CH316157A - Process for the preparation of pyrimidine derivatives - Google Patents
Process for the preparation of pyrimidine derivativesInfo
- Publication number
- CH316157A CH316157A CH316157DA CH316157A CH 316157 A CH316157 A CH 316157A CH 316157D A CH316157D A CH 316157DA CH 316157 A CH316157 A CH 316157A
- Authority
- CH
- Switzerland
- Prior art keywords
- methoxy
- phenyl ring
- ethoxy
- ester
- substituents
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
Procede <B>de</B> preparation <B>de</B> derives <B>de la</B> pyrimidine La presente Invention a pour objet un pro- c6d6 de preparation de derives de la pyrimi- dine. Process <B>for</B> the preparation of <B>pyrimidine derivatives</B> The subject of the present invention is a process for the preparation of pyrimidine derivatives.
0n a trouve que les 2-amino-4-hydroxy- 5-benzyl-pyrimidines de formule generale It has been found that the 2-amino-4-hydroxy-5-benzyl-pyrimidines of general formula
dans laquelle Ph represente un noyau phenyle portant encore au moins deux substituants, dont 1'un au moins est un groupe methoxy ou ethoxy, constituent des produits intermediaires precieux pour la preparation des 2,4-diamino- 5-benzyl-pyrimidines correspondantes, lesquel- les ont une activite antibacterielle exception- nellement 6levee, qui les rend particulierement appropriees ä 1'application en surface sur des blessures, et qui conservent aussi leur activite en presence de corps fluides, et sont de ce fait precieuses pour 1e traitement d'infections de Forganisme. in which Ph represents a phenyl ring bearing at least two further substituents, at least one of which is a methoxy or ethoxy group, constitute valuable intermediate products for the preparation of the corresponding 2,4-diamino-5-benzyl-pyrimidines, which - they have an exceptionally high antibacterial activity, which makes them particularly suitable for surface application on wounds, and which also retain their activity in the presence of fluid bodies, and are therefore valuable for the treatment of infections of the organism.
Le procede selon 1'invention, pour la pre- paration de 2-amino-4-hydroxy-5-benzyl-pyri- midines repondant ä la formule ci-dessus, est caracterise en ce que 1'on fait reagir de la gua- nidine-avec un ester a-formylhydrocinnamique dont 1e noyau phenyle est substitue comme in diqu6 ci-dessus. The process according to the invention, for the preparation of 2-amino-4-hydroxy-5-benzyl-pyrimidines corresponding to the above formula, is characterized in that one reacts gua- nidine-with an α-formylhydrocinnamic ester whose phenyl ring is substituted as indicated above.
Ledit ester a-formylhydrocinnamique peut etre prepare ä partir d'un ester hydrocinnami- que convenable (formule II, dans laquelle R est un reste d'alcool inferieur, R' est un reste methoxy ou ethoxy, R2 est un reste ethoxy, chloro ou bromo, et R3 et R4 sont de 1'hydro- gene ou des restes methoxy, ethoxy, chloro ou bromo), que 1'on formyle (formule 11I). Par reaction avec la guanidine, Fester ainsi obtenu donne un 2-amino-4-hydroxy-5-benzyl-pyrimi- dine correspondant ä la formule IV. Said α-formylhydrocinnamic ester can be prepared from a suitable hydrocinnamic ester (formula II, in which R is a lower alcohol residue, R' is a methoxy or ethoxy residue, R2 is an ethoxy, chloro or bromo, and R3 and R4 are hydrogen or methoxy, ethoxy, chloro or bromo residues, which are formylated (formula III). On reaction with guanidine, the ester thus obtained gives a 2-amino-4-hydroxy-5-benzyl-pyrimidine corresponding to formula IV.
Une conversion ultdrieure en 1e composd diamino peut dtre effectude par chloruration et amination ; an peut aussi proc6der par thia- tion et amination, dune maniere analogue ä celle d6crite dans les brevets anglais Noe 671926 et 671927 en combinaison avec 1e proc6d6 du brevet am6ricain No 2415793. Further conversion to the diamino compound can be effected by chlorination and amination; an can also proceed by thiation and amination, in a manner analogous to that described in British patents No. 671926 and 671927 in combination with the method of American patent No. 2415793.
