CH291378A - Process for preparing pteroylglutamic acid. - Google Patents
Process for preparing pteroylglutamic acid.Info
- Publication number
- CH291378A CH291378A CH291378DA CH291378A CH 291378 A CH291378 A CH 291378A CH 291378D A CH291378D A CH 291378DA CH 291378 A CH291378 A CH 291378A
- Authority
- CH
- Switzerland
- Prior art keywords
- group
- reaction
- acid
- parts
- compound containing
- Prior art date
Links
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 title claims description 6
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 title claims description 5
- 229960000304 folic acid Drugs 0.000 title claims description 5
- 235000019152 folic acid Nutrition 0.000 title claims description 5
- 239000011724 folic acid Substances 0.000 title claims description 5
- 238000004519 manufacturing process Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- GADGMZDHLQLZRI-VIFPVBQESA-N N-(4-aminobenzoyl)-L-glutamic acid Chemical compound NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 GADGMZDHLQLZRI-VIFPVBQESA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- -1 2,4,5-triamino-6-benzoyloxy pyrimidine Chemical compound 0.000 description 1
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 0.000 description 1
- QJIUMVUZDYPQRT-UHFFFAOYSA-N 6-chloro-2,4-pyrimidinediamine Chemical compound NC1=CC(Cl)=NC(N)=N1 QJIUMVUZDYPQRT-UHFFFAOYSA-N 0.000 description 1
- 206010002064 Anaemia macrocytic Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 201000006437 macrocytic anemia Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002832 nitroso derivatives Chemical class 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Procédé de préparation d'acide ptéroy1glutaniique. La présente invention se rapporte à la préparation d'acide ptéroylglutamique. Cet acide, dont la désignation chimique est acide N-[4- { [ (2-amino-4-hydroxy-6-pyrimido-[4,5- b] pyrazyl) méthyl] amino 1 benzoyl] - glutami que, est efficace dans la stimulation et la for mation de l'hémoglobine et utile dans le traite ment de l'anémie macrocytique, de la psilosis et autres affections.
Il est connu également sous le nom d'acide folique.
Suivant, l'invention, on prépare l'acide ptéroylglutamique en faisant réagir une 2,4,5 triamino-6-araleoxypyrimidine, de l'acide p- amino-benzoylglutamique et un composé con tenant le groupement
EMI0001.0015
les valences libres de ce groupement étant saturées par des éléments non métalliques éli minés au cours de la réaction.
Lorsque le procédé suivant la présente in vention est mis en #uvre en utilisant un di- halopropionaldéhyde comme composé renfer mant ledit groupement, on peut représenter la réaction ayant lieu par l'équation suivante:
EMI0001.0019
clans laquelle R représente le reste de l'acide glutamique, R' un radical aralcoylë et X un atome d'halogène.
L'acide para-amino-benzoylglutamique peut être utilisé sous forme d'un de ses sels. La 2,4,5 - triamino - 6 - ar alcoxypy rimidine peut être, par exemple, la 2,4,5-triamino-6- benzoyloxy pyrimidine que l'on peut obtenir par des méthodes décrites dans la littérature chimique. Au lieu de 2,3-dilialopropionaldéhyde, on pourrait utiliser une 1,1,3-trihaloacétone par exemple. Il est désirable de conduire la. con densation dans des conditions acides à un pH supérieur à 1, par exemple compris entre 1 et 5.
La température peut varier de 0 C à environ 100 C.
Il est préférable en outre de réaliser la réaction dans l'eau ou un solvant sensible ment aqueux, qui peut être constitué par des mélanges d'eau et de solvants miscibles- à l'eau. Après la condensation et au cours de la puri fication du produit, il est désirable que celui-ci soit chauffé dans des conditions alcalines ou acides, dans le but de terminer la conversion des radicaux aralcoxy en radicaux hydroxyles. Cette purification est avantageusement réali sée en dissolvant le produit réactionnel dans de l'alcali aqueux et en le précipitant dans des conditions acides à un pH inférieur à 3,1.
Dans l'exemple suivant de réalisation du présent procédé, les quantités sont indiquées en parties en poids. <I>Exemple:</I> On a préparé comme suit la. 2,4,5-triamino.
6-aralcoxypyrimidine de départ: A une solution de 3,6 parties de sodium dans 100 parties d'alcool benzylique, on ajoute 21,6 parties de 2,4-diamino-6-chloro- pyrimidine. On chauffe le mélange à 150 à 160 C pendant 3 heures, après quoi on éli mine par distillation l'excès d'alcool benzyli- que. On lave avec de l'eau le résidu huileux, ce qui laisse un solide caoutchouteux. On dis sout ce solide caoutchouteux dans 300 parties d'acide acétique chaud à 301/o. On clarifie la solution pour éliminer les impuretés et on la chauffe à 80 C.
On ajoute alors goutte à goutte tune solution concentrée de nitrite de sodium, jusqu'à ce qu'on obtienne une tache permanente sur le papier iodo-amidonné. Il se forme un précipité pourpre brillant. On sé pare celui-ci par filtration après refroidisse ment, on le lave avec de l'eau et on le sèche. Poids: 31,8 parties. On purifie le solide par recristallisation dans l'acétone, dans laquelle il forme une solution bleu vert.
On niet en boue 15 parties de cette 2,4-diaiïiino-5-nitroso- 6-benzoy loxy py rimidine dans 592 partie d'éthanol et on chauffe à environ 50 C. On fait alors barboter rapidement de l'hydrogène sulfuré dans ce mélange jusqu'à ce que se soit produite tune décoloration complète du composé nitroso, ce qui demande environ 20 minutes. Il se forme un précipité jaune, que l'on sépare par filtration de la solution chaude et que l'on rejette.
On chauffe le filtrat sous vide jusqu'à, élimination complète de l'hydrogène sulfuré résiduel.
La solution alcoolique de 2,4,5-trianiino-6- benzoy loxy pyrimidine ainsi obtenue, qui pèse environ 400 parties, est diluée avec 450 par ties d'eau et additionnée de 8,14 parties d'acide para- amino-benzoylgltitamique. On ajuste le pH à 3 et on ajoute goutte à goutte et simultanément des solutions de 13,2 parties de 2,3-dibromo-propioiialdéhi-de dans 14 par ties d'acide acétique glacial et 3,04 parties de bichromate de sodium clans 17 parties d'eau au cours d'une période de 20 minutes et en maintenant la température à. 45 C et le pli à. 3.
On continue pendant 30 autres minutes le chauffage à 45 C, après quoi on refroidit le mélange et on sépare par filtration le préci pité brun clair. Après séchage, celui-ci pèse approximativement 22,1 parties et présente à l'analyse chimique une pureté de 15,7%.
La purification est réalisée en utilisant le procédé décrit à l'exemple 1 du brevet N 289840.
Process for preparing pteroylglutaniic acid. The present invention relates to the preparation of pteroylglutamic acid. This acid, whose chemical designation is N- [4- {[(2-amino-4-hydroxy-6-pyrimido- [4,5- b] pyrazyl) methyl] amino 1 benzoyl] - glutami acid, is effective in the stimulation and formation of hemoglobin and useful in the treatment of macrocytic anemia, psilosis and other conditions.
It is also known as folic acid.
According to the invention, pteroylglutamic acid is prepared by reacting a 2,4,5 triamino-6-araleoxypyrimidine, p-amino-benzoylglutamic acid and a compound containing the group
EMI0001.0015
the free valences of this group being saturated with non-metallic elements removed during the reaction.
When the process according to the present invention is carried out using a di-halopropionaldehyde as compound containing said group, the reaction taking place can be represented by the following equation:
EMI0001.0019
where R represents the remainder of glutamic acid, R 'an aralkyl radical and X a halogen atom.
Para-amino-benzoylglutamic acid can be used in the form of one of its salts. 2,4,5 - triamino - 6 - ar alkoxypy rimidine can be, for example, 2,4,5-triamino-6-benzoyloxy pyrimidine obtainable by methods described in the chemical literature. Instead of 2,3-dilialopropionaldehyde, a 1,1,3-trihaloacetone could be used, for example. It is desirable to drive there. condensation under acidic conditions at a pH greater than 1, for example between 1 and 5.
The temperature can vary from 0 C to around 100 C.
It is further preferable to carry out the reaction in water or a substantially aqueous solvent, which may consist of mixtures of water and water-miscible solvents. After condensation and during purification of the product, it is desirable that the product be heated under alkaline or acidic conditions, in order to complete the conversion of aralkoxy groups to hydroxyl groups. This purification is advantageously carried out by dissolving the reaction product in aqueous alkali and by precipitating it under acidic conditions at a pH lower than 3.1.
In the following example of embodiment of the present process, the amounts are indicated in parts by weight. <I> Example: </I> We have prepared the. 2,4,5-triamino.
Starting 6-aralkoxypyrimidine: To a solution of 3.6 parts of sodium in 100 parts of benzyl alcohol, 21.6 parts of 2,4-diamino-6-chloropyrimidine are added. The mixture is heated at 150 to 160 ° C. for 3 hours, after which the excess benzyl alcohol is distilled off. The oily residue is washed with water, leaving a rubbery solid. This rubbery solid is dissolved in 300 parts of hot 301% acetic acid. The solution is clarified to remove impurities and heated to 80 C.
A concentrated solution of sodium nitrite is then added dropwise until a permanent stain is obtained on the iodine-starch paper. A brilliant purple precipitate forms. This is separated by filtration after cooling, washed with water and dried. Weight: 31.8 parts. The solid is purified by recrystallization from acetone, in which it forms a blue green solution.
15 parts of this 2,4-diaiïiino-5-nitroso-6-benzoyloxy py rimidine are slurried in 592 parts of ethanol and heated to about 50 C. Hydrogen sulfide is then bubbled rapidly through this mixture. mixing until complete discoloration of the nitroso compound has occurred, which takes about 20 minutes. A yellow precipitate forms, which is filtered off from the hot solution and discarded.
The filtrate is heated in vacuo until the complete elimination of residual hydrogen sulfide.
The alcoholic solution of 2,4,5-trianiino-6-benzoyloxy pyrimidine thus obtained, which weighs about 400 parts, is diluted with 450 parts of water and added with 8.14 parts of para-amino-benzoylgltitamic acid. . The pH is adjusted to 3 and solutions of 13.2 parts of 2,3-dibromo-propioiialdehyde in 14 parts of glacial acetic acid and 3.04 parts of sodium dichromate are added dropwise and simultaneously. 17 parts water over a 20 minute period and maintaining the temperature at. 45 C and the fold at. 3.
Heating at 45 ° C. is continued for another 30 minutes, after which the mixture is cooled and the light brown precipitate is filtered off. After drying, this weighs approximately 22.1 parts and shows a purity of 15.7% on chemical analysis.
The purification is carried out using the method described in Example 1 of patent N 289840.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US291378XA | 1949-12-03 | 1949-12-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH291378A true CH291378A (en) | 1953-06-15 |
Family
ID=21847441
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH291378D CH291378A (en) | 1949-12-03 | 1950-12-01 | Process for preparing pteroylglutamic acid. |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH291378A (en) |
-
1950
- 1950-12-01 CH CH291378D patent/CH291378A/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US2507473A (en) | Coumaran derivatives and process for preparing same | |
| CH291378A (en) | Process for preparing pteroylglutamic acid. | |
| Wadsworth Jr | Preparation and reactions of 1, 4-bis (alkoxycarbonyl)-1, 4-dialkyl-2-tetrazenes | |
| CH638183A5 (en) | PYRROLIDINE AND PIPERIDINE DERIVATIVES. | |
| Bonner et al. | Amide derivatives of D-glucosamine | |
| EP0304648B1 (en) | Process for the preparation of 6-piperidino-2,4-diamino-pyrimidine-3-oxide, and compounds | |
| SU504476A3 (en) | The method of obtaining-bis- (2- / 3,4-dioxyphenyl / -2-hydroxyethyl) -hexamethylenediamine | |
| FR2609985A1 (en) | PROCESS FOR N-O TRIFLUOROACETYLATION OF SATURATED ALIPHATIC MONOCARBOXYLIC A, O DIAMINOACIDS | |
| CH350971A (en) | Process for the preparation of sulfanilamidopyridazines | |
| Manthey et al. | The autoxidation of 3-hydroxyanthranilic acid in the presence of amino acids | |
| FR2664894A1 (en) | NOVEL STREPTOGRAMIN DERIVATIVES AND THEIR PREPARATION. | |
| FR2853901A1 (en) | PROCESS FOR THE PREPARATION OF DERIVATIVES OF HEXAHYDROPYRIDAZINE-3-CARBOXYLIC ACID | |
| FR2574792A1 (en) | PROCESS FOR THE PREPARATION OF PYRROLIDINE DERIVATIVES | |
| CA1206475A (en) | Process for preparing new imidazo [1,2-a] quinolines and the salts thereof | |
| EP0165225A1 (en) | Process for the preparation of 5-azaindole and intermediates | |
| FR2508041A1 (en) | PROCESS FOR PRODUCING NICOTINYL ESTER OF 6-AMINONICOTINIC ACID | |
| CH320587A (en) | Process for the preparation of quaternary ammonium salts | |
| RU2348623C1 (en) | Method of obtaining 3,5-diamino-1,2,4-thiadizol | |
| CH627446A5 (en) | NEW BENZAMIDE DERIVATIVES. | |
| CH500209A (en) | 1 2 5-benzotriazepine derivatives c n s depressants | |
| JP2000053651A (en) | Production of formylimidazoles | |
| FR2495147A1 (en) | 6-Alkoxy:carbonyl:hydrazino-3 -substd.-amino-pyridazine(s) - and use as intermediates in prepn. of 6-hydrazino-3-substd.-amino-pyridazine(s) | |
| CH276049A (en) | Process for preparing pteroylglutamic acid. | |
| FR2471967A1 (en) | PROCESS FOR THE PREPARATION OF N, N-DISUBSTITUTED P-PHENYLENEDIAMINE DERIVATIVES | |
| Bergel et al. | 341. Cyto-active amino-acids and peptides. Part III. Synthesis of para-substituted phenyl and alkoxymethyl ethers of tyrosine |