KR820001338B1 - Process for preparation of benzyl pyrimidines - Google Patents

Abstract

Benzyl pyrimidines(I; R1, R2,R3 = H, methyl, methoxy, Cl; R4 = C1-6 alkoxy, aryloxy, cyclohexaory or benzyloxy substituted methyl, phenyl, chlorophenyl, hydroxyl, C1-2 alkoxy, dialkylamino, 3-alkylisoxazolyl-5-methyl; Hal is halogen), having antibiotic activity, were prepd. by reacting compd. (II) with compd. (III). Thus, 2,4-diamino-5-(3,4,5- trimethoxy benzyl)-pyrimidine 5.8 g was dissolved in pyridine 60 ml at 60≰C, chlorodimethyl ether 3.0 ml was added and then pyridine was eliminated by distillation under reduced pressure. The residue was recrystallized with ethanol 250ml to give 2-methoxymethylamino-4-amino-5-(3,4,5-trimethoxylbanzyl)-pyrimidine HCl 15.5 g (m.p. 227≰C).

Description

[Name of invention]

Method for preparing benzyl pyrimidine

Detailed description of the invention

The present invention relates to novel benzyl pyrimidines such as the following general formula (I) and pharmaceutically acceptable addition salts of these with acids.

Wherein R ¹ , R ² and R ³ are the same or different from each other and represent hydrogen, methyl, methoxy, or chlorine. R ⁴ is a linear or branched, saturated or unsaturated alkyl group having 1-6 carbon atoms, wherein the carbon chain may be interrupted by 1-3 oxygen atoms, and some of those carbon atoms are alicyclic having 5-6 carbon atoms. It may form a ring and may also be substituted by a chlorine atom, hydroxyl group, or secondary amino group, wherein nitrogen also forms part of the cycloaliphatic amine. And R ⁴ is -alk-R ⁵ (where alk is a straight or branched chain alkylene having 1-4 carbon atoms) R ⁵ is a phenyl group which may be substituted by chlorine or an alkyl group having 1-4 carbon atoms Or a heteroaromatic ring containing one or two oxygen and nitrogen atoms.

Substituent R ⁴ includes methoxymethyl, n-butyloxymethyl, cyclohexoxymethyl, β-chloroethyloxymethyl, β-ethoxy ethoxymethyl, β-methoxyethoxymethyl, β-chloro-α-methyl- Ethoxymethyl, β-dimethylaminoethyl, β-morpholinoethyl, β-pyrrolidinoethyl, 3-dimethylaminofulotyl, allyloxymethyl, benzyl, 4-chlorobenzyl, phenethyl, 3-methylisooxa There are zolyl-2-methyl, 3-tertbutylisoxazolyl-2-methyl and β-hydroxyethyl groups.

Among the compounds of formula (I), it is noteworthy that R ⁴ is an alkoxy group having 1-6 carbon atoms (alkyl thereof may be further substituted by a chlorine atom or an alkoxy group having 1-2 carbon atoms), allyl Methyl substituted by oxy, or cyclohexoxy or benzyloxy groups, or phenyl, chlorophenyl, hydroxyl, alkoxy, dialkylamino having 1 or 2 carbon atoms, wherein alkyl has 1 or 2 carbons. A pyrrolidino, or a methyl group substituted by a morpholino group, or a compound which is a 3-alkylisooxazolyl-5-methyl group wherein alkyl has 1-4 carbon atoms. Usually substituents R ¹ , R ² and R ³ are in the 3-, 4- and 5-positions of the benzene ring.

Common among the compounds of formula (I) are those wherein R ⁴ is -alk-OR ⁶ , wherein R ⁶ is hydrogen, a straight or branched chain alkyl group having 1-6 carbon atoms and the alkyl is chlorine, or 1-4 It may be substituted by a lower alkoxy group having a carbon atom, clohexyl, phenyl, or benzyl group and alk is a straight or branched chain alkylene group having 1-4 carbon atoms.

