IE46319B1 - Pyrimidine derivatives - Google Patents

Description

The present invention is concerned with pyrimidine derivatives.

The pyrimidine derivatives provided by the present invention have the following general formula wherein R represents an alkyl or alkoxyalkyl group and R^ represents the 1,2,5,6-tetrahydropyridin-l-yl group or a chlorine'atom.

The pyrimidine derivatives of formula I are useful 10 intermediates in. the manufacture of the oxadiazolopyrimidine derivatives which form the subject of Patent Specification The term alkyl” used in this Specification, alone or in combination, means straight-chain and branched-chain saturated hydrocarbon groups containing 1-3 carbon atoms such as., for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert.butyl. The term alkoxy means alkyl ether groups in which the alkyl moiety has the significance given earlier. 46318 Preferred pyrimidine derivatives of formula 1 are those in which R represents an alkyl group, especially an alkyl group containing 1-4 carbon atoms.

The pyrimidine derivatives of formula 1 in which R 5 represents the 1,2,5,6-tetrahydropyridin-l-yl group can be prepared, for example, by reacting 2,4-diamino-6-[3,6-d.ihydro-1 (2H)-pyridyl] pyrimidine-3-oxide or the tautomeric 6-amino-4-[3,6-dihydro-lf2H)-pyridyl]-1,2-dihydro-l-hydroxy-2-imino-pyrlm.idine and 2-amino-4-[3,6-dihydro-l(2H)10 -pyridyl]-l,6-dihydro-l-hydroxy-6-imino-pyrimidine of the formulae with a chloroformio acid ester of the general formula Cl—COOR (V) wherein R has the significance given earlier.

The reaction is carried out in an inert solvent or solvent mixture in the presence of an acid binding agent.

Suitable solvents for the present purpose are chlorinated hydrocarbons such a's methylene chloride and chloroform, ethers such as diethyl ether, tetrahydrofuran and dioxan, and dimethylformamide or mixtures thereof. The reaction can also be carried out in a water-containing solvent or in the presence of water in a two-phase system such as, for example, methylene chloride/water. Examples of acid binding agents are bases such as triethylamine, ethyldiisopropylamine, dimethylamine, pyridine and alkali metal hydroxides. When the reaction is carried out in the presence of a liquid base, then this can also serve as the solvent. The reaction is conveniently carried out at a temperature between about -10°C and room temperature, preferably between about 0°C and 10°C.

' Alternatively, the pyridine derivatives of formula I in which Rj represents the 1,2,5 ,6-tet'rahydropyridin-l-yl group can be prepared by reacting a pyrimidine derivative of the general formula —COOR (Ia) ,N , wherein R has the significance given earlier, with 1,2,5,6-tetrahydropyridine. 6 318 - 5 The reaction is carried out in an inert solvent or solvent mixture. Suitable solvents for this purpose are chlorinated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene and xylene or mixtures thereof. The reaction is preferably carried out under the atmosphere of an inert gas, preferably argon or nitrogen, at a temperature between about 0°C and SO°C, preferably at room temperature. Excess 1,2,5,3-tetrahydropyridine can also be used in place of an inert solvent.

The compound of formula II or its tautomers of formulae III and IV can be prepared in an analogous manner to the preparation of known compounds. Two processes are illustrated in the following Formula Scheme. Regarding the precise reaction conditions, reference is made to the detailed Examples hereinafter.

NH/· Formula Scheme NC—CH2x> .0 (VIII) (IX) NC HC^^OCH3 xN\ (X) O Λ NC I H„C. 2U\ (XI) <7 (XI) The pyrimidine derivatives of formula Ia can be prepared by reacting 2,4-diamino-6-ohloropyrimidine-3-oxide of formula VII with a chloroformic acid ester of formula V. The reaction is carried out under the conditions given hereinbefore for the reaction of the compound of formula II or a tautomer thereof of formula III or IV with a chloroformic acid ester of formula V. 6 319 - 8 The following Examples illustrate the manner in which the pyrimidine derivatives provided by the present invention can be prepared. The melting points are not corrected.

Example 1 A) 144.5 g (1 mol) of 2,4~diamino-6-chloropyrimidine are suspended in 2000 ml of ethanol. While stirring, the suspension is warmed to 35°c (ca 15 minutes), th'e greater part of the substance passing into solution. The mixture is then cooled to 6°-8°C and, at this temperature, there are added dropwise within the course of 40 minutes 175 ml (ca 1 mol) of 40% peracetic acid in glacial acetic acid. After completion of the addition, the mixture is stirred at 6°-8°C for a further 30 minutes. The mixture is then left to warm up to room temperature and stirred at this temperature for 3 hours. 2000 ml of petroleum ether are then added, the mixture is left to stir for 1 hour and then left to stand overnight. The separated precipitate is filtered off, back-washed with 200 ml of petroleum ether and dried under reduced pressure, there being obtained 2,4-diamino-6-chloropyrimidine-3-oxide. Recrystallisation yields analytically-pure product' of melting point 193°c.

