DE2352107A1 - NEW CHEMICAL COMPOUNDS, THEIR PRODUCTION METHODS AND APPLICATIONS OF THESE COMPOUNDS, IN PARTICULAR TO THE SYNTHESIS 2,4-DIAMINO- (3 ', 4', 5'-TRIMETHOXY-) 1-BENZYL-PYRIMIDINE - Google Patents

Description

ΡεθΑΡΊο

MR / HB / UMR / 23.154 .... / · .-., .., - Kp,
.7.08. 1973 c ·:. ·.! - · - ^ rnan ZJDZlU /

6 iViüiic ».. ,,: L, Kosental7
Tel. 2ΙΘ39Θ9

Societe d'Etudes Chimiques, abbreviated SOCECHIM 2, rue Goethe

LUXEMBOURG (Grand-Duche de Luxembourg)

"New chemical compounds, their manufacturing processes and applications of these compounds, especially in synthesis 2,4-diamino (3 ', 4', 5'-trimethoxy) 1-benzyl pyrimidine. "

The present invention deals with new chemical compounds and the process for their preparation. It also affects several Applications of these new compounds that enable the formation of other compounds that are also new, and the preparation in a new way of known compounds, such as 2,4-diamino- (3 ', 4', 5'-trimethoxy-) 1-benzyl-pyrimidine, .das is used because of its pharmacological peculiarities.

The novel compounds according to the invention consist of the 4-amino-2,6-diOXy- (di- or trialcoxy-) 1-benzyl-pyrimidines following formula:

409846/1037

(RO)

where η is an integer and equal to 2 or 3 and R is is lower radical alkyl, preferably having 1 to 4 carbon atoms owns.

These compounds can in particular by condensation of alkyl (di- or trialcoxy) benzyl malonate of the following formula to be prepared:

OR '

with the guanidine NH =

where R 'is a lower radical alkyl with preferably 1 to 4 Means carbon atoms.

In a special production method according to the invention the mentioned compound of 2-amino-2,6-dioxy- (3 ', 4', 5 '· Trimethoxy-) 1-benzyl-pyrimidine formed with the following formula:

409846/1 037

HO

Said condensation reaction proceeds preferably in an alcoholic agent, for example in solution in ethanol.

A first application of the compound according to the invention consists in the preparation of the 4-amino-2,6-dihalogen (di- or Trialcoxy-) 1-benzyl-pyrimidines of the following formula:

X (RO) _n

> C \

CH ₂ ρ _N

X ^^ ^N 'NH ₂

in which X represents a halogen. The preparation takes place by the action of a suitable halogenating agent on the mentioned Links. In a preferred embodiment X represents chlorine and the corresponding compounds are formed by the action of a chlorinating agent such as phosphorus oxychloride POCL ^ or phosphorus pentachloride PCLf- prepared.

Another application of the present invention is in the preparation of 2,4-diamino-6-halo (di- or trialcoxy) 1-benzyl-pyrimidines of the following formula:

409846/1037

in which X represents a halogen, the 4-amino-2,6-dihalo (di- or trialcoxy-) 1-benzyl-pyrimidine subjected to selective amination, for example using liquid ammonia will.

Some of the products obtained in this way are already known, such as 2,4-diamino-6-ChlO3K 3 ', 4', 5 ^f -trimethoxy-) 1-benzyl-pyrimidine, which is the 2,4-diamino- (3'j 4 ', 5'-trimethoxy-) 1-benzyl-pyrimidine can provide,

which has pharmacological properties. In an analogous way it is possible, any member of the family of the 2,4-diamino- (di- or trialcoxy-) 1-benzyl-pyrimidines by dehalogenation corresponding 2,4-diamino-6-halo (di- or trialcoxy) 1-benzyl-pyrimidines.

The starting compound of the main process on which the present invention is based, namely the alkyl (di- or trialcoxy) benzyl malonate, can be prepared by malonic condensation according to a process known per se, which is described by Nathan L. DRAKE and William B. TUEMMLER in "Podophyllotoxin and Picropodophyllin. The Synthesis of an Open Chain Analog "(J. Amer. Chem. Soc. 77 , 1206; 1955) for the preparation of ethyl (3, 4, 5-trimethoxy) benzyl malonate starting from (3> 4, 5-trimethoxy-) benzyl chloride and of ethyl malonate. It should be remembered here that the (3 * 4, 5-trimethoxy) benzyl chloride itself can be prepared by the action of a suitable chlorinating agent, e.g. thionyl chloride SOCLp on (3, 4, 5-trimethoxy) benzylic alcohol, which in turn can e.g. by the action of released hydrogen (Na + ethyl alcohol) on an alcoyl-3, 4, 5-trimethoxy-benzoate (reaction of Bouveault and Blanc) or by the action of lithium aluminum hydride

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ORIGINAL. iNöPECTED

LiALH. prepared on the (3, 4, 5-trimethoxy) benzotrichloride will. These reactions can be carried out under the same conditions, using dimethoxy derivatives instead of trimethoxy derivatives assumed and / or a lower Alkoylmalonat is used, which is different from Ethylmalonat.

The (di- or trialcoxy) benzyl malonates obtained in this way represent new compounds, with the exception of the ethyl (3, 4, 5-trimethoxy) benzylmalonate already described. These new compounds were sought in this form by the present invention.

Without departing from the scope of the present invention, one could also prepare compounds of the following form:

(RO) OH

ix ■

in which R and η have the meaning already mentioned and m is an integer equal to the numbers 2, 3 or 4. Analogous compounds could also be prepared in which the phenyl group contains one or more aromatic, alicyclic, saturated or unsaturated aliphatic and possibly halogenated radicals, acyls, NO ₂ , NH ₂ 'halogens, etc. in place of 2 or 3 alcoxy substituents. could own.

Those produced in this way by the halogenation processes Compounds also represent new products which are the subject of the present invention.

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Other objects, features and advantages of the present invention will be made clear in the following description, in which some embodiments of the invention are explained.

EXAMPLE I

Preparation of 4-amino-2,6-dioxy- (3 ', 4 ¹ , 5'-trimethoxy-) 1-benzyl-pyrimidine by condensation of guanidine on ethyl- (3> 4-j 5-trimethoxy-) benzylmalonate.

Ethyl (3 , 4, 5-trimethoxy) benzyl malonate occurs in the form of whitish crystals that melt at 78-79 ° C.

In a flask with a capacity of one liter, which is provided with three extension tubes, which a cooling system, or a Dry system based on CaClp adapted a stirring device is, 10 g (0.147 mol) of sodium ethylate, 250 ml of anhydrous Ethanol added, after which 50.0 g (0.147 mol) of ethyl (3, 4, 5-trimethoxy) benzyl malonate be dissolved in the solution thus obtained.

Separately, a solution of 10 g (0.147 mol) of sodium ethylate is added prepared in 100 to 200 ml of anhydrous ethanol and 14.2 g (0.149 mol) of guanidine chlorohydrate were added to this solution. In a nitrogen atmosphere, the sodium chloride that becomes forms, filtered and washed with small amounts of anhydrous ethanol, so that the volume of the now clear solution that by combining the original filtrate and the washing liquid, does not contain more than 250 ml of ethanol. This clear solution is added to the solution in the flask equipped with three tube connections and the whole is heated to reflux, the reflux being maintained for between 12 and 18 hours, preferably for about 15 hours.

4098 4 6/1037

The ethanol is then separated out by vacuum distillation and 300 ml of water are added to the distillation residue with stirring. The mixture is then made with a 10 percent strength Hydrochloric acid solution acidified "until a pH of 4 to 5 adjusts itself. A white precipitate then forms, which is secreted by filtration, then with water and finally lent washed with a water-alcohol mixture (50/50). The solid body is under vacuum at 50 ° C for a whole Dried overnight.

In this way, 31.5 g of 4-amino-2,6-dioxy (3, 4, 5-trimethoxy) 1-benzylpyrimidine (yield: 70 %) , which melts at 312-314 ° C., are obtained.

EXAMPLE II

Preparation of ethyl (3 , 4,5-trimethoxy-) benzyl malonate.

This compound is produced by the condensation of (3, 4, 5-trimethoxy) benzyl chloride Prepared on ethyl malonate following a malonic condensation process.

This condensation is described below after briefly referring to the preparation of 3, 4, 5-trimethoxy-benzyl chloride is received.

a) Preparation of (3, 4, 5-trimethoxy) benzylic alcohol.

This alcohol is produced by catalytic reduction of the corresponding chlorocarbonylated derivative, which is an unstable compound, with the help of lithium aluminum hydride LiAlH / manufactured.

The following procedure is used, for example: In a flask with three tube attachments with a capacity of 2 Liters becomes a slurry of

17> 3 g LiAlHi made in 215 ml anhydrous tetrahydrofuran. ⁴ 409846/1037

This slurry or suspension under nitrogen and is maintained with stirring, a solution of 100.0 g (3, 4, 5-trimethoxy-) Benzotrichloride fed in 250 ml of anhydrous tetrahydrofuran. When this addition is complete, the reflux temperature is maintained for two and a half hours. Then you let Cool the lithium aluminum hydride excess and destroy it by adding water drop by drop. The reaction mixture then sets.

The organo-aluminum intermediate compound obtained is then hydrolyzed by adding 500 ml of aqueous solution with 10% sulfurous acid. When the hydrolysis is complete, the whole is stirred for 30 minutes, after which the reaction mixture becomes liquid. The water phase is drawn out with the help of 1.5 l of ether (the amount is added in three times). The organic phase is separated and then washed with approximately 500 ml of an aqueous solution containing 5 % sodium bicarbonate. It is then washed with water until the wash water is neutral.

This organic phase is then dried over anhydrous calcium sulfate, after which the ether is deposited by vacuum evaporation will.

In this way, 48.6 g (yield: 57 %) of (3, 4, 5-trimethoxy) benzylic alcohol are obtained in the form of an oily, practically colorless mass. The crude product thus obtained can be used for phase b) described below.

b) Preparation of (5, 4, 5-trimethoxy) benzyl chloride.

This compound is prepared by chlorination, for example with the thionyl chloride SOC1 "of (3 _S 4, 5-trimethoxy) benzylic alcohol.

The procedure is as follows

409846/1037

In a flask with three Ronran attachments and one capacity of 1 liter is a solution of 48.6 g (0.246 mol) (3, 4, 5-trimethoxy) benzylic Alcohol and 30.3 g (0.250 mol) of N, N-dimethylaniline prepared in 320 ml of anhydrous benzene. This Mix slowly, with stirring and after the flask has been placed in an ice bath, 29.4 g (0.247 mol) of thionyl chloride added in 75 ml of anhydrous benzene. After this addition is complete, the flask is removed from the ice bath and the reaction mixture is allowed to warm to ambient temperature. After that it is refluxed for about one Hour is maintained, heated, after which the whole is then allowed to cool to ambient temperature and then 100 ml hydrochloric acid diluted to 1/5 is added.

The organic phase is separated by pouring off and Washed under water until the washing water is neutral the benzene is separated out by vacuum distillation and in this way 49.8 g (size-wise yield) of one are obtained whitish mass from crude (3, 4, 5-trimethoxy) benzyl chloride is formed.

This crude product is recrystallized from petroleum ether and obtained in this way 44.75 g (yield: 85%) of pure (3, 4, 5-trimethoxy) benzyl chloride, which melts at 59-61 ⁰ C.

c) Maloni condensation

The condensation of the ethyl malonate on the after in b) process described prepared (3, 4, 5-trimethoxy-) benzyl chloride takes place e.g. in the following way:

In a flask with a capacity of 1 liter, which is provided with three tube attachments, a solution of 5.3 g of NaOH is made from one 95% purity (0.209 mol) prepared in 190 ml of ethyl malonate. Then, slowly and with stirring, a solution becomes in one hour of 44.75 g (0.206 mol) (3, 4, 5-trimethoxy) benzyl chloride (in-

409846/1037

stable compound) added, fresh in 120 ml of ethyl malonate was prepared.

Thereafter, the reaction mixture is heated to 105-110 ⁰ C for 20 hours. Finally, it is cooled and a few drops of ice-cold acetic acid and then 17 ml of water are added. The solution is clarified and then fed onto glass wool and finally onto sintered glass.

The excess of ethyl malonate is precipitated by vacuum distillation, after which the pasty residue obtained by the distillation is recrystallized in the hexane. After three recrystallizations to obtain 56.0 g of pure ethyl (3, 4, 5-trimethoxy) benzyl malonate (yield: 80%), vorliegt- the whitish in the mold, melting at 78-79 ⁰ C crystals.

EXAMPLE III

Production of 4-amino-2,6-dichloro (3 '»4', 5'-trimethoxy-) 1-benzyl pyrimidine.

This compound is prepared by the chlorination of the corresponding dihydroxated derivative, namely that prepared in Example I. 4-amino-2,6-dioxy- (3 ', 4', 5'-trimethoxy-) 1-benzyl-pyrimidine, prepared.

In a 250 ml flask equipped with three raw approaches, one with a condenser and another with a stirrer and the remaining one is provided with a drying device based on CaClp, 30.0 g (0.098 mol) 4-amino-2,6-dihydro- (3 "4,5'-trimethoxy-) 1-benzyl-pyrimidine, 125 ml (1.37 mol) POCl ,, e.g. a large excess of this chlorinating agent, and 1 ml of N, N-dimethylaniline (catalyst) fed. Then the mixture is heated to the reflux temperature and the reflux 5 to 9, preferably 7 Maintained for hours. The excess POCl is then separated off by distillation. The distillation return

409846/1037

stand, which is in the form of a very watery mass.e brown in color, is poured into a container that is an ice column contains. This container is vigorously stirred for half a day (the aqueous mass is very difficult to crystallize).

The reaction mixture is made alkaline to a pH value in the order of magnitude of 10 with the aid of a saturated Na ₂ CO 2 solution in order to prevent the desired product from falling out. -Then the brownish precipitate that forms is filtered and afterwards washed in water and dried.

In this way, 20 g of the desired product (yield: 60%), which melts at 182-184 ° C., are obtained.

EXAMPLE IV

Production of 2,4 ~ diamino-6-chloro- (5 ', 4', 5 '-Trimethoxy-) 5-benzyl pyrimidine.

This compound is prepared by selective amination of the compound prepared in Example III.

10 g (0.029 mol) of 4-amino-2,6-dichloro (3 ', 4 ¹ , 5'-trimethoxy) 1-benzyl-pyrimidine are placed in an autoclave with a capacity of 1 liter. Then add 500 ml of absolute ethanol and saturate this solution with 100 ml of liquefied ammonia at a lower temperature of 5 ° C.

The autoclave is closed and heated to a temperature in the order of 120 to 200 ⁰ C under a pressure of 20 to 60 atmospheres for a heating time in the order of 10 to 22 hours, for example at 160 ° C for 16 hours, so that the Pressure rises to 40 atmospheres. Thereafter, the heating is stopped and the temperature and pressure are allowed to return to their initial values, which takes about 20 more hours. The ethanol is separated out by vacuum distillation. The solid residue of the distillation is in an aqueous

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2352: 07

Acetic acid solution dissolved, after which the whole thing is brought to a pH on the order of 12, e.g. by adding a concentrated sodium hydroxide solution. A precipitate forms which is filtered and air dried. One receives on this way 6.6 g of crude product.

After recrystallization in alcohol to obtain the desired product, which melts at 212-213 ^0C.

EXAMPLE V

Production of 2,4-diamino (3 ' , 4 ', 5'-trimethoxy-) 1-benzyl-pyrimidine.

This known compound, which is the active principle of known medicaments, is prepared by dechlorinating the 2,4-diamino-6-chloro (3 ', 4 ¹ , 5'-trimethoxy) 1-benzyl-pyrimidine which is used in Example IV was made.

In a 250 ml flask, 5.0 g (0.0154 mol) of 2,4-diamino-6-chloro (3 ', 4', 5'-trimethoxy) 1-benzyl-pyrimidine, 40 ml of NaOH are successively added Entered 1N and 10 g of zinc powder. The mixture is ^{heated to approximately 40 °} C. for approximately 14 hours with thorough stirring. Then the whole thing is allowed to cool to ambient temperature and finally 150 ml of ethyl acetate are added. The excess zinc powder is filtered out and the filtration residue is washed with ethyl acetate and then with water. The organic phase of the aqueous phase is separated by pouring off. The organic phase is dried over anhydrous calcium sulfate. The solvent is then eliminated by vacuum distillation of the organic phase mentioned. 2.8 g of a brown residue (efficiency: 80 %) are obtained in this way, which consists of impure 2,4-diamino- (3'j 4 ', 5'-trimethoxy-) 1-benzyl-pyrimidine.

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ORlGiMAL! MSPEGTED

After recrystallization in a mixture of 25 ml of ethanol and 5 ml of water, crystals are obtained which melt at 212-214 ° C. and which are known as 2,4-diamino-6-chloro- (3 ' , 4', 5'-trimethoxy -) 1-Benzyl-pyrimidine indicates. The crystals mentioned were obtained by dosing nitrogen, dosing chlorine, examining the infrared spectrum and the nuclear, ■ magnetic! Resonance spectrum.

The mother liquor of the above recrystallization allows the deposition of brown crystals of 2,4-diamino- (3 ', 4 ^1, 5'-trimethoxy) 1-Benzyl-pyrimidine, melting at 202-204 ⁰ C (this fusion point is identical with the one given in the literature).

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Claims (22)

-Ί4 - PATENT CLAIMS New chemical compounds, characterized in that they are derived from the 4-amino-2,6-dioxy (di- or trialcoxy-) 1-benzyl-pyrimidines of the following formula are formed: (RO) in which η is a number equal to the numbers 2 or 3 and R is a lower radical alcoyl preferably having 1 to 4 carbons offat omen i st. 2. Compound according to claim 1, characterized in that it is formed from 4-amino-2,6-dioxy- (3 ' , 4', 5'-trimethoxy-) 1-benzyl-pyrimidine of the following formula: H ₃ CO H ₃ CO OH HO NH, 409846/1037 3. - Process for the preparation of the compounds according to claim 1, characterized in that an alcoyl (di- or trialcoxy) benzyl malonate of the following Formula: (RO) J. X O ) CH η η OR ' OR ' with the guanidine NH = is condensed, where R 'is a lower alcoyl radical with preferably 1 to Is carbon atoms. 4. - The method according to claim 1, characterized in that said condensation in one alcoholic medium, e.g. in solution in ethanol »when heated to a temperature which is at most equal to the reflux temperature, e.g. for a period of 12 to 18 Hours at this reflux temperature. 5. - The method according to claim 3 or 4, characterized j that the guanidine is added in the form of its chlorohydrate, and that this is done beforehand treated with an excess of sodium ethylate to to regenerate the free base. 409Ö4S / 1 037 6. - The method according to claim 5, characterized in that the product can be obtained by distilling alcohol, adding water to the distillation residue and adding hydrochloric acid up to a pH value in the order of 4 to 5 to destroy the excess sodium ethylate is. 7. - Application of the compounds of claim 1 to the preparation of 4-amino-2,6-dihalo (di- or trialcoxy) 1-benzyl-pyrimidines the formula: (O> - CH in which X represents a halogen, characterized in that a halogenating agent for acting on the compounds mentioned is brought. 8. - Use according to claim 6, characterized in that when X is chlorine, a Chlorinating agents such as phosphorus oxychloride POCl ,, or Phosphorus pentachloride PCIc is used. 40984 6/1037 9. - Application according to claim 7> characterized that at a temperature which is at most equal to the reflux temperature, e.g. equal to the The reflux temperature is for a period of 5 to 9 hours in the presence of an excess of a halogenating agent works, which is precipitated by distillation at the end of the reaction, after which the residue in alkalized in an aqueous medium up to a pH value of the order of magnitude of 10 in order to prevent precipitation of the desired product. 10. Application of the compound of claim 1 to the preparation of 2,4-diamino-6-halo (di- or trialcoxy) 1-benzyl pyrimidines of the formula: (RO) _n NH ₂ NH ₂ in which X represents a halogen, characterized in that in a first step a halogenating agent for Action on the compounds mentioned is brought to the 4-amino-2,6-dihalogeno- (di- or trialcoxy-) 1-benzyl-pyrimidines which are subjected to selective amination in a second step. 11.- Application according to claim 10, characterized in that liquid ammonia is used, to carry out the selective amination process when working in an alcoholic medium. 409846/10 3 7 12. - Use according to claim 11, characterized in that in the selective amination work phase at a temperature in the order of 120 to 200 ⁰ C, under a pressure of 20 to 60 atmospheres and for a time in the order of 10 to 22 Working hours in an alcoholic environment. 13. - Application according to claim 11, characterized that one in the said selective amination work phase at a temperature in the On the order of 160 ° C, under a pressure of approximately 40 atmospheres and works for a period of 16 hours. 14. - Application according to claim 11, characterized that you can get the desired product by distilling the alcohol by dissolving the residue in aqueous acetic acid, by alkalinization up to a pH value in the order of magnitude of 12 and obtained by depositing the formed repetition. 15. Application of the products of claim 10 to the preparation of 2,4-diamino (di- or trialcoxy) 1-benzyl pyrimidines by dehalogenisation of the products mentioned, e.g. with the help of zinc powder. 16. - Application of the products of claim 10 to the preparation of the 2,4-diamino (3 ^f , 4 ', 5'-trimethoxy) 1-benzyl-pyrimidines by dehalogenation of the 2,4-diamino-6-halogen (3 ', 4', 5'-trimethoxy-) 1-benzyl-pyrimidines, in particular by dechlorinating the 2,4-diamino-6-chloro (3 ', 4', 5'-trimethoxy) 1-benzyl -Pyrimidines. 409846/1037 ORiGiMAL INSPECTED 17 · - Method according to one of claims 3 to 16, characterized . characterized in that said alcoyl (di- or trialcoxy) benzylinalonate by the action of a Alcoylmalonates to the corresponding (di- or trialcoxy) benzyl chloride is prepared. 18. - The method according to claim 17, characterized in that said (di- or trialcoxy) benzyl chloride is prepared by the action of a chlorinating agent, for example thionyl chloride SOCl ₂ on the (di- or trialcoxy) benzylic alcohol. 19. - The method according to claim 15, characterized in that de.r said (di- or trialcoxy) "Benzylic alcohol by the action of the ethylic Sodium-alcohol mixture to the corresponding alcoyl- (Di ~ or trialcoxy) benzoate or by the action of lithium aluminum hydride LiAlH, on the appropriate (di- or trialcoxy) benzoyl chloride is prepared. 20. - New compounds, characterized in that they differ from the 4-amino-2,6-dihalogen (di- or trialcoxy-) 1-benzyl-pyrimidines are formed, from the formula: X (RO) _n <O) CH 409846/10 37 ORIGINAL INSPECTED 235210 in which η is an integer 2 or 3, R is a lower alcoyl-. radical with preferably 1 to 4 carbon atoms and X is a halogen. 21. - New compound, characterized in that it is derived from the 4-amino-2, -6-dichloro (3 ', 4', 5'-trimethoxy-) i-benzyl-pyrimidine the formula: is formed. 22.- New compounds, characterized in that they correspond to the formula: (RO) CH. —OR ' fi ^H C-OR ¹ 0 in which R is a lower alcoyl radical with preferably 1 to 4 carbon atoms, η is an integer equal to 2 or 3 and R 'is a lower radical aleoyl with preferably 1 to 4 carbon atoms, with the proviso that when R'-C _{2 is} Hf-, R and n, seen as a whole, are not -CH, and 3 represent. 409846/1037 ORIGINAL INSPECTED