Particularly common are compounds of formula (I), wherein R ¹ , R ² and R ³ are methoxy groups. Compounds of formula (I) and salts thereof have antimicrobial activity against diseases caused by bacteria and protozoa, and when combined with sulfonamide, have bactericidal activity. They can be used for the treatment of infectious diseases such as, for example, bacterial infections of the respiratory, digestive and urinary tracts, infectious diseases of the throat, nose and ears, and other malaria.

Examples of suitable sulfonamides include 2-sulfanylamidopyrimidine, 2-sulfanyl amido-5-methoxypyrimidine, 4-sulfanylamido-2,6-dimethoxypyrimidine, 3-sul Panylamido-5-methoxyisoxazole, 2-sulfanamido-4,5-dimethyloxazole, 3-sulfanamido-6-methoxypyrazine, 4-sulfanylamido-2,6 -Dimethylpyrimidine, 4-sulfanylamido-5,6-dimethoxypyrimidine and 2-sulfanylamido-3-methoxypyrazine.

Common acids used to prepare pharmacologically acceptable salts include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, lactinic acid, tartric acid and citric acid.

However, hydrochloric acid and sulfuric acid are particularly common among the aforementioned inorganic acids, which form salts which crystallize well with the compounds of the present invention.

Compounds of formula (I) and salts thereof may be combined with sulfonamides in a ratio of 1: 10-5: 1. Usually, the ratio of 1: 1-1: 5 is common. Appropriate amounts are those containing 20-500 mg of compound of formula (I).

The compound of the present invention as general formula (I) is prepared by the following method.

a) The compound of general formula (II) is reacted with the compound of general formula (III).

Or b) reacting a compound of formula (IV) with a compound of formula (V).

Or c) reacting a compound of formula (VI) with a compound of formula (V).

Hal is a halogen such as Cl or Br, X is a leaving group and R ⁷ and R ⁸ are lower alkyl.

Methods a) -c) do not contain any limitations on various conventional synthetic methods, including cycling reactions with compounds of formula (V).

The reaction in method a) is generally carried out at a temperature of 0-200 ° C. depending on the reactivity of the compound of formula (II) in the presence of an aprotic diluent such as dioxane, tetrahydrofuran, benzene, chlorobenzene, chloroform, or pyridine. Is done.

The reaction in process b) is carried out at a temperature of 50-150 ° C. using an alcohol such as methanol or ethanol or dimethylformamide or dimethyl sulfoxide as solvent. When leaving group X is a slowly reacting aliphatic amino group, a temperature of about 150 ° C is required. The leaving group of the compound of formula (IV) is alkoxy, usually methoxy, ethoxy or secondary aliphatic amino group, usually morpholino or dimethylamino group, or primary aromatic amino group, usually an alino group or imidazole-1-yl group. .

In order to illustrate the action of the compound according to the present invention, an infectious disease caused by asymptomatic streptococci was tested using an Aronson sepsis model and compared with the conventional drug Trimethoprim. Thirty female rats were infected with a lethal dose of S. aureus 1941 and treated 2 hours later with a mixture of 300 mg of 2-sulfanamido-4,5-dimethyloxazole and 60 mg of the compound according to the invention. In addition to the untreated comparative group, the second group was treated with a mixture of 300 mg of 2-sulfanamido-4,5-dimethyloxazole and 60 mg of trimetatrim (reference material). After 44 hours, the number of live animals was measured and divided by the number of surviving animals from the flock treated with the reference material. The value obtained here (trimethoprim factor) is the degree of action of the compound according to the invention compared to trimetoprim. That is, F = 2 means that the compound is twice as active as the trimethoprim.

The following table shows that the compounds according to the invention are up to three times better than trimetaprim.

TABLE 1

The present invention also relates to the use of a compound of formula (I) as a active ingredient, in particular chemotherapeutic agents and sulfonamide pharmaceuticals containing a compound of formula (I) in combination with sulfonamide and a conventional carrier and excipient. Chemotherapeutic agents are prepared in conventional manner using known carriers or excipients and conventional adjuvant agents, depending on the intended route of administration.

