CH297285A - Process for preparing 2,4-diamino-5-paranitrobenzyl-6-methyl-pyrimidine. - Google Patents
Process for preparing 2,4-diamino-5-paranitrobenzyl-6-methyl-pyrimidine.Info
- Publication number
- CH297285A CH297285A CH297285DA CH297285A CH 297285 A CH297285 A CH 297285A CH 297285D A CH297285D A CH 297285DA CH 297285 A CH297285 A CH 297285A
- Authority
- CH
- Switzerland
- Prior art keywords
- diamino
- pyrimidine
- methyl
- paranitrobenzyl
- preparing
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title description 3
- SLGQNHYYIRHGIG-UHFFFAOYSA-N 6-methyl-5-[(4-nitrophenyl)methyl]pyrimidine-2,4-diamine Chemical compound CC1=NC(N)=NC(N)=C1CC1=CC=C([N+]([O-])=O)C=C1 SLGQNHYYIRHGIG-UHFFFAOYSA-N 0.000 title description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 238000005576 amination reaction Methods 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 230000026030 halogenation Effects 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LAGUGKGDULGFKJ-UHFFFAOYSA-N ethyl 5-(4-nitrophenyl)-3-oxopentanoate Chemical compound CCOC(=O)CC(=O)CCC1=CC=C([N+]([O-])=O)C=C1 LAGUGKGDULGFKJ-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 201000004792 malaria Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- ZHYYQAZTIRQEKC-UHFFFAOYSA-N 2-amino-4-methyl-5-[(4-nitrophenyl)methyl]-1H-pyrimidin-6-one Chemical compound NC1=NC(=C(C(=N1)O)CC1=CC=C(C=C1)[N+](=O)[O-])C ZHYYQAZTIRQEKC-UHFFFAOYSA-N 0.000 description 1
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 1
- LXNGLGDIPZGTHE-UHFFFAOYSA-N 5-[(4-chlorophenyl)methyl]-6-methylpyrimidine-2,4-diamine Chemical compound CC1=NC(N)=NC(N)=C1CC1=CC=C(Cl)C=C1 LXNGLGDIPZGTHE-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- STIAPHVBRDNOAJ-UHFFFAOYSA-N carbamimidoylazanium;carbonate Chemical compound NC(N)=N.NC(N)=N.OC(O)=O STIAPHVBRDNOAJ-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical compound NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Procédé de préparation de la 2,4-dianiino-5-paranitrobenzyl-6-méthyl-pyrimidine. On donne au brevet, No <B>294175</B> des indi- eations concernant l'activité combattive de la malaria de nouvelles 5-benzyl-2,4-diamino- p#-rimidines de formule:
EMI0001.0008
dans laquelle X représente un atome de chlore, de brome ou un groupe nitro et R un atome d'hydrogène ou un groupe méthyle.
Ce brevet principal porte sur un procédé de préparation de l'une de ces nouvelles pyrimidines, <B>à</B> savoir la 2,4-diamino-5-para- chlorobenzyl-6-méthyl-pyrimidine.
Le présent brevet additionnel a pour objet un procédé de préparation de la 2,4-diamino- 5-paranitrobenzyl-6-métliyl -pyrimidine, nou veau composé possédant également une acti vité eombattive de la malaria le rendant uti lisable en thérapeutique.
Ce procédé est caractérisé en ce que l'on condense de la guanidine avec un composé de formule:
EMI0001.0018
dans laquelle R' représente un groupe alcoyle inférieur, puis en ce que l'on transforme la 2-amino-4-hydroxy-5-paranitrobenzyl-6-méthyl- pyrimidine obtenue en la 2,4-diaminopyrimi- dine correspondante, par halogénation et ami- nation.
Voici,<B>à</B> titre d'exemple, comment le pro <B>cédé</B> de l'invention peut être réalisé en pra tique: On prépare l'ester de départ,<B>à</B> savoir le p-nitrobenzylacétoacétate d'éthyle,<B>à</B> partir de .bromure de p-nitrobenzyle, d'hydroxyde de sodium et d'acétoacéta-te d'éthyle dans de l'alcool<B>à</B> 90%, selon la méthode de Burgess, ,T. Chem. Soc.<B>2017 (A 27).</B> On obtient avec <B>65</B> % de rendement un produit brut qui fond <B>à</B> 40-430 (selon la bibliographie 43--450).
Le p-nitrobenzylacétoacétate d'éthyle brut ainsi obtenu est condensé avec de la guanidine. Dans ce but, on<B>le</B> dissout dans<B>1</B> litre dalcool absolu auquel on ajoute 22<B>g</B> de carbonate de guanidine et le mélange est chauffé au reflux pendant<B>5</B> heures. Le mélange réactionnel est versé dans 2 litres d'eau, neutralisé avec de l'acide acétique et la 2-a-mino-4-hydroxy-5-p- nitrobenzyl-6-méthylpyr imidine est obtenue par filtration.