Les exemples qui suivent servent ä illustrer 1'invention. Dans ces exemples, toutes les tem- p6ratures sont donn6es en degr6s centigrades. Exemple <I>1</I> 2-amino-4-hydroxy-5- (3,4-dimethoxy-5-bromo- benzyl)-pyrimidine. L'ester formylhydrocinnamique de d6part a 6t6 pr6par6 comme suit 0n a est6rifi6 162 g d'acide 3,4-dim6thoxy- 5-bromo-cinnamique (F. B. Wittmer et L. C. Racford, Journal of Organic Chemistry, Vo- lume 10, page 527, 1945) par chauffage ä reflux avec 1,5 1 d'6thanol et 3 ml d'acide sul- furique pendant environ quinze heures. L'ester a 6t6 s6par6 de la facon ordinaire par extrac- tion ä 1'6ther ä partir dune solution alcaline. Le rendement a 6t6 de 150 g d'ester Brut. The following examples serve to illustrate the invention. In these examples, all temperatures are given in degrees Centigrade. Example <I>1</I> 2-Amino-4-hydroxy-5-(3,4-dimethoxy-5-bromo-benzyl)-pyrimidine. The starting formylhydrocinnamic ester was prepared as follows: 162 g of 3,4-dimethoxy-5-bromocinnamic acid was esterified (F. B. Wittmer and L. C. Racford, Journal of Organic Chemistry, Volume 10, page 527, 1945) by heating under reflux with 1.5 liters of ethanol and 3 ml of sulfuric acid for about fifteen hours. The ester was separated in the usual way by ether extraction from an alkaline solution. The yield was 6t6 of 150 g of crude ester.
L'ester ei-dessus a 6t6 r6duit ä la temp6- rature ordinaire, avec 1e catalyseur au nickel de Raney, Jans de 1'6thanol comme solvant, en employant une proportion d'environ 40 g du compos6 pour 150 ml d'6thanol et 10 g du ca- talyseur. L'ester reduit a 6t6 s6par6 par filtration du catalyseur, 1e solvant a 6t6 (vapor6 dans 1e vide, et Fester, disti116 ä 205-2100/10 mm. The above ester was reduced at room temperature, with Raney nickel catalyst, without ethanol as solvent, using a ratio of about 40 g of the compound to 150 ml of ethanol and 10 g of catalyst. The reduced ester was filtered off from the catalyst, the solvent was evaporated in vacuo, and the ester was distilled at 205-2100/10 mm.
Dans un Ballon ä fond rond, muni dun condenseur ä reflux, an a ajoutd ä 30 g de fil de sodium dans un litre d'dther s6ch6 au sodium, un m61ange de 150 g du y-(3,4-dim6- thoxy-5-bromoph6nyl)-propionate d'6thy1e ob- tenu comme d6crit ci-dessus, et de 150 ml de formiate d'6thy1e. 0n a laissd reposer 1e m6- lange pendant environ quarante-huit heures (tout en detruisant si n6cessaire les amas de sodium), au bout desquelles la plus grande par- tie du sodium m6tallique avait disparu. In a round-bottomed flask fitted with a reflux condenser, to 30 g of sodium thread in one liter of dried sodium ether was added a mixture of 150 g of y-(3,4-dim6- thoxy- ethyl 5-bromophenyl)-propionate obtained as described above, and 150 ml of ethyl formate. The mixture was allowed to stand for about forty-eight hours (while destroying the sodium clumps if necessary), after which most of the metallic sodium had disappeared.
De la guanidine (pr6par6e ä partir de 62,5 g de chlorhydrate de guanidine dans environ 300 ml d'dthanol et de 15 g de sodium dissous dans environ 300 ml d'6thanol) est introduite dans 1e mdlange contenant fester a-formylhy- drocinnamique. 0n fait dvaporer 1'6ther au bain de vapeur et 1e m61ange dthanolique restant est chauff6 au reflux pendant seine heures, en remuant de temps en temps pour dloigner du fond du flacon 1e pr6cipit6 y adh6rant. Le m6- lange est alors versd Jans 3 litres d'eau et neu- tralis6 avec de Facide acdtique glacial. Il est avantageux, ä ce moment, d'amener 1e pH <I>ä</I> environ 8 avec une solution d'ammoniaque. 0n laisse reposer 1e m61ange pendant environ 12 heures, en raclant 1e fond de temps ä autre. RTI ID="0002.0270" WI="4" HE="4" LX="1122" LY="834"> Le pr6cipit6 est filtr6, lav6 ä Feau, puls plu- sieurs fois ä 1'6ther. Le composd purifi6 fond ä 238-240 , apres recristallisation dans un grand volume d'6thanol. Exemple <I>2</I> <I>2 -</I> amino-4-hydroxy-5-(2-methoxy-5-chloroben- zyl)-pyrimidine. Guanidine (prepared from 62.5 g of guanidine hydrochloride in about 300 ml of ethanol and 15 g of sodium dissolved in about 300 ml of ethanol) is introduced into the mixture containing a-formylhydrocinnamic ester. . The ether is evaporated on a steam bath and the remaining ethanol mixture is heated at reflux for six hours, stirring occasionally to remove any adhering precipitate from the bottom of the flask. The mixture is then poured into 3 liters of water and neutralized with glacial acetic acid. It is advantageous, at this time, to bring the pH <I>ä</I> to about 8 with an ammonia solution. The mixture is allowed to stand for about 12 hours, scraping the bottom occasionally. RTI ID="0002.0270" WI="4" HE="4" LX="1122" LY="834"> The precipitate is filtered, washed with water, pulsed several times with ether. The purified compound melts at 238-240, after recrystallization from a large volume of ethanol. Example <I>2</I> <I>2-</I> amino-4-hydroxy-5-(2-methoxy-5-chlorobenzyl)-pyrimidine.