General preparations are those suitable for oral administration such as tablets, film tablets, dragees, capsules, pills, powders, solutions and suspensions.

Example 1

2-methoxymethylamino-4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine hydrogen chloride.

5.8 g of 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine was dissolved in 60 ml of pyridine at 60 ° C. and 3.0 ml of chlorodimethyl ether was added dropwise to the solution at the same temperature. The pyridine was then distilled off under reduced pressure and the residue was recrystallized from 250 ml of ethanol to give 2-methoxymethylamino-4-amino-5- (3,4,5-trimethoxybenzyl) -pyridine at a melting point of 227 ° C. 5.5 g of midine HCl (74% of theory) were obtained.

Example 2

2-cyclohexoxymethylamino-4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine hydrogen chloride

After dissolving 5.8 g of 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine in 80 ml of dioxane at 80 ° C., 2.97 g of chloromethyl cyclohexyl ether was added dropwise to this solution. The mixture was stirred at 90 ° C. for 30 minutes. After cooling, ether was added to the precipitate, which was then recrystallized from methylglycol to give 6.8 g of 2-cyclohexoxymethyl amino-4-amino-5- (3,4,5-triethoxybenzyl) -pyrimidine HCl at a melting point of 208 캜. (77% of theory was obtained).

The following compounds were prepared according to the methods of Examples 1 and 2.

3. 2-Ethoxymethylamino-4-amino-5- (2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine and chloromethylethyl ether at a melting point of 206 캜; 3,4,5-trimethoxybenzyl) -pyrimidine. HCl.

4. 2-n-propoxymethylamino-4- at melting point 249 ° C. from 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine and chloromethyl n-furophyll ether Amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine. HCl.

5. 2-n-butoxy methylamino-4-amino at melting point 235 ° C. from 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine and chloromethyl n-butyl ether -5- (3,4,5-trimethoxybenzyl) -pyrimidine. HCl.

6. 2,4-Diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine and chloromethyl. 2-n-hexoxymethylamino-4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine at a melting point of 228 ° C. from n-hexyl ether. HCl.

7. 2-allyloxymethylamino-4-amino-5 at melting point 220 ° C. 222 ° C. from 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine and chloromethyl allyl ether -(3,4,5-trimethoxybenzyl) -pyrimidine. HCl.

8. From 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine and chloromethyl β-chloroethyl ether, (β-chloroethoxymethyl amino 0- at a melting point of 218 ° C. 4-Amino-5- (3, 4, 5-trimethoxybenzyl) -pyrimidine HCl.

9. From 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine and chloromethyl 2-chloro-1-methyl ethylether, 2- (2-chloro at a melting point of 230 ° C. -1-methyl-ethoxymethylamino) -4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine. HCl.

10. 2-benzyloxymethyl amino-4-amino-5- (, melting point 227 ° C. from 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine and chloro methylbenzyl ether 3,4,5-trimethoxybenzyl) -pyrimidine. HCl.

11. 2- (β-methoxyethoxymethyl, melting point 226 ° C. from 2,4-diamino-5- (3,2,5-trimethoxybenzyl) -pyrimidine and chloromethyl β-methoxy ethyl ether Amino) -4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine. HCl.

12. 2- (β-ethoxyethoxymethyl at a melting point of 216 ° C. from 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine and chloromethyl β-ethoxyethyl ether Amino) -4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine. HCl.

13. 2-cyclo hexoxy methyl amino-4-amino-5- (4-methoxy having a melting point of 297 ° C. from 2,4-diamino-5- (4-methoxy) -pyrimidine and chloromethyl cyclohexyl ether Benzyl) -pyrimidine. HCl.

14. 2-benzyloxymethylamino-4-amino-4-5- (3 at a melting point of 182 ° C. from 2,4-diamino-5- (3,4-dimethoxybenzyl) -pyrimidine and chloromethyl benzyl ether , 4-dimethoxybenzyl) -pyrimidine. HCl.

