadiazole.

Example 2

2 g (6.9 mmol) methyl 5- [3,6-dihydro-1 (2H) -pyridyl-2-oxo-2H- [1,2,4] oxadiazolo [2,3-a] pyrimidine The -7-carbamate is suspended in acetonitrile and treated with a solution of 1.6 g of 3-azabacyclo [3,2,2] nonane dissolved in 20 ml of acetonitrile. Initially a clear solution was produced but the precipitation of the corresponding 3-azabicyclo [3,2,2] nonan salt was very rapidly produced and its structure was confirmed by X-ray structural analysis. Recrystallization yields a pure salt with a melting point of 164 to 168 ° C.

Example 3

3 g (10.5 mmol) methyl 5- [3,6-dihydro-1 (2H) -pyridyl] -2-oxo-2H- [1,2,4] oxadiazolo [2,3-a] pyri The midine-7-carbamate is dissolved in 2N sodium hydroxide and then left to stand. Cooling immediately precipitates the corresponding sodium salt, which is recrystallized from acetonitrile and water to give the corresponding sodium salt which begins to decompose from 145 ° C.

Claims (1)

A method for preparing an oxadiazolopyrimidine derivative of the general formula (IA) and a salt thereof by transesterifying a compound of the general formula (I) with an alcohol of the general formula R′-OH.

In the above general formula R ′ is an alkyl or alkoxyalkyl group R is an alkyl or alkoxyalkyl group different from R '.