0n a prepare ä partir de 26 g de 2-m6- thoxy-5-chlorohydrocinnamate d'6thy1e, 9 g de formiate d'6thy1e et 2,45 g de sodium dans de 1'6ther sec, 1e d6riv6 formy16 en op6rant de la maniere d6crite ä 1'exemple 1. From 26 g of ethyl 2-methoxy-5-chlorohydrocinnamate, 9 g of ethyl formate and 2.45 g of sodium in dry ether, the formy16 derivative was prepared by operating from the manner described in Example 1.
Ce d6riv6 est condensd avec de la guani- dine (obtenue ä partir de 10 g de chlorhydrate de guanidine et de 2,45 g de sodium, dans de 1'6thanol) et 1'on obtient la 2-amino-4-hydroxy- pyrimidine, fondant ä 278-284o. This derivative is condensed with guanidine (obtained from 10 g of guanidine hydrochloride and 2.45 g of sodium, in ethanol) and 2-amino-4-hydroxy- is obtained. pyrimidine, melting at 278-284o.
Ce produit peut eire transform6 en 1e com- pos6 2,4-diarnino correspondant, de la fagon suivante : an traite 6 g de la pyrimidine ci- dessus avec du chlorure de phosphoryle et du pentachlorure de phosphore, puls avee de 1'ammoniac alcoolique ä 1550 ; an obtient la pyrimidine cristalline Blanche, laquelle fond ä 169-1710 apres recristallisation dans de 1'dtha- nol. Exemple <I>3</I> 2-amino-4-hydroxy-5-(3-ethoxy-4-methoxy-ben- zyl)-pyrimidine. This product can be transformed into the corresponding 2,4-diarnino compound as follows: an treats 6 g of the above pyrimidine with phosphoryl chloride and phosphorus pentachloride, pulsed with alcoholic ammonia at 1550; an obtains the White crystalline pyrimidine, which melts at 169-1710 after recrystallization from ethanol. Example <I>3</I> 2-Amino-4-hydroxy-5-(3-ethoxy-4-methoxy-benzyl)-pyrimidine.
90 gr de 3-6thoxy-4-m6thoxyhydrocinna- mate d'6thy1e en solution dans de 1'6ther ont 6t6 formy16s par addition de 90 g de formiate d'6thy1e en prdsence de 8,5 g de fil de sodium, selon la fapn d'opfer d6crite ä 1'exemple 1. 90 g of ethyl 3-ethoxy-4-methoxyhydrocinnamate in solution in ether were formed by adding 90 g of ethyl formate in the presence of 8.5 g of sodium thread, according to the fapn of opfer described in Example 1.
Le compos6 formyld Brut ainsi obtenu est condens6 avec de la guanidine (obtenue en partant de 35 g de chlorhydrate de guanidine et de 8,5 g de sodium dans de 1'dthanol) et 1'on obtient la 2-amino-4-hydroxypyrimidine cher- ch6e. The crude formyld compound thus obtained is condensed with guanidine (obtained starting from 35 g of guanidine hydrochloride and 8.5 g of sodium in ethanol) and 2-amino-4-hydroxypyrimidine is obtained. looking for.
A partir de la pyrimidine brute ainsi pr6- par6e, an peut obtenir la 2,4-diaminopyrimi- dine, laquelle fond ä 197-1980 apres recris- tallisation dans de Fdthanol. Exemple <I>4</I> <I>2 -</I> amino <I>- 4 -</I> hydroxy-5-(3-ethoxy-4-methoxy-5- bromobenzyl)-pyrimidine. From the crude pyrimidine thus prepared, one can obtain 2,4-diaminopyrimidine, which melts at 197-1980 after recrystallization from ethanol. Example <I>4</I> <I>2-</I> amino <I>-4-</I> hydroxy-5-(3-ethoxy-4-methoxy-5-bromobenzyl)-pyrimidine.