15. 2- (β-chloroethoxy methylamino) -4-amino-5 at a melting point of 222 ° C. from 2,4-diamino-5- (2-chlorobenzyl) -pyrimidine and chloromethyl β-chloroethyl ether -(2-chlorobenzyl) -pyrimidine.

16. 2- (β-ethoxyethoxymethylamino) -4-amino at melting point 218 ° C. from 2,4-diamino-5- (4-chlorobenzyl) -pyrimidine and chloromethyl β-ethoxyethyl ether -5- (4-chlorobenzyl) -pyrimidine.

17. 2-allyloxymethyl amino-4-amino-5- (2,4 at a melting point of 200 ° C. from 2,4-diamino-5- (2,4-dimethoxybenzyl) -pyrimidine and chloromethyl allyl ether -Dimethoxybenzyl) -pyrimidine. HCl.

18. 2- (3-methyl at melting point 290 ° C. from 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine and 3-methyl-5-chloromethyl-isoxazole Isoxazol-5-yl) -methylamino-4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine. HCl.

19. 2- (3-ethyl having a melting point of 291 ° C. from 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine and 3-ethyl-5-chloromethyl-isoxazole Isoxazol-5-yl) -methylamino-4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine. HCl.

20. 2- (3- at a melting point of 290 ° C. from 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine and 3-isofurophyl-5-chloromethyl isoxazole Isofurophilisoxazol-5-yl) -methylamino-4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine. HCl.

21. 2- (tert-butyl) having a melting point of 280 ° C from 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine and tert-butyl-5-chloromethyl-isoxazole Isoxazol 5-yl) -methylamino-4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine. HCl.

Example 22

2-benzylamino-4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine.

5 g of α-anilig-β- (3,4,5-trimethoxybenzyl) -acrylonitrile, 5.9 g of benzylguanidinium sulfate and 1.6 g of sodium methylate in 50 ml of ethanol were refluxed for 4 hours. 10 ml was then added to the mixture and allowed to cool, after which the crystals were filtered and washed with water.

The product was recrystallized from isofuropanol to give 4.1 g (72% of theory) of 2-benzyl amino-4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine at a melting point of 135 ° C.

The following compound was obtained by the method according to Example 22.

23. 2-allylamino 4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine at melting point of 132 ° C. using allylguanidine sulfate.

24. 2- (Phenethyl-β-amino) -4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine at 124 ° C. using phenylguanidine sulfate.

25. 2- (4-Chlorobenzylamino) -4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine at melting point 143 ° C. using 4-chlorobenzylguanidine-sulfate.

26. 2- (β-dimethylamino ethylamino) -4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine at a melting point of 139 ° C. using β-dimethylamino ethylguanidine sulfate.

27. 2- (β-morpholino ethylamino) -4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine at a melting point of 140 ° C. using β-morpholinoethylguanidine sulfate .

28. 2- (β-Pyloridinoethylamino) -4-amino-5- (3,4,5-trimethoxybenzyl) pyrimidine at a melting point of 130 ° C. using β-phyllolidino itylguanidine sulfate.

29. 2- (3-dimethylamino-n-furophyl-1-amino) -4-amino-5- (3, having a melting point of 139 DEG C using 3-dimethylamino-n-furophyl-1-guanidine sulfate 4,5-trimethoxybenzyl) -pyrimidine.

30. 6.4 g of α-cyano-β- (3,4,5-trimethoxybenzyl) -propionaldehyde dimethylacetyl, 3 g of β-hydroxyethylguanidine sulfate and 1.1 g of sodium methylate in 100 ml of ethanol for 5 hours At reflux. Ethanol was then distilled off and the residue was dissolved in 100 ml of water. 3.4 g of 2- (βhydroxyethylamino) -4-amino-5- (3,4,5 trimethoxybenzyl) pyrimidine which is extracted with chloroform and recrystallized with isopropanol and then melted at 146 ° C. (50% of theory) was obtained.