The aforementioned 2,4-diamino-6-chloropyrimidine-3-oxide can also be prepared as follows: g (0.52 mol) of 2,4-diamino-6-chloropyrimidine are dissolved in 1500 ml of ethanol at 35°C. The solution is 6 318 cooled to -10°C and a solution of 100 g (0.57 mol) of 3-chloro-perbenzoic acid in 500 ml of ethanol is slowly added dropwise in the course of 1 hour. The suspension is subsequently stirred at -10°C for 7 hours and left to stand at °C overnight. The suspension is neutralised with 24 g of sodium hydroxide in 100 ml of water. The solid material is filtered off and recrystallised from ethanol, there being obtained pure 2,4-diamino-6-chloropyrimidine-3-oxide. 155 g (0.967 mol) of 2,4-diamino-6-chloropyrimidine-310 -oxide are mixed and stirred under an argon atmosphere with 640 ml of o-xylene and 260 ml (2.83 mol) of 1,2,5,6-tetrahydropyridine. The mixture is then heated to reflux for 30 minutes, the internal temperature rising from 115°C to 123°C. The mixture is then cooled to 5°C, treated with 40 g of sodium hydroxide in 400 ml of water and stirred at 5°C for 1 hour. The precipitate formed is filtered off, washed with 200 ml of water and recrystallised from 3000 ml of water, there being obtained pure 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide of melting point 263°20 -265°C (decomposition). g (0.218 mol) of 2,4-diamino-6-[3,6-dihydro-l(2H)-pyridyl]pyrimidine-3-oxide are mixed in 600 ml of methylene chloride with 90 ml of triethylamine and cooled to 5°C. 90 ml (1.14 mol) of chloroformic acid methyl ester are added dropwise while stirring. The mixture is stirred at 5°C for 30 minutes and at room temperature for 18 hours. Then, the mixture is treated with 100 ml of methanol and subsequently extracted with 400 ml of methylene chloride, washed with water, dried over potassium carbonate and evaporated under reduced pressure. Recrystallisation of the residue from methanol yields dimethyl 6-[3,6-dihydro-l(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide of melting point 2O2°-2O3°C.

The last-mentioned 3-oxide can also be prepared as follows: g (0.0965 mol) of 2,4-diamino-6-[3,6-dihydro-l(2H)-pyridyl]pyrimidine-3-oxide are suspended and stirred in 100 ml of-methylene chloride and 200 ml of water. While stirring, there are simultaneously added dropwise 25 ml (0.317 mol) of chloroformic acid methyl ester in 50 ml of methylene chloride and 30 ml of 28% sodium hydroxide so that the pH value is held between 7.5 and 8.5. After completion of the addition, the suspension is stirred for a further hour and the precipitate formed is subsequently filtered off. The filtrate is washed with methylene chloride and thereafter combined with the precipitate. The whole is recrystallised from methylene chloride/methanol, there being obtained dimethyl 6-[3,6-dihydro-l(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide of melting point 2O2°-2O6°C (decomposition).

B) 56 g (0.349 mol) of 2,4-diamino-6-chloropyrimidine-3-oxide in 500 ml of dimethylformamide and 100 ml of triethylamine are cooled to 0°C. 80 ml (1.015 mol) of chloroformic acid methyl ester are added dropwise while stirring - ll within 1 hour. After completion of the addition, the mixture is stirred for 48 hours. The precipitate is filtered off, suspended in a mixture of 2500 ml of methylene chloride and 500 ml of methanol and stirred for 80 minutes. The insoluble residue is filtered off and dried, there being obtained pure dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide of melting point 2O4°C (decomposition). The organic phase is washed with water and concentrated, a further amount of pure material being obtained.

A suspension of 10 g ¢0.036 mol) of dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 40 ml of methylene chloride is treated with 20 ml (0.22 mol) of 1,2,5,6-tetrahydropyridine and stirred at room temperature under an argon atmosphere for 16 hours. The resulting precipitate is filtered off and recrystallised from a mixture of methylene chloride and methanol, there being obtained pure dimethyl 6- [3,6-dihydro-l(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide of melting point 2O3°C.

The aforementioned 2,4-diamino-6-[3,6-dihydro-l(2H)~ -pyridyl]pyrimidine-3-oxide can also be prepared as follows: g (1 mol) of 1,2,5,6-tetrahydropyridine are mixed under an argon atmosphere with 113 g (1 mol) of cyanoacetic ester and heated to 110°C, the ethanol formed being distilled off continuously. After 18 hours, the mixture is distilled under reduced pressure, there being obtained N46319 -(2'-cyanoacetyl)-1,2,5,6-tetrahydropyridine of melting point 58°-59°C.

A solution of 25 g (0.167 mol) of N-(2*-cyanoacetyl)-1,2,5,6-tetrahydropyridine and 32.2 g (0.218 mol) of trimethyloxoniumtetrafluoroborate in 230 ml of dry methylene chloride is stirred under an argon atmosphere for 20 hours. The mixture is then poured into a cold solution of- 31.8 g of potassium carbonate in 34.5 ml of water and stirred at 0°C for 30 minutes. The organic phase is separated, washed with a potassium carbonate solution, dried over potassium carbonate and evaporated under reduced pressure. The residue is dissolved in 150 ml of ethanol under an argon atmosphere. The solution is treated with 6 g of cyanamide, stirred overnight and subsequently treated with 5 g of hydroxylamine hydrochloride and 15 g of potassium carbonate. The mixture is stirred at room temperature for 35 hours.

