METHOD OF PREPARING ERYTHROMYCIN A CYCLIC 11,12-CARBONATE

Abstract: The invention solves the problem of the industrial meth­ od of production of erythromycin A cyclic 11,12-carbonate by transesterification of 1,2-diole or 1,3-diole carbonates by means of anhydrous erythromycin A or its salts in anhy­ drous organic solvents or in the medium of a transesterified substrate in the presence of a phase transfer catalyst (PTC). According to the invention quarternary ammonium and phosphonium compounds may be used in the transesteri­ fication process with addition of inorganic compounds, such as salts, alkali metal or alkaline earth metal oxides or hy­ droxides. Ammonium or phosphonium hydroxides or car­ bonates do not require any addition of inorganic com­ pounds. According to the invention, as catalysts of the PTC type there may also be used coronary ethers and cryptands with addition of inorganic compounds. As quarternary ammonium compounds there are used salts, such as triethylbenzylammonium (TEBA) chloride or carbonate, tetrabutylammonium bromide, trioctylmethylam­ monium chloride, whereas among phosphonium com­ pounds there are advantageously used tetrabutylphos­ phonium chloride or carbonate. Among crown ethers there is used 1,4,7,10,13,16-hexaoxacyclo-octadecane and among cryptands 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8,8,8]-­ hexacosane.

Description: Method of Preparing Erythromycin-A Cyclic 11,12-Carbonate The subject matter of the invention 18 a method of preparing erythromycin A cyclic 11,21carbonate used as an antibacterial with more ad- vantageous properties than the parent. antibiotic, simultaneously not being its prodrug. The preparation of erythromycin A cyclic 11,12-carbonate consists in transesterification of ethylene carbonate using erythromycin A or its salts. A process for preparing erythromycin cyclic carbonate in the reaction of erythromycin with a considerable excess of ethyl ene carbonate in an inert solvent in the presence of alkaline catalysts, particularly of K2C03 is known from the U.S.A. patent specification No. 3 417 077. However in the described process the total reaction of the substrate 18 not only not complete, but considerable quantities of 10,11anhydroerythromycin A are formed, The degree of the reacted substrate in the desired direction may be increased. According to the Polish patent specification No. 70 623 it can be done due to the use of anhydrous substrates and reduction of temperature with a simultaneous diminution of ethylene carbonate excess. According to the Polish patent speci- fiction No. 93 849 erythromycin thiocyanate or lactate may be used as outputproducts. In both cases the reaction is carried out in an aprotic solvent, advantageously in toluene, The high degree of the reacted substrate is obtained, according to the Polish patent specification No. 86 961, by the use of ethylene carbonate as solvent, constituting simultaneously the substrate in the process of transesterification. The discussed process, independently of the' way it is run, is taking place in a two-phase sys- tem, namely the liquid and the solid phase. In the mentioned Polish patent specifications the solid phase is constituted by K2CO3 as catalyst. Although the quantities of the K2CO3 catalyst are less large than in the case of the U.S.A. patent specification,-' it is used on the average as 1 part by weight per 2 parts of erythromycin. The disadvantage of the discussed methods consists of long duration of the reaction, favoring the formation of by-products as e.g. of 10,11anhydroerythromycin A, particularly at increased temperature. One of the causes or this phenomenon consists in the use of big quantities of highly alkaline inorganic catalysts in an anhydrous medium of organic solvents, in which they dissolve badly. It has been found that the use in the reaction as catalysts of substances of the PTC /Phase Transfer Catalyst/ type, such as quarternary ammonium compounds, phosphonium compounds, crewn ethers or cryptands, enables to reduce considerably the quantity of the used alkaline -catalyst, to snorten the duration of the transesterification reaction or the cyclic 1,2- or 1,3-diole carbonate by means or erythromycin or of its salts In the case of introductton of definite quarternary ammonium or phosphonium compounds it even permits to eliminate from the process the alkaline catalyst. The trans esterification process proceeds in dehydrated organic solvents. An additional advantage consists in the min imization of the appearance in the reaction products of 10,11-anhydroerythromycin A, which constitutes a decomposition product of erythromycin A cyclic 11,12-carbonate. Besides of that a'diminution of the quantity Or cyclic 1,2-diole carbonate /and even the application of cyclic 1,3-diole carbonate/, constituting the basic reactant in the transesteri- fication process, Is advantageous in comparison with the known methods. By the method according to the invention the transesterification reaction either of dehydrated cyclic 1,2-diole carbonates, advantageously of ethylene or propylene carbonate, or of dehydrated cyclic 1,3-diole carbonates, advantageously of trimethylene carbonate using dehydrated erytromycin or its salts, is conducted either in an anhydrous organic solvent or in an anhydrous diole carbonates constituting simultaneously one of the reaction substrates, in the presence of the PTC type catalyst, such as a quartenary ammonium or phosphonium compound with addition of an inorganic compound As organic solvants are advantageously used toluene or acetone. As quartarnE3ry ammonium compounds are used: triethylbenzylammonium chloride /TEBA/, tetrabutylammonium bromide, trioctylmethylammonium chloride and as phosphonium compound tetrabutylphosphonium chloride. It has been found as advantageous to use triethylbenzylammonium chloride in an organic solvent, such as benzene or its homologuess, whereas trioctylmethylammonium chloride in such an organic solvent as e,g, acetone or acetonltrtle. Inorganic compounds used according to the invention consist either of salts of alkali metals or of alkaline earth metals, such as sodium, -potas slum, lithium, calcium, barium carbonates or acid carbonates, advantageously potassium carbonate, or of hydroxides or oxides of the above mentioned metals or mixtures of these compounds. AB PTC catalysts may be also applled according to the invention crown ethers or cryptands. The use of crown ethers in the erythromycin A cyclic 11,12-carbonate productlon improves the solubility of inorganic cations, increasing thus the effectiveness of the catalysis by basic inorganic salts. The use of crown ethers contalning 12 carbon atoms and 6 oxygen atoms in the basic moiety, especially of 1,4,7,13,16-hexaoxacyclo- octadecane is particularly advantageous, Equal results are obtained with cryptands, advantageously 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo-[8,8,8]hexacosane, Should as PTC catalyst a quartenary ammonium or phosphonium compound be used, an equilibrium in the liquid phase would ta.ke place between the initial ammonium or phosphonium salt and the quarternary compound newly formed in the reaction medium containing the anion derived from the alkali metal or rrom the alkaline earth metal compound. According to the invention it is particul- arly important to run the transesterification reaction in the presence of produced outside of the reaction medium either quarternary ammonium hydr- oxides alone or their salts with weak acids, advantageously carbonates, or analogous phosphonium compounds, although this process is in a certain degree limited. In such transesterification process both the quarternary ammonium compound and the phosphonium compound constitute independent catalysts. The use of FTC catalysts brings about a con- siderable increase of concentration of the cata lyat in the organic solvent, what may also provoke the formation of undesirable degradation products. It is therefore necessary to choose .properly the concentration, the kinds of catalysts and the organic solvent, as well as the parameters of the process in order to secure its most effective course from the point of view of the industrial production. Pursulng the method according to the present invention, erythromycin or the intermediate Droduct obtained during its isolation, as for example erythromycin thiocysnate or lactate-may be used in the discussed transesterification process. Erythromycin A cyclic 11,12-carbonate obtained according to the invention has a 6,9-hemiacetal structure /Slawinski W., Bojarska-Dahlig H., Glabsky T., Dziegielewska I., Biedrzycki M., Naperty S., Rec. trav. Chim. 94, 236, 1975/. Crystallized from the 50% aqueous solution of acetone its melting point is 2190 - 224 C, its specific rotatory power [&alpha;]D21= -54% = 2, dioxan/. Its total formula: C38H65NO14. /M = 759,95/. Analysis for the formula: calculated: 60.33% C; 8.78% H; 1.81% N; obtained: 60.0% C; 8.4% H; 1.8% N. molecular mass: 760 IR: 1815 /carbonate/, 1755 /lactone/, 1740 lactone hydrogen bond/cm-1. 1H NMR = 3.29/OMe/, 2.26/MNe2/, 1.59/Me/, 1.35/Me/. Mass spectrum: molecular ion 761. Example I. 100.0 g /0,136 mole/ of erythromycin containing less than 2% water were dissolved in 400 cm3 of toluene and the obtained solution azeotropically dried. 8.0 g /0.058 mole/ of potassium carbonate, 15,0 g /0.15 mole/ of potassium bicarbonate, 2,C g /Q.0088 mole/ of triethyl- benzylammonium chloride and 40,0 g /0,454 mole/ of ethylene carbonate were subsequetly added. The whole stirred at temperature of 400C during 6 hours and the course of the reaction controlled with the thin-layer chromatography /TLC/ method, The reaction mixture was filtered and ethanol added to the filtrate. The obtained solution was subjected to azeotropic distillstion under reduced .presEure and the remaining product crystallized from the ethanol - water mixture, 65,9 g /83% of the theoretical yield/ of erythromycin A cyclic 11,12-carbonate with its melting point of 219 2230O were obtained. The product was identified with the HPLC /High Performance Liquid Chromatography/ method. The HPLC /hemiacetal form/ analysis was performed with the application of the method of reversed phases in a column filled with LiChrosor RF-2, its grain size being 5 #m, with the use aa mobile phase of the system acetonitrile - aqueous solution of ammonium acetate of the concentration of 0,2 mole/litre - water /6:1:3 and UV detect tion at # = 218 nm, Retention time TR is 10.2 minutes. Example II, 70.0 g /0,0784 mole/ of dry erythromycin thiocyanate were suspended in a mixture of 200 cm3 of toluene a.nd 100 om3 of water. The whole was warmed up to temperature of 500C and a 10% aqueous solution of NaOH added to obtain pH - 9,5. The phases were subsequently separated and the organic layer dried, To the org anic solution, after filtering off the desiccant, g g /0.036 mole/ of potassium carbonate, 1,0 g /0.0031 mole/ of tetrabutylammonium bromide and 22.9 g /0,22 mole/ of propylene carbonate were added, whereupon the mixture was stirred at temperature of 200C during 10 hours. The reaction mixture was then washed with water. Toluene was distilled off from the organic phase under reduced pressure and the dry residue cristallized from the acetone - water mixture. 44,0 g /85 of the theoretical yield/ of the product as in example I were thus obtained. The erythromycin A cyclic 11,12-carbonate was identified by the RPLC method, Retention time TR, as well as its melting point as in example I, Example III, 50.0 g /0.068 mole/ of dry erythromycin were dissolved in 200 cm3 of toluene and to the obtained solution 5.0 g /0.024 mole/ of triethylbenzylammonium hydroxide and 20.0 g /0,228 mole/ of ethylene carbonate added. The whole was stirred at tenperature of 50 C during 10 hours. The reaction mixture was filtered and the antibiotic separated from the filtrate in the way as in example II, obtaining thus 37,7 g /74% of the theoretical yield/ of the product with its melting point of 200 - 224 C. Retention time TR as in example I. Example IV, To the dried solution of 25.0 g /0,034 mole/ of erythromycin in 150 Cm3 of acetone 7.6 g /0.05 mole/ of barlum oxide and 2.5 g /0.0062 mole/ of trioctylmethylammonium chloride were added and stirred at temperature of 400C during 10 hours. The precipitate was removed, water subsequently dropped in into the organic filtrate at its continuous stirring, 18.4 g /71% of the theoretical yleld/ of the product as in example I were thus obtained. Example V. 25.0 g /0.034 mole/ of dry erythromycin were dissolved in 100 cm3 of toluene and to the obtained solution 2.65 g /0.018 mole/ of pot assium carbonate. 0+5 g /0.0022 mole/ of triethylbenzylammonium chloride and 13.7 g /0.136 mole/ of trimethylene carbonate subsequently added. The whole was stirred at temperature of 400C during 12 hours. The reaction mixture was filtered and the antibiotic separated from the obtained toluene phase in the same way as in example I, Thus 18.2 g /70% of the theoretical yield/ of the product with its melting point of 219 - 220C and the retention - time TR as in example I were obtained. Example VI, 10.0 g /0.0136 mole/ of azeotropically dried erythromycin dissolved in 35.2 g /0.40 mole/ of liquid ethylene carbonate stirred J at temperature of 500C, 0.3 g /00011mole/ of triethylbenzylammonium chloride and 1.0 g /0.0072 mole/ of potassium carbonate were added to the obtained solution and stirred at the saine temperature during 3 hours, The reaction mixture was diluted with water ana thus 8; ;2 g /79% of the theoretical yield/ of th product with its melting point or 2190 2240C and the retention time TR as in example I obtained, Example VII. 25,0 g /0.034 mole/ of dry erythromycin were dissolved in 100 cm3 of toluene and to the solution 3,7 g /0,027 mole/ of potas sium carbonate, 0,8 g /0,0027 mole/ of tetrabutylphosphonium chloride and 12,5 g /0,142 mole/ of ethylene carbonate subsequently added. The whole was stirred at temperature of 30 C during 10 hours. The reaction mixture was filtered, the antibiotic separated from the'filtrate in the same way as in example I and thus 18.5 g /71% of the theoretical yield/ of the product with its melting point of 219 -221 Cand the retention time TR as in example I obtained, Example VIII. 25.0 g /0.034 mole/ of azeo tropically dried erythromycin were dissolved in 100 cm) of toluene, to the solution 2.5 g /0.018 mole/ of potassium carbonate, 0.075 g /0,0003 mole/ of 1,4,7,10,13,16-hexaoxacyclo-octadecane and 12.5 g /0,142 mole/ of ethylene carbonate subsequently added and stirred at temperature of 200C during 12 hours. The reaction finished, the reaction mixture and subsequently the remaining toluene layer were washed with water. The anti biotic was separated from the organic phaee as in example II and thus 19,5 /75% of the theoretical yields of the product with its melting point of 2200 - 2230C and the retention time TR as in example I obtained. Example IX. 25.0 g /0.034 mole/ of dry erythromycin were dissolved in 100 cm3 of tolu ene, subsequently' into the obtained solution 2,5 g /0.018 mole/ of potassium carbonate, 0,15 g /0.0004 mole/ of 4,7,13,16,21,24-hexaoxa-1,10diazabicyclo [8,8,8] hexacosane and 12.0 g /0.136 mole/ of ethylene carbonate added and stirred at temperature of 500C during 10 hours. The reaction mixture is filter4ed, the antibiotic separated from the filtrate as in example I and 19.7 g /76% of the theoretical yield/ of the product as in example I thus obtained.

Claims: Claims 1, Method of preparing erythromycin A cyclic 11,12-carbonate by transesterification of ethylene carbonate, using dehydrated erythromycin or its salts, characterized in that the transesterific- ation process of cyclic 1,2-diole and 1,3-diole carbonates in an anhydrous organic solvent, advantageously either In toluene, in acetone or in an anhydrous cyclic dlole carbonate, is performed in the presence of either a quarternary ammonium or phosphonium compound or of one of theee compounds as a PTC catalyst with addition of either an in- organic salt, an alkali metal or alkaline earth metal hydroxide or oxide or their mixture or else the process of esterification is performed in the presence of a catalyst of the PTC type, such as a crown ether or a cryptand with the addition of the above mentioned inorganic compounds or of their mixture, the obtained erythromycin A cyclic 11,12carbonate being subsequently separated and purified. 2, Method according to claim 1, character ized in that in the process of transesterification there are used cyclic 1,2-diole carbonates, ad- vantageously ethylene carbonate or propylene carbonate. 3. Method according to claim 1, characterized in that in the process 'of transesterification there are used cyclic 1,3-diole carbonates, advantageously trimethylene carbonate. 4. Method according to claim 1, character ized in that as a quarternary ammonium compound there are advantageously used either triethylbenzyl- ammonium chloride, tetrabutylammonium bromide, trioctylmethylammonium chloride with addition of either an inorganic salt, of an alkali metal or an alkaline earth metal hydroxide or oxide or of their mixture or triethylbenzylammonium hydroxide or carbonate alone. 5e Method according to claim 1, characterized in that as a phosphonium compound there is advantageously used either 'tetrabutylphoephonium chloride with addition of either an inorganic salt, of an alkali-metal or alkaline earth metal hydroxide or oxide or of their'mixture or tetrabutylphosphonium hydroxide or carbonate alone. 6. Method according to claim 1, characterized in that as a -crown ether there is advantage ously used ether containing 12 carbon atoms and 6 oxygen atoms, named 1,4,7,10,13,16-hexaoxacyclo- octadecane. 7. Method according to claim 1, characterized in that as a cryptand there is advantageously used 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8,8,8] hexacosane.

Inventors: BIEDRZYCKI, MAREK, DR. ING., CHMIELNICKI, PIOTR, DAHLIG, HALINA, PROF. DR. ING., GLABSKI, TADEUSZ, DR. ING.
Applicants: TARCHOMINSKIE ZAKLADY FARMACEUTYCZNE "POLFA"
Application year: 1984
Main classification: C07H17
IPC codes: C07H17