31. In 100 ml of dimethyl sulfoxide, 5.6 g of α- (3,4,5-trimethoxybenzyl) -β-dimethylamino-acrylonitrile, 3.8 g of β-ethoxyethylguanidine sulfate and 2 g of sodium methylate were 150 ° C. Stirred for 3 h. Dimethyl sulfoxide was then distilled off under reduced pressure and 100 ml of water was added to the residue. The oily product was extracted with chloroform and the extract was concentrated and the residue was repeatedly recrystallized with a mixture of ethyl acetate and isoprophyl ether to give 2- (β-ethoxyethylamino) -4-amino at a melting point of 147 ° C. 1.4 g (20% of theory) of -5- (3,4,5-trimethoxybenzyl) -pyrimidine were obtained.

32. 12 g of β-imidazoyl-1-yl-propionitrile, 6 g sodium methylate and 19.6 g 3,4,5-trimethoxybenzaldehyde in 200 ml of methanol were refluxed for 12 hours. To this was added 37 g of (3-ethoxy-n-furophil-1-yl) -guanidine sulfate and additionally 6 g of sodium methylate, methanol was slowly distilled off and the residue was stirred at 110 ° C. for 2 hours. 200 ml of water was added to the reaction mixture, followed by stirring. The quasi-solid product was extracted with chloroform. The residue obtained from the chloroform extract was recrystallized from a mixture of ethyl acetate and isoprophylether to give 2- (3-ethoxy-n-furophyl-1-amino) -4-amino-5- ( 12 g (32% of theory) of 3- (3,4,5-trimethoxybenzyl) -pyrimidine were obtained.

33. 2- [β (β-methoxyethoxy) -ethoxymethylamino] -4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidine hydrogen chloride at a melting point of 206-209 ° C. Obtained from trimethopuryl and β- (β-methoxyethoxy) -ethylchloro methylether by the method described in Example 1. (R ⁴ = -CH ₂ -OC ₂ -H ₄ -OC ₂ H ₄ -OCH ₃ )

34. Example of 2- [β (β-butoxyethoxy) -ethoxymethyl amino] -4-amino-5- (3,4,5-trimethoxy) -benzyl pyrimidine hydrogen chloride at melting point of 213 ° C. Obtained from trimethopuryl and β- (β-n-butoxyethoxy) -ethyl chloromethyl ether by the method described in 1.

(R ⁴ = -CH ₂ -OC ₂ H ₄ -OC ₂ H ₄ -OC ₄ H ₉ (n))

EXAMPLE OF PREPARATION

These active ingredients were mixed with corn starch and granulated using an aqueous solution of gelatin.

The dry particles were sieved and mixed with additives and the mixture was then purified by conventional methods.

These active ingredients were granulated using an aqueous solution of gelatin, and the dried particles were mixed with corn starch, talc and magnesium stearate.

This mixture was made into tablets by conventional methods.

The finely pulverized active ingredient was suspended in an aqueous solution of thilos mucus. Then, other active ingredients were added continuously while stirring. Finally, water was added to the mixture to make 100.0 g.

Claims (1)

A process for producing benzyl pyrimidine as in the following general formula (I), wherein the following compound of the general formula (II) is reacted with a compound of the general formula (III).

In the above structural formula; R ¹ , R ² , and R ³ , which are the same or different from each other, are hydrogen, methyl, methoxy, or chlorine, and R ⁴ is a methyl group substituted with alkoxy or allyloxy, cyclohexoxy or benzyloxy of 1 to 6 carbon atoms ( Wherein the alkyl group is additionally substituted with a chlorine atom or with 1 to 2 carbon atoms, which in turn is substituted with an alkoxy of 1 to 4 carbon atoms) or phenyl, chlorophenyl, hydroxyl, alkoxy of 1 to 2 carbon atoms, dialkylamino (here In which alkyl is 1 to 2 carbon atoms) or alkyl of 1 to 3 carbon atoms substituted with pyrrolidino or morpholino, or R ₄ is 3-alkylisoxazolyl-5-methyl, where alkyl is 1 to 4 carbon atoms And Hal is halogen.