| Abstract | Azalidi predstavljaju skupinu makrolidnih antibiotika u čiji je makrociklički laktonski prsten uveden dušikov atom čime su poboljšana mnoga njihova biološka svojstva. Najpoznatiji predstavnik ove skupine je azitromicin, 9-deokso-9-dihidro-9a-metil-9a-aza-9a-homoeritromicin A. Azalidi posjeduju brojne slobodne hidroksilne skupine koje su pogodne za uvođenje raznih supstituenata i sintezu novih spojeva. Uvođenjem zaštitnih skupina na pojedina reaktivna mjesta na molekuli moguće je sintetizirati željeni spoj. U ovom radu opisana je višestupnjevita sinteza novog azalidnog derivata na uvećanoj skali. Pripravljeni su prekursori koji će poslužiti za pripravu novih potencijalno aktivnih derivata azalida. U prvom stupnju sinteze, demetiliranjem 9-deokso-9a-aza-9a-homoeritromicina A na položaju 3’-N- pripravljen je 3'-N-demetil-9-deokso-9a-aza-9a-homoeritomicin A (2). Uvođenjem benziloksikarbonilne zaštitne skupine na dušikove atome, sintetiziran je 9a,3'-N,N-dibenziloksikarbonil-9-deokso-9a-aza-9a-homoeritromicin A (3). U sljedećem stupnju, reakcijom acetiliranja spoja 3 dobiven je 11,2',4''-O-triacetil-9a,3'-N,N-dibenziloksikarbonil-9-deokso-9a-aza-9a-homoeritromicin A (4). Zatim, reakcijom spoja 4 s etilkloroksoacetatom i uz 4-dimetilaminopiridin (DMAP) kao katalizator priređen je 11,2’,4’’-O-triacetil-9a,3’-N,N-dibenziloksikarbonil-12-O-(2-etoksi-2-okso-acetil)-9-deokso-9a-aza-9a-homoeritromicin A (5). U posljednjem stupnju sinteze kiselinskog derivata, hidrolizom spoja 5 pripravljen je 11,2’,4”-O-triacetil-9a,3’-N,N-dibenziloksikarbonil-12-O-oksalooksi-9-deokso-9a-aza-9a-homoeritromicin A (7). Također, katalitičkim hidrogeniranjem spoja 5 sintetiziran je 11,2’,4’’-O-triacetil-9a,3’-N,N-demetil-12-O-(2-etoksi-2-okso-acetil)-9-deokso-9a-aza-9a-homoeritromicin A (8). Strukturna i spektroskopska karakterizacija novopriređenih spojeva provedena je 1H i 13C NMR spektroskopijom. |
| Abstract (english) | Azalides represent a group of macrolide antibiotics whose macrocyclic lactone ring has a nitrogen atom introduced, which improves many of their biological properties. The best-known representative of this group is azithromycin, 9-deoxo-9-dihydro-9a-methyl-9a-aza-9a-homoerythromycin A. Azalides possess numerous free hydroxyl groups that are suitable for the introduction of various substituents and the synthesis of new compounds. By introducing protective groups to individual reactive sites on the molecule, it is possible to synthesize the desired compound. This paper describes a multi-step synthesis of a new azalide derivative on an enlarged scale. Precursors have been prepared and they will be used for the preparation of new potentially active azalide derivatives. In the first stage of synthesis, 3'-N-demethyl-9-deoxo-9a-aza-9a-homoerythromycin A (2) was prepared by demethylating 9-deoxo-9a-aza-9a-homoerythromycin A at the 3'-N- position. By introducing a benzyloxycarbonyl protecting group on nitrogen atoms, 9a,3'-N,N-dibenzyloxycarbonyl-9-deoxo-9a-aza-9a-homoerythromycin A (3) was synthesized. In the next step, the acetylation reaction of compound 3 gave 11,2',4''-O-triacetyl-9a,3'-N,N-dibenzyloxycarbonyl-9-deoxo-9a-aza-9a-homoerythromycin A (4). Then, by reaction of compound 4 with ethyl chloroxoacetate and with 4-dimethylaminopyridine (DMAP) as a catalyst, 11,2',4''-O-triacetyl-9a,3'-N,N-dibenzyloxycarbonyl-12-O-(2-ethoxy-2-oxo-acetyl)-9-deoxo-9a-aza-9a-homoerythromycin A (5) was prepared. In the last stage of the synthesis of the acid derivative, 11,2',4”-O-triacetyl-9a,3'-N,N-dibenzyloxycarbonyl-12-O-oxalooxy-9-deoxo-9a-aza-9a (7) was prepared by hydrolysis of compound 5. Also, 11,2',4''-O-triacetyl-9a,3'-N,N-demethyl-12-O-(2-ethoxy-2-oxo-acetyl)-9-deoxo-9a-aza-9a-homoerythromycin A (8) was prepared by catalytic hydrogenation of compound 5. Structural and spectroscopic characterization of the newly prepared compounds was carried out by 1H and 13C NMR spectroscopy. |