The precipitated salts are filtered off and washed with ethanol. The filtrate is evaporated and the residue is crystallised from water, there being obtained 2,4-diamino-6-[3,6-dihydro-l(2H)-pyridyl]pyrimidine-3-oxide of melting point 262°-266°C (decomposition).

Example 2 A) 30 g (0.145 mol) of 2,4-diamino-6-[3,6-dihydro-l(2H)-pyridyl]pyrimidine-3-oxide in 400 ml of methylene chloride are mixed with 65 ml of ethyldiisopropylamine and cooled to 5°C. The mixture is treated while stirring with 70 ml 463/9 (0.735 mol) of chloroformio acid ethyl ester and stirred at 5°C for 30 minutes and subsequently at room temperature for 13 hours. The mixture is extracted with 200 ml of methylene chloride, washed with 200 ml of water, dried over potassium carbonate and evaporated under reduced pressure. Recrystallisation of the residue from ethanol yields diethyl 6-[3,6-dihydro-l(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide of melting point 154°-155°C.

B) 20.7 g (0.1 mol) of 2,4-diamino-6-[3,6-dihydro-l(2H)10 -pyridyl]pyrimidine-3-oxide are mixed with 250 ml of methylene chloride and 35 ml of triethylamine and cooled to 5°C. 40 ml (0.308 mol) of chloroformio acid isobutyl ester are added dropwise while stirring. After completion of the addition, the mixture is stirred at 5°C for 15 minutes and then at room temperature for 2 hours. The solution is treated with 200 ml of water and extracted with methylene chloride. The organic phase is evaporated and the residue is crystallised from ethanol. There is obtained diisobutyl 6-[3,6-dihydro-l(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-320 -oxide of melting point 137°-139°C (decomposition).

C) 20 g (0.0965 mol) of 2,4-diamino-6-[3,6-dihydro-l(2H)-pyridyl]pyrimidine-3-oxide are mixed with 250 ml of methylene chloride and 35 ml of triethylamine, stirred and cooled to 5°C. The mixture is treated with 45 ml (0.345 mol) of chlarofoxmic acid n-butyl ester and stirred at room temperature for 6 hours. The mixture obtained is washed with water, extracted with methylene chloride and evaporated - 14 under reduced pressure. The residue is recrystallised from ethanol, there being obtained di-n-butyl 6-[3,6-dihydro-l(2H) -pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide of melting point 131°-132°C.

D) 10 g (0.0484 mol) of.2,4-diamino-6-(3,6-dihydro-l(2H)-pyridyl]pyrimidine-3-oxide are suspended in 150 ml of methylene chloride and 20 ml o.f triethylamine. The suspension is cooled to 5°C and 28 g (0.145 mol) ox chloroformic acid octyl ester are added dropwise while stirring.

The mixture is cooled for 30 minutes and then stirred at room temperature for 1 hour. The mixture is extracted with methylene chloride, washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue is recrystallised from methylene chloride/ethanol, there being obtained dioctyl 6-[3,6-dihydro-l(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide of melting point 64°C.

E) 10 g (0.0484 mol) of 2,4-diamino-6-(3,6-dihydro-l(2H)-pyridyl]pyrimidine-3-oxide are stirred at 5°C in 150 ml of methylene chloride and 30 ml of triethylamine and treated with 20 ml (0.173 mol) of chloroformic acid 2-methoxyethyl ester. The mixture is stirred at room temperature for 4 hours, then washed with water and extracted with methylene chloride. The organic phases are evaporated under reduced pressure and the residue is recrystallised from diethyl ether, there being Obtained bis(2-methoxyethyl) 6-(3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide of melting point 126°-128°C.

Claims (10)

1. ) Pyrimidine derivatives of the general formula (I) wherein R represents an alkyl or alkoxyalkvl group and Rj represents the 1,2,5,6-tetrahydropyridin-l-yl group or a chlorine atom.

2. ) Pyrimidine derivatives of formula I given in claim 1, wherein represents the 1,2,5,6-tetrahydropyridin-l-yl group.

3. ) Pyrimidine derivatives according to claim 1 or claim 10 2, wherein R represents an alkyl group.

4. ) Pyrimidine derivatives according to claim 3, wherein R represents an alkyl group containing 1-4 carbon atoms.

5. ) Dimethyl 6-[3,6-dihydro-l(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide. 15

6. ) Diethyl 6-(3,6-dihydro-l(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide.

7. ) Diisobutyl 6-[3,6-dih.ydro-l(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide.

8. ) Di-n-butyl 6-[3,6-dihydro-l(2H)-pyridyl]-2,4-pyrimidine -dicarbamate-3-oxide. 5

9. ) Dioctyl 6-[3,6-dihydro-l(2H)-pyridyl]-2,4-pyrimidine-di carbamate-3-oxide.

10. ) Bis(2-methoxyethyl) 6-[3,6-dihydro-l(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide.