HRP940257A2 - Preparation and properties of certain tylosin derivatives - Google Patents
Preparation and properties of certain tylosin derivatives Download PDFInfo
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- HRP940257A2 HRP940257A2 HRP-1498/89A HRP940257A HRP940257A2 HR P940257 A2 HRP940257 A2 HR P940257A2 HR P940257 A HRP940257 A HR P940257A HR P940257 A2 HRP940257 A2 HR P940257A2
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- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical class O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 12
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 50
- 238000000034 method Methods 0.000 description 41
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical class COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 150000001408 amides Chemical class 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- 238000010791 quenching Methods 0.000 description 9
- 230000000171 quenching effect Effects 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- -1 tylosin oxime Chemical class 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 150000002923 oximes Chemical class 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 229930194936 Tylosin Natural products 0.000 description 6
- 239000004182 Tylosin Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 229960004059 tylosin Drugs 0.000 description 6
- 235000019375 tylosin Nutrition 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000000638 solvent extraction Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 229950010526 relomycin Drugs 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 229910019020 PtO2 Inorganic materials 0.000 description 1
- 229910005948 SO2Cl Inorganic materials 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000001841 imino group Chemical class [H]N=* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- Saccharide Compounds (AREA)
Description
Područje tehnike u koju izum spada The technical field to which the invention belongs
Int. Cl. : C07H 17/08 Int. Cl. : C07H 17/08
Tehnički problem Technical problem
Predmet izuma je postupak za pripravu novih biološki aktivnih derivata tilozina, prikazanih općom formulom I The subject of the invention is a process for the preparation of new biologically active derivatives of tylosin, represented by the general formula I
[image] [image]
u kojoj A ima značenje -CO-NH- ili -NH-CO grupe, gdje R ima značenje -CHO, -CH(OCH3)2 ili CH2OH, gdje R1 ima značenje mikarozila ili vodika a[image] vijugava veza ima značenje dvostruke ili jednostruke veze. in which A has the meaning of -CO-NH- or -NH-CO group, where R has the meaning of -CHO, -CH(OCH3)2 or CH2OH, where R1 has the meaning of mycarosyl or hydrogen and [image] the helical bond has the meaning of double or single bonds.
Stanje tehnike State of the art
Tilozin je 16-člani makrolidni antibiotik proizveden fermentacijom i opisan u Tetrahedron Letters 2339, 1970. i u U. S. patentu 3,178,341. Tylosin is a 16-membered macrolide antibiotic produced by fermentation and described in Tetrahedron Letters 2339, 1970 and in U.S. Patent 3,178,341.
Poznato je, da je sintetizirana serija imino, derivata tilozina kemijskom transformacijom C-9 keto i/ili C-20 aldehidne skupine uključujući tilozin oksim, 4-demikaroziltilozin oksim, relomicin oksim i njihove 10,11,12,13-tetrahidroderivate odnosno odgovarajuće dimetilacetal derivate (neodlučena jug. pat. prijava 674/87 ili europska pat. prijava 0 278 082 A2). It is known that a series of imino derivatives of tylosin were synthesized by chemical transformation of C-9 keto and/or C-20 aldehyde groups including tylosin oxime, 4-demycarosyltylosin oxime, relomycin oxime and their 10,11,12,13-tetrahydroderivatives, i.e. the corresponding dimethylacetal derivatives (undecided South Pat. Application 674/87 or European Pat. Application 0 278 082 A2).
Poznato je, da se reakcijom Beckmann-ova pregrađivanja oksima u prisutnosti protonskih ili Lewis-ovih kiselina ili preko in situ pripravljenih O-arilsulfonata ketoksima u prisutnosti vode pregrađuju u amide odnosno kod cikličkih sistema u laktame (Org. React. 11, 1 1960; Houben-Weyl Bdd. VII/2b, 1986, 1976; J. Chem. Soc. 1948, 1518). Arilsulfoklorid-bazna metoda je najpogodnija za provođenje Beckmannovog pregrađivanja osjetljivih oksima (J. AM. Chem. Soc. 87, 5646, 1965). It is known that by the reaction of Beckmann partitioning of oximes in the presence of protonic or Lewis acids or via in situ prepared O-arylsulfonates, ketoximes in the presence of water are partitioned into amides or, in the case of cyclic systems, into lactams (Org. React. 11, 1 1960; Houben-Weyl Bdd. VII/2b, 1986, 1976; J. Chem. Soc. 1948, 1518). The arylsulfochloride-base method is most convenient for carrying out the Beckmann partitioning of sensitive oximes (J. AM. Chem. Soc. 87, 5646, 1965).
Prema poznatom stanju tehnike na području 15-članih makrolida iz reda tilozina, reakcija Beckmann-ovog pregrađivanja tilozin oksima i njegovih derivata nije dosada opisana. According to the known state of the art in the field of 15-membered macrolides from the order of tylosin, the reaction of Beckmann partitioning with tylosin oxime and its derivatives has not been described so far.
Opis rješenja tehničkog problema s primjerima izvođenja Description of the solution to the technical problem with implementation examples
Nađeno je, da se derivati tilozina prikazani formulom I It was found that tylosin derivatives represented by formula I
[image] [image]
gdje je where is
[image] mogu pripraviti slijedećim procesima: [image] can be prepared by the following processes:
Proces A/ Process A/
koji obuhvaća reakciju Beckmann-ovog pregrađivanja spojeva formule II which includes the Beckmann partitioning reaction of compounds of formula II
[image] [image]
gdje je where is
[image] [image]
sa aromatskim sulfokloridima formule 4-R-C6-H4-SO2-Cl, gdje je R alkil, halogen ili acilamino grupa uz prisutnost organskih ili anorganskih baza, formirajući spojeve formule I with aromatic sulfochlorides of the formula 4-R-C6-H4-SO2-Cl, where R is an alkyl, halogen or acylamino group in the presence of organic or inorganic bases, forming compounds of the formula I
[image] [image]
gdje je where is
[image] [image]
Proces B/ Process B/
koji obuhvaća hidrolizu spojeva formule i comprising the hydrolysis of compounds of formula i
[image] [image]
gdje je where is
[image] [image]
sa katalitičkom količinom organskih kiselina u neprotonskim otapalima u prisutnosti vode ili s anorganskim kiselinama u prisutnosti neprotonskih otapala, dajući spojeve formule I with a catalytic amount of organic acids in aprotic solvents in the presence of water or with inorganic acids in the presence of aprotic solvents, giving compounds of formula I
[image] [image]
gdje je where is
[image] [image]
Proces C/ Process C/
koji obuhvaća katalitičku hidrogenaciju spojeva formule I which includes the catalytic hydrogenation of compounds of formula I
[image] [image]
gdje je where is
[image] [image]
sa H2 uz prisutnost plemenitih metala kao katalizatora u inertnim otapalima, dajući spojeve formule I with H2 in the presence of noble metals as catalysts in inert solvents, giving compounds of formula I
[image] [image]
[image] [image]
[image] [image]
Prema procesu A/ sadašnjeg izuma, reakcija Beckmann-ovog pregrađivanja oksima (IIa-IIh) se provodi s 1-4 mola aromatskih sulfoklorida formule III According to process A/ of the present invention, the reaction of the Beckmann partitioning of oxime (IIa-IIh) is carried out with 1-4 moles of aromatic sulfochlorides of formula III
4-R-C6H4-SO2Cl (III) 4-R-C6H4-SO2Cl (III)
gdje R ima značenje C1-C3 alkila, halogena ili acilamino grupe formule IV where R has the meaning of C1-C3 alkyl, halogen or acylamino group of formula IV
-NH-COR1 (IV) -NH-COR1 (IV)
gdje R1 ima značenje metila, i 1-5 mola anorganskih (NaHCO3, NaOH) ili organskih (piridin, trietilamin) baza na temperaturi od 0-5°C do sobne temperature, kroz 30 minuta do 6 sati, u smjesi nekog nižeg ketona (acetona, metiletilketona) i vode. Nakon završene reakcije otapalo se otpari kod sniženog pritiska a produkti (Ia-Ih) se izoliraju gradijent pH ekstrakcijom halogeniranim ugljikovodicima npr. kloroformom ili metilenkloridom. where R1 means methyl, and 1-5 moles of inorganic (NaHCO3, NaOH) or organic (pyridine, triethylamine) bases at a temperature from 0-5°C to room temperature, for 30 minutes to 6 hours, in a mixture of a lower ketone ( acetone, methyl ethyl ketone) and water. After the reaction is complete, the solvent is evaporated under reduced pressure and the products (Ia-Ih) are isolated by pH gradient extraction with halogenated hydrocarbons, for example chloroform or methylene chloride.
Prema procesu B/ sadašnjeg izuma, hidroliza spojeva (Ia, Ic) se provodi u 50%-tnom acetonitrilu uz prisutnost katalitičke količine organske kiseline kao što je trifluoroctena kiselina na sobnoj temperaturi kroz 30 minuta do 24 sata, dok se spojevi (Ie i Ie’) hidroliziraju u prisutnosti katalitičke količine anorganske kiseline kao što su npr. solna ili sumporna kiselina. Izolacija produkata (Ib, Id, Ij, Ij’) se provodi ekstrakcijom sa halogeniranim otapalima iz vodeno-alkalnih otopina i uparavanjem do suhog ostataka. According to process B/ of the present invention, the hydrolysis of compounds (Ia, Ic) is carried out in 50% acetonitrile in the presence of a catalytic amount of an organic acid such as trifluoroacetic acid at room temperature for 30 minutes to 24 hours, while the compounds (Ie and Ie ') are hydrolyzed in the presence of a catalytic amount of inorganic acid such as hydrochloric or sulfuric acid. Isolation of the products (Ib, Id, Ij, Ij') is carried out by extraction with halogenated solvents from aqueous-alkaline solutions and evaporation to a dry residue.
Prema procesu C/ sadašnjeg izuma, katalitička hidrogenacija spojeva (Ia, Ib, Ie, Ie’, Ij, Ij’) se provodi s pritiskom vodika od 0.2 do 2.0 MPa u prisutnosti plemenitih metala kao katalizatora u inertnim otapalima, na sobnoj temperaturi kroz 2 do 6 sati. Podesni katalizatori su Pd/C, Rd/C, PtO2 ili ranij nikl, a otapala niže C1-C4 alkoholi, etilacetat, dietileter ili tetrahidrofuran. Nakon završene reakcije katalizator se odfiltrira a produkti (If, If’, Ig, Ih, Ii, Ik, Ik’) se izoliraju uparavanjem do suhog ostatka. According to process C/ of the present invention, the catalytic hydrogenation of compounds (Ia, Ib, Ie, Ie', Ij, Ij') is carried out with a hydrogen pressure of 0.2 to 2.0 MPa in the presence of noble metals as catalysts in inert solvents, at room temperature for 2 until 6 o'clock. Suitable catalysts are Pd/C, Rd/C, PtO2 or early nickel, and solvents lower C1-C4 alcohols, ethyl acetate, diethyl ether or tetrahydrofuran. After the reaction is completed, the catalyst is filtered off and the products (If, If', Ig, Ih, Ii, Ik, Ik') are isolated by evaporation to a dry residue.
Struktura spojeva dokazana je spektrometrijskom analizom IR, UV, 1H NMR, 13C NMR i masenom analizom. The structure of the compounds was proven by spectrometric analysis IR, UV, 1H NMR, 13C NMR and mass analysis.
Novo priređeni derivati tilozina pokazuju biološku aktivnost a praktično značenje imaju kao intermedijeri za sintezu novih 17-članih azalidnih antibiotika. The newly prepared tylosin derivatives show biological activity and have practical significance as intermediates for the synthesis of new 17-membered azalide antibiotics.
Spojevi ovog izuma formule I mogu se nazvati kao 1-oksa-9-aza-=cikloheptadekan-8,17-dion-3[[(6-deoksi-2,3,-di-O-metil-βD-alopiranozil)oksi]metil]-13-[[3,6-dideoksi-4-O-(2,6-dideoksi-3-C-metil-=α-L-ribo-heksopiranozil)-3-(dimetilamino)-β-D-glukopiranozil]oksi]-2-etil-15-hidroksi-5,10,14-trimetil-4,6-dien-12-acetaldehidi ili alternativno kao azahomotilozini (“IUPAC Nomenclature of Organic Chemistry, 1979 Edition” Pergamon Press, New YORK, 491-511). The compounds of this invention of formula I may be named as 1-oxa-9-aza-=cycloheptadecane-8,17-dione-3[[(6-deoxy-2,3,-di-O-methyl-βD-allopyranosyl)oxy ]methyl]-13-[[3,6-dideoxy-4-O-(2,6-dideoxy-3-C-methyl-=α-L-ribo-hexopyranosyl)-3-(dimethylamino)-β-D -glucopyranosyl]oxy]-2-ethyl-15-hydroxy-5,10,14-trimethyl-4,6-dien-12-acetaldehydes or alternatively as azahomothylosines (“IUPAC Nomenclature of Organic Chemistry, 1979 Edition” Pergamon Press, New YORK, 491-511).
Prema toj nomenklaturi spojevi ovoga izuma se nazivaju: According to this nomenclature, the compounds of this invention are called:
Ib 8a-aza-8a-homotilozin Ib 8a-aza-8a-homotylosin
Id 4’-demikarozil-8a-aza-8a-homotilozin Id 4'-demicarosyl-8a-aza-8a-homotylosin
Ih 8a-aza-8a-homo-10,11,12,13-tetrahidrotilozin Ih 8a-aza-8a-homo-10,11,12,13-tetrahydrotylosin
Ii 4’-demikarozil-8a-aza-8a-homo-10,11,12,13-tetrahidrotilozin Ia, Ic i Ig kod kojih je R dimetilacetal kao odgovarajući dimetil-acetali, Ii 4'-demicarosyl-8a-aza-8a-homo-10,11,12,13-tetrahydrotylosin Ia, Ic and Ig where R is dimethylacetal as the corresponding dimethyl acetals,
Ie 8a-aza-8a-homorelomicin Ie 8a-aza-8a-homorelomycin
Ij i Ij’ kao 4’-demikarozilderivati a spojevi If, If’, Ik i Ik’ kao odgovarajući 10,11,12,13-tetrahidroderivati. Ij and Ij' as 4'-demycarosylderivatives and compounds If, If', Ik and Ik' as corresponding 10,11,12,13-tetrahydroderivatives.
Izum je ilustriran slijedećim primjerima: The invention is illustrated by the following examples:
Primjer 1. Example 1.
8a-aza-8a-homotilozin dimetilacetal (Ia) 8a-aza-8a-homotylosin dimethyl acetal (Ia)
Otopine p-toluensulfoklorida (0.40 g, 2.10 mmol) u acetonu (10 ml) i NaHCO3 (0.30 g, 3,57 mmol) u vodi (37 ml) dokapavaju se uz miješanje na temperaturi od 0 do 5°C, kroz 30 minuta, u otopinu tilozin oksim dimetilacetala, IIa (1.0 g, 1.02 mmol) u acetonu (15 ml). Reakcijska smjesa miješa se 3 sata na istoj temperaturi, aceton otpari uparavanjem kod sniženog pritiska, zaostaloj vodenoj suspenziji doda 10 ml kloroforma te zakiseljavanjem s 1 N HC1 pH podesi na 5.5. Slojevi se odvoje i vodeni ponovno ektrahira kloroformom na pH 5.5 (1x10 ml) i pH 7.5 (3x20 ml). Kloroformni ekstrakti se suše nad K2CO3 te upare do suha. Kod pH 7.5 izolirano je 0.72 g (72.0 %) naslovnog produkta slijedećih fizikalno kemijskih karakteristika. Solutions of p-toluenesulfochloride (0.40 g, 2.10 mmol) in acetone (10 ml) and NaHCO3 (0.30 g, 3.57 mmol) in water (37 ml) are added dropwise with stirring at a temperature of 0 to 5°C over 30 minutes. , in a solution of tylosin oxime dimethyl acetal, IIa (1.0 g, 1.02 mmol) in acetone (15 ml). The reaction mixture is stirred for 3 hours at the same temperature, acetone is evaporated by evaporation under reduced pressure, 10 ml of chloroform is added to the remaining aqueous suspension and the pH is adjusted to 5.5 by acidification with 1 N HCl. The layers are separated and the aqueous is re-extracted with chloroform to pH 5.5 (1x10 ml) and pH 7.5 (3x20 ml). Chloroform extracts are dried over K2CO3 and evaporated to dryness. At pH 7.5, 0.72 g (72.0 %) of the title product with the following physical and chemical characteristics was isolated.
IR (CHCl3) 3405, 1705, 1650, 1610, 1500 cm-1 IR (CHCl3) 3405, 1705, 1650, 1610, 1500 cm-1
1H NMR (CDCl3) δ ppm 7.19 (H, d, H-11), 5.85 (H, d, H-10), 5.70 (H, d, H-13), 5.33 (H, d, NH) nestaje nakon izmučkavanja s D2O, 3.661 (3H, s, 3’’’OCH3),, 3.47 (3H, s, 2’’’ OCH3), 3.34 (6H, s, 2x20-(OCH3)) 1H NMR (CDCl3) δ ppm 7.19 (H, d, H-11), 5.85 (H, d, H-10), 5.70 (H, d, H-13), 5.33 (H, d, NH) disappears after trituration with D2O, 3.661 (3H, s, 3'''OCH3), 3.47 (3H, s, 2''' OCH3), 3.34 (6H, s, 2x20-(OCH3))
13C NMR (CDCl3) δ ppm 173.27 (C-1), 166.42 (C-9), amidni C=O), 144.87, (C-11), 138.33 (C-13), 135.00 (C-12), 119.53 (C-10), 104.07 (C-20), 103.56 (C-1’), 101.08 (C-1’’’), 96.28 (C-1’’), 61.69 (C-3’’’ OCH3), 59.60 (C-2’’’ OCH3), 53.73 (C-20 OCH3), 50.92 (C-20 OCH3) 13C NMR (CDCl3) δ ppm 173.27 (C-1), 166.42 (C-9), amide C=O), 144.87, (C-11), 138.33 (C-13), 135.00 (C-12), 119.53 (C-10), 104.07 (C-20), 103.56 (C-1'), 101.08 (C-1'''), 96.28 (C-1''), 61.69 (C-3''' OCH3) , 59.60 (C-2''' OCH3), 53.73 (C-20 OCH3), 50.92 (C-20 OCH3)
Primjer 2. Example 2.
8a-aza-8a-homotilozin (Ib) 8a-aza-8a-homotylosin (Ib)
Metoda A Method A
Iz 0.250 g (0.269 mmol) tilozin-9-oksima, IIb, otopljena u 5 ml acetona, 0.118 g (0.62 mmol) p-toluensulfoklorida otopljena u 3 ml acetona i 0.087 g (1.04 mmol) NaHCO3 otopljenog u 12 ml vode, izolirano je prema postupku opisanom u primjeru 1. naslovnog produkta 0.15 g (60.0 %) sa slijedećim fizikalno-kemijskim konstantama: From 0.250 g (0.269 mmol) of tylosine-9-oxime, IIb, dissolved in 5 ml of acetone, 0.118 g (0.62 mmol) of p-toluenesulfochloride dissolved in 3 ml of acetone and 0.087 g (1.04 mmol) of NaHCO3 dissolved in 12 ml of water, isolated is according to the procedure described in example 1 of the title product 0.15 g (60.0 %) with the following physico-chemical constants:
IR (CHCl3) 3405, 1715, 1665, 1615, 1500 cm-1 IR (CHCl3) 3405, 1715, 1665, 1615, 1500 cm-1
1H NMR (CDCl3) δ ppm 9.76 (H, s, H-20), 7.19 (H, d, H-11), 5.80 (H, d, H-10), 5.75 (H, d, H-13) 5.39 (H, d, NH) nestaje nakon izmučkavanja s D2O, 1H NMR (CDCl3) δ ppm 9.76 (H, s, H-20), 7.19 (H, d, H-11), 5.80 (H, d, H-10), 5.75 (H, d, H-13) 5.39 (H, d, NH) disappears after quenching with D2O,
13C NMR (CDCl3) δ ppm 203.39 (C-20), 173.43 (C-1), 1.66.60 (C-9), amidni C=O), 145