0n a pr6pare Fester a-formylhydrocinna- mique initial ä partir de 105 g de 3-dthoxy-4- m6thoxy-5-bromohydrocinnamate d'6thy1e, 30 g de formiate d'6thy1e et 7,2 g de fil de sodium dans de 1'dther. The initial α-formylhydrocinnamic ester was prepared from 105 g of ethyl 3-ethoxy-4-methoxy-5-bromohydrocinnamate, 30 g of ethyl formate and 7.2 g of sodium fil in 1 'other.
L'ester formyld Brut est condensd avec de la guanidine (prdpar6e avec 30 g de chlorhy- drate de guanidine et 7,2 g de sodium dans de 1'6thanol), selon les indications donndes ä 1'exemple 1. The crude formyl ester is condensed with guanidine (prepared with 30 g of guanidine hydrochloride and 7.2 g of sodium in ethanol), according to the indications given in Example 1.
L'amino-hydroxy-pyrimidine brute obtenue peut etre transform6e en d6riv6 diamino par chloruration et amination. Apres recristallisa- tion dans de 1'dthanol an obtient des plaques in- colores fondant ä 193-2030. Exemple <I>5</I> <I>2 -</I> amino <I>- 4</I> -hydroxy-5-(3-ethoxy-4-methoxy-5- bromo-x-chlorobenzyl)-pyrimidine. L'ester a-formylhydrocinnamique de ddpart a 6t6 pr6par6, selon la m6thode d6crite ä 1'exemple 1, par formylation de 50 g de 3-dthoxy-4-m6thoxy-5-bromo-x-chlorohydrocin- namate d'6thy1e, avec 15 g de formiate d'6thy1e en prdsence de 4,1 g de fil de sodium, dans de 1'6ther. The crude amino-hydroxy-pyrimidine obtained can be transformed into a diamino derivative by chlorination and amination. After recrystallization from ethanol, colorless plaques are obtained, melting at 193-2030. Example <I>5</I> <I>2 -</I> amino <I>- 4</I> -hydroxy-5-(3-ethoxy-4-methoxy-5-bromo-x-chlorobenzyl) -pyrimidine. The starting α-formylhydrocinnamic ester was prepared, according to the method described in example 1, by formylation of 50 g of ethyl 3-ethoxy-4-methoxy-5-bromo-x-chlorohydrocinnamate, with 15 g of ethyl formate in the presence of 4.1 g of sodium thread, in ether.
L'ester formyld brut obtenu est condensd avec de la guanidine (provenant de 13,2 g de chlorhydrate de guanidine et de 4,1 g de so- dium dans de 1'6thanol). Exemple <I>6</I> 2-amino-4-hydroxy-5-(3,4-dimethoxy-5-chloro- benzyl)-pyrimidine. The crude formyl ester obtained is condensed with guanidine (from 13.2 g of guanidine hydrochloride and 4.1 g of sodium in ethanol). Example <I>6</I> 2-Amino-4-hydroxy-5-(3,4-dimethoxy-5-chloro-benzyl)-pyrimidine.
L'ester de d6part a 6t6 obtenu par formy- lation de 3,4-dim6thoxy-5-chlorobenzylhydro- cinnamate d'6thy1e (81 g) avec 81g de for- miate d'6thy1e en pr6sence de 6,9 g de sodium dans 500 ml d'dther sec. The starting ester was obtained by formylation of ethyl 3,4-dimethoxy-5-chlorobenzylhydrocinnamate (81 g) with 81 g of ethyl formate in the presence of 6.9 g of sodium in 500 ml of dry ether.
Le formylhydrocinnamate brut ainsi pr6- par6 est traitd avec de la guanidine (prove- nant de 30 g de chlorhydrate de gaanidine et 6,9 g de sodium dans 500 ml d'dthanol), comme ä 1'exemple 1, et an obtient 1e compose 2-amino-4-hydroxy brat. The crude formylhydrocinnamate thus prepared is treated with guanidine (from 30 g of gaanidine hydrochloride and 6.9 g of sodium in 500 ml of ethanol), as in Example 1, and gives the compound 2-amino-4-hydroxy brat.
Claims (5)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH316157T | 1953-03-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH316157A true CH316157A (en) | 1956-09-30 |
Family
ID=4496272
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH316157D CH316157A (en) | 1953-03-17 | 1953-03-17 | Process for the preparation of pyrimidine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH316157A (en) |
-
1953
- 1953-03-17 CH CH316157D patent/CH316157A/en unknown
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