Après précipitation de ce dernier composé, on le chauffe au reflux avec de l'oxyehlorure de phosphore<B>(100</B> em3) pendant<B>30</B> minutes. Après évacuation de l'excès de chlorure de phosphoryle par distillation dans le vide, le résidu est versé sur de, la, glace et le mélange est rendu légèrement alcalin<B>à</B> l'aide d'ammo niaque.
La 2-amino-4-ehloropyrimidine est sé parée par filtration, transférée dans une bombe et chauffée<B>à 155-1600</B> pendant <B>16</B> heures avec<B>100</B> ems d'une solution alcooli- que qui a été saturée de gaz ammoniac entre <B>0</B> et 511. Le contenu de la bombe est évaporé <B>à</B> sec et le résidu solide est lavé avec<B>25</B> em3 d'une solution<B>2N</B> d'hydroxyde de sodium. Le solide obtena est purifié par dissolution dans de l'acide chlorhydrique dilué et précipi tation<B>à</B> l'aide d'hydroxyde de sodium.
Après deux recristallisations, comme indiqué ci-des sus, on obtient la 2,4-diamino-5-paraliitro- benzyl-6-méthyl-pyi,imidine sous forme de cristaux fondant<B>à</B> 240-2420<B>C.</B>
Process for preparing 2,4-dianiino-5-paranitrobenzyl-6-methyl-pyrimidine. New 5-benzyl-2,4-diamino- p # -rimidines of the formula are given in Patent No. <B> 294175 </B> concerning the fighting activity of malaria:
EMI0001.0008
in which X represents a chlorine atom, a bromine atom or a nitro group and R a hydrogen atom or a methyl group.
This main patent relates to a process for preparing one of these novel pyrimidines, <B> namely </B> 2,4-diamino-5-para-chlorobenzyl-6-methyl-pyrimidine.
The subject of the present additional patent is a process for the preparation of 2,4-diamino-5-paranitrobenzyl-6-methyl-pyrimidine, a new compound also possessing a combating activity against malaria, making it useful in therapy.
This process is characterized in that guanidine is condensed with a compound of formula:
EMI0001.0018
in which R 'represents a lower alkyl group, then in that the 2-amino-4-hydroxy-5-paranitrobenzyl-6-methyl-pyrimidine obtained is converted into the corresponding 2,4-diaminopyrimidine, by halogenation and amination.
Here is, <B> to </B> by way of example, how the <B> assigned </B> process of the invention can be carried out in practice: The starting ester is prepared, <B> to < / B> namely ethyl p-nitrobenzylacetoacetate, <B> to </B> from p-nitrobenzyl bromide, sodium hydroxide and ethyl acetoaceta-te in alcohol <B > at </B> 90%, according to the Burgess method,, T. Chem. Soc. <B> 2017 (A 27). </B> With <B> 65 </B>% yield, a crude product is obtained which melts <B> at </B> 40-430 (according to bibliography 43 --450).
The crude ethyl p-nitrobenzylacetoacetate thus obtained is condensed with guanidine. For this purpose, it is <B> </B> dissolved in <B> 1 </B> liter of absolute alcohol to which is added 22 <B> g </B> of guanidine carbonate and the mixture is heated under reflux for <B> 5 </B> hours. The reaction mixture is poured into 2 liters of water, neutralized with acetic acid and 2-a-mino-4-hydroxy-5-p-nitrobenzyl-6-methylpyr imidine is obtained by filtration.
After precipitation of the latter compound, it is heated to reflux with phosphorus oxyehloride <B> (100 </B> em3) for <B> 30 </B> minutes. After removing the excess phosphoryl chloride by vacuum distillation, the residue is poured onto ice and the mixture is made slightly alkaline <B> with </B> using ammonia.
The 2-amino-4-ehloropyrimidine is separated by filtration, transferred to a bomb and heated <B> to 155-1600 </B> for <B> 16 </B> hours with <B> 100 </B> ems of an alcoholic solution which has been saturated with ammonia gas between <B> 0 </B> and 511. The contents of the bomb are evaporated <B> to </B> to dryness and the solid residue is washed with <B> 25 </B> em3 of a <B> 2N </B> solution of sodium hydroxide. The solid obtained is purified by dissolving in dilute hydrochloric acid and precipitating <B> with </B> the aid of sodium hydroxide.
After two recrystallizations, as indicated above, 2,4-diamino-5-paraliitro-benzyl-6-methyl-pyi, imidine is obtained in the form of crystals melting <B> at </B> 240-2420 < B> C. </B>
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US297285XA | 1950-09-26 | 1950-09-26 | |
| CH294175T | 1950-12-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH297285A true CH297285A (en) | 1954-03-15 |
Family
ID=25733459
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH297285D CH297285A (en) | 1950-09-26 | 1950-12-22 | Process for preparing 2,4-diamino-5-paranitrobenzyl-6-methyl-pyrimidine. |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH297285A (en) |
-
1950
- 1950-12-22 CH CH297285D patent/CH297285A/en unknown
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