CH283756A

CH283756A - Process for the preparation of an aromatic aminodiol.

Info

Publication number: CH283756A
Authority: CH
Inventors: Company Parke Davis
Original assignee: Parke Davis & Co
Priority date: 1948-03-16
Filing date: 1948-12-15
Publication date: 1952-06-30

Description

Procede de preparation d'un aminodiol aromatique. La presente invention se rapporte ä la pre- paration de nouveaux aminodiols aromatiques de formule OH NHz R5 -C-CH-CH2OH R4 # "-# ga dann laquelle R3 est Uli atome d'hydrogene ou un radical alcoyle inferieur, R4 et R5, qui peuvent etre identiques ou differents, repre- sentent des atomes d'hydrogene ou d'halogene, des radicaux alcoyle ou alco@-loxy inferieurs. 0n a constate que ces aminodiols se pretent particulierement bien pottr la preparation de composes ayant une aetivite antibiotique. Process for the preparation of an aromatic aminodiol. The present invention relates to the preparation of new aromatic aminodiols of the formula OH NHz R5 -C-CH-CH2OH R4 # "-# ga in which R3 is a hydrogen atom or a lower alkyl radical, R4 and R5, which may be the same or different, represent hydrogen or halogen atoms, lower alkyl or alko-loxy radicals It has been found that these aminodiols lend themselves particularly well to the preparation of compounds having antibiotic activity.

0n voit que les aminodiols representes par la formule precedente peuvent exister sous forme d'isomeres de structure aussi bien que sous forme d'isomeres optiques (dus ä la pre- sence de deux atomes de earbone asymetri- ques). Par isomeres de structure , an en- tend les deizves cis et Irans, c'est-ä-dire les derives qui se distinguent par la Position sterique, relativement ä. un meme plan, des groupes polaires fixes sur les deux atomes de earbone asymetriques. Les produits ayant la configuration trans sont designes comme ayant la forme pseudo (y,), pour les differencier des produits ayant la configurat.ion cis ou forme de structure r6-itliere (reg.). Les groupes polaires relies aux atomes de carbone asymetriques des eomposes pseudo sont dis- poses dann 1'espaee, de maniere analogue ä la disposition sterique des groupes polaires re- lies aux atomes de earbone asymetriques de la pseudo-ephedrine. Par contre, les groupes polaires relies aux atomes de carbone asyme- t.riques des composes reguliers sont disposes dans l'espace de la meme faeon que les grou- pes polaires relies aux atomes de carbone asy- m6triques de 1'ephedrine (reg: ephedrine). It is seen that the aminodiols represented by the above formula can exist as structural isomers as well as optical isomers (due to the presence of two asymmetric carbon atoms). By structural isomers, an means the cis and ins derivatives, that is to say the derivatives which are distinguished by the steric position, relative to. same plane, fixed polar groups on the two asymmetric carbon atoms. Products having the trans configuration are referred to as having the pseudo (y,) form, to differentiate them from products having the cis configuration or r6-itliere (reg.) structural form. The polar groups connected to the asymmetric carbon atoms of the pseudo compounds are arranged in space, analogous to the steric arrangement of the polar groups connected to the asymmetric carbon atoms of pseudoephedrine. On the other hand, the polar groups linked to the asymmetric carbon atoms of the regular compounds are arranged in space in the same way as the polar groups linked to the asymmetric carbon atoms of ephedrine (reg: ephedrine).

Le present brevet a pour objet un procede de preparation de 1'un de ces aminodiols aro- matiques. This patent relates to a process for the preparation of one of these aromatic aminodiols.

Ce procede est caraeterise en ce que Fon condense de la benzaldehyde avec du ss-nitro- ethanol en presence dun agent de condensa- tion de nature alcaline, en ce que 1'on soiimet 1e 1-phenyl-2-nitropropane-1,3-diol obtenü ä, une reduction et en ce que Fon isole 1e dl-V-1- phenyl-2-aminopropane-1,3-diol du melange reactionnel en mettant ä Profit la differenee de solubilite entre les isomeres yp et reg. This process is characterized in that benzaldehyde is condensed with ss-nitroethanol in the presence of an alkaline condensing agent, in that 1-phenyl-2-nitropropane-1,3 -diol obtained at, a reduction and in that Fon isolates the first dl-V-1-phenyl-2-aminopropane-1,3-diol of the reaction mixture by taking advantage of the difference in solubility between the isomers yp and reg.

Le dl-yp-l-phenyl-2-aminopropane-1,3-diol obtenu est une nouvelle substance qui est cris- tallisee et qui presente un poixt de fusion de 86--87 C. The dl-yp-l-phenyl-2-aminopropane-1,3-diol obtained is a new substance which is crystallized and which has a melting point of 86--87 C.

De pieference, an execute la condensation de la benzaldehyde av RTI ID="0001.0267" WI="3" HE="4" LX="1423" LY="2029"> ec 1e ss-nitroethanol en presence d'au moins une mol.-g de 1'agent de eondensation alcalin par mol.-g de benzalde- hyde. Cette reaction est avantageusement effectuee ä une temperature inferieure ä 50 C, Jans un solvant organique inerte tel du'un alcool aliphatique inferieur. Comme agent de condensation, an peut employer un compose fortement basique tel qu'un oxyde d'un nietal alcalin, un hy droxyde d'un metal alca- lin, un. alcoolate ou un amide d'un metal alcalin. 0n obtient de cette fa@on comme pro- duit de condensation un sel metallique du 1 ph6nyl-2-nitropropane-1,3-diol. Ce produit peut etre isole sous forme de sel metallique, ou bien ce sel peut etre traite avec un aeide pour liberer 1e nitrodiol lui-meme. Le nitro- diol libre est une huile instable. Le sel de sodium du 1-phenyl-2-nitropropane-1,3-diol est une substance solide blanche n'ayant pas de point de fusion defini; sa solution, dans du NaOH 0,1 n, presente un maximum d'absorp- tion caracteristique des rayons ultra-violets ä 890 mu et pour rette longueur d'onde: Preferably, an executes the condensation of benzaldehyde with RTI ID="0001.0267" WI="3" HE="4" LX="1423" LY="2029"> ec 1e ss-nitroethanol in the presence of at least one mol.-g of alkaline condensation agent per mol.-g of benzaldehyde. This reaction is advantageously carried out at a temperature below 50° C., Jans an inert organic solvent such as a lower aliphatic alcohol. As the condensing agent, an can employ a strongly basic compound such as an oxide of an alkali metal, an hydroxide of an alkali metal, an. alcoholate or an amide of an alkali metal. In this way, a metal salt of 1-phenyl-2-nitropropane-1,3-diol is obtained as the condensation product. This product can be isolated as a metal salt, or this salt can be treated with an aid to release the nitrodiol itself. Free nitrodiol is an unstable oil. 1-Phenyl-2-nitropropane-1,3-diol sodium salt is a white solid with no definite melting point; its solution, in 0.1 n NaOH, exhibits a characteristic absorption maximum of ultraviolet rays at 890 mu and for this wavelength:

La reduction du eompose nitrodiol peut etre effectuee ä Paide d'hydrogene et dun ca- talyseur metallique d'hydrogenation, ou par des redueteurs ehiniiques tels que des sels re- ducteurs ou un melange acide-metal. 0n pre- fere totitefois 1'hydrogenation catalytique. The reduction of the nitrodiol compound can be carried out using hydrogen and a metal hydrogenation catalyst, or by chemical reducers such as reducing salts or an acid-metal mixture. Catalytic hydrogenation is always preferred.

Parmi les catalyseurs utilisables ä Bette fin, an peut mentionner 1'oxyde de Palladium, le Palladium sur charbon active et 1e nickel de Raney. L'hy drogenation peut se faire sous des Pressions d'hydrogene v ariant de la Pression atmospherique (env. 7.,05 kg/em2) jusqu'ä, une Pression d'environ 140 kg/cm2 et ä des tem- p6ratures variant de 20 ä 50 C. Divers sol- vants organiques peuvent etre empl.oy es comme milieu de reduction, mais an obtient les meilleurs resultats en utilisant 1'aeide ace- tique ou des alcools aliphatiques inferieurs. Among the catalysts which can be used at Bette fin, there may be mentioned palladium oxide, palladium on activated carbon and Raney nickel. Hydrogenation can take place under hydrogen pressures varying from atmospheric pressure (about 7.05 kg/cm2) up to a pressure of about 140 kg/cm2 and at temperatures varying 20 to 50 C. Various organic solvents can be used as the reducing medium, but best results are obtained using acetic acid or lower aliphatic alcohols.

Lorsqu'on effeetue 1ä reduetion ä 1'aide d'agents chimiques, an peut utiliser 1e ehlo- rure stanneux, 1'hydrosulfite de sodium (Na2S204. 2 H20) et 1e sulfate ferreux; comme exemples de melanges acide-metal, an mentionnera le melange fer-acide acetique et 1e melange zinc-H2S0,1. L'alliage nickel-alu- minium, tel qu'il se trouve dans la pouclre catalytique de nickel Raney, combine avec 1'acide acetique, constitue un me1ange qiii donne aussi de Bons resultats. Pour separer 1'isoniere de structure pseudo recherehe de 1'isomere correspon- dant reg. se trouvant egalement dans 1e m6- lange reactionnel apres la reduction, an se sert avantageusement de la eristallisation fraetionnee en mettant ä Profit la differente de solubilite des deux fornies de structure dann certains solvants organiques. Comme sol- vants pour rette separation an peut eiter: le ehloroforme, 1e tetraehlorure de carbone, 1'acetate d'ethy 1e, le niethanol, 1'ethanol, 1'iso- propanol, 1'acetone, le methanol aqueiix, 1'ethanol aqueux, 1'aeetone aqueuse, ete.; res solo ants peuvent etre utilises seins ou combi- nes. When the reduction is carried out with the aid of chemical agents, one can use stannous chloride, sodium hydrosulphite (Na2S204.2H20) and ferrous sulphate; as examples of acid-metal mixtures, mention should be made of the iron-acetic acid mixture and the zinc-H2S0.1 mixture. The nickel-aluminum alloy, as found in catalytic Raney nickel powder, combined with acetic acid, is a mixture which also gives good results. To separate the pseudo desired structure isomer from the corresponding isomer reg. also present in the reaction mixture after the reduction, an advantageous use is made of the fractionated crystallization by taking advantage of the difference in solubility of the two structural forms in certain organic solvents. As solvents for this separation an can be: chloroform, carbon tetrachloride, ethyl acetate, niethanol, ethanol, isopropanol, acetone, aqueous methanol, aqueous ethanol, aqueous acetone, etc.; res solo ants can be used breasted or combined.

Si Fon veut dedoubler 1'isomere dl-pseudo obtenu, en ses isomeres optiques levogyre et dextrogyre, an peut former un compose d'ad dition de type sel de 1'amine racemique (dl) avec un aride optiquement actif tel que l.'aeide d-tartrique, 1-tartrique, etc., puis sepa rer ensuite les deux sels isoineriqi.es formes par recristallisation Jans un solvant appro prie. Il faut ensuite re-enerer les isonieres optiques individuels en neutralisant s6pare inent chacun des produits d'addition preala blement separes. If Fon wants to split the resulting dl-pseudo isomer into its levorotatory and dextrorotatory optical isomers, one can form a racemic amine (dl) salt-like adduct with an optically active arid such as l. aeide d-tartaric, 1-tartaric, etc., then separating the two isoineriqi.es salts formed by recrystallization in an appropriate solvent. It is then necessary to re-energize the individual optical isoniers by neutralizing separately each of the previously separated adducts.

Le produit obtenu par le proeede selon 1'inv ention a une v aleur partieuliere pour la preparation de eomposes organiques posse dant une aetivite antibiotique. The product obtained by the process according to the invention has a particular value for the preparation of organic compounds possessing antibiotic activity.

L'invention est illustree par 1'exemple sui v ant <I>Exe#iit ple:</I> 0n dissout 1,1.g de sodinin dann 20 eni de niethanol et an verse la solution resultante dann une solution eonstittiee par 5 g de benz aldehyde et par 4,5 g de #)-nitroethanol Jans 20 em3 de methanol. rlpres av oir laisse reposer ä la temperature ainbiante et Pendant une tourte duree de temps, 1e ge.l forme lors du melange des reaetifs se transfornie en une poudre blanehe insoluble. Le produit pr@ci pit.e est recueilli, lave av ec du niethanol, puis avee de 1'ether et enfin seche. Le produit ainsi obtenu est 1e sel de sodium du 1-pli6nyl 2-nitropropane-1,3-diol. Ce sel ne presente pas The invention is illustrated by the following example <I>Exe#iit ple:</I> 0n dissolve 1.1.g of sodinin in 20 eni of niethanol and pour the resulting solution into a solution constituted by 5 g of benz aldehyde and 4.5 g of #)-nitroethanol Jans 20 em3 of methanol. After having left to stand at the ambient temperature and for a short period of time, the gel formed during the mixing of the reagents is transformed into an insoluble white powder. The precipitated product is collected, washed with niethanol, then with ether and finally dried. The product thus obtained is the sodium salt of 1-pli6nyl 2-nitropropane-1,3-diol. This salt does not present

de point de Fusion defini. Si an 1e desire, an peut, en acidifiant ce sel, obtenir 1e nitrodiol libre qui est une huile instable. melting point defined. If desired, one can, by acidifying this salt, obtain the free nitrodiol which is an unstable oil.

0n dissout 20 g du sel de sodium du 1 ph6nyl-2-nitropropane-1,3-diol. obtenu comme decrit ei-dessus, dann 200 cm-' d'acide acetique glaeial. 0n y ajoute 0,75 g d'oxyde de Palla dium comme catalyseur d'hydrogenation et an agite le melange Pendant 12 heisres envi ron sous une Pression cl'liydrogene de 3 atm. 0n separe 1e eatalyseur par Filtration et. an eoncentre le filtrat dann 1e vide jusqu'ä un dixieme du volume original, puis an dilue avec cinq volumes d'eau. La solution est en suite traitee avec un volume d'acetate d'6thy1e ou d'etlier et 1'extrait est mis de cöte. La Phase aqueuse est rendue alcaline ä un pH de 12 au moyen dune solution concentree de NaOH et traitee avec cinq portions d'acetate d'6thy1e de 100 cm3 chaeune. Les extraits sont combines et wehes, et 1'acet.ate d'ethyle est evapoH pour obtenir 1e 1-ph6nyl-2-a.minopro pane-1,3-diol. Par cristallisation de ce produit (qui coiistitne un nielan #@-e des isomeres dl pseudo et cll-reg.) dann du chloroforme, an obtient 1'isoniere dl-reg. de point de Fusion 103-101 C. Apres la separation de 1'isomere dl-reg. et par evaporation du filtrat et cris tallisation fractionnee du residu dass du me thanol, an obtient 1e dl-pseudo-l-ph6nyl-2 aminopropane-1,3-diol reclierclie, de formule 0n dissolve 20 g of the sodium salt of 1-phenyl-2-nitropropane-1,3-diol. obtained as described above, in 200 cm - 'of glacial acetic acid. 0.75 g of palladium oxide is added thereto as a hydrogenation catalyst and the mixture is stirred for about 12 hours under a hydrogen pressure of 3 atm. 0n separates the 1e catalyst by Filtration and. concentrate the filtrate in vacuum to one tenth of the original volume, then dilute it with five volumes of water. The solution is then treated with one volume of ethyl acetate or ethyl ester and the extract set aside. The aqueous phase is made alkaline to pH 12 with concentrated NaOH solution and treated with five 100 cc portions of ethyl acetate each. The extracts are combined and mixed, and the ethyl acetate is evaporated to yield 1-phenyl-2-a.minopropane-1,3-diol. By crystallization of this product (which coiistitne a nielan #@-e of the isomers dl pseudo and cll-reg.) in chloroform, an obtains 1'isonière dl-reg. melting point 103-101 C. After separation of the dl-reg. and by evaporation of the filtrate and fractional crystallization of the methanol residue, an obtained dl-pseudo-1-phenyl-2 aminopropane-1,3-diol, of formula

Ce produit a un point de fusion de 86 ä 87 C. This product has a melting point of 86 to 87 C.

Claims

CLAIM: Process for the preparation of an aromatic aminodiol, characterized in that Fon condenses from 1a. benzaldehyde with ss-nitro6t.ha-nol in the presence of an alkaline condensing agent, in that the 1-phenyl-2-nitropropane-1,3-diol obtained is subjected to reduction and in that 1 dl-V-1-phenyl-2-aminopropane-1,3-diol is isolated from the reaction mixture by taking advantage of the difference in solubility between the V and reg isomers. dl-V-1-phenyl-2-aminopropane-1,3-diol is a crystalline substance with a melting point of 86 Å. 87 C. SOL`S-CLAIMS: 1. Proegde according to claim, charac- t.erise in that Fon uses at least wie mol.-g of said condensing agent per mol.-g of benzaldehy # de.

2. Process according to claim, characterized in that said rednetion is a hydrogenation using hydrogen and a metallic hydrogenation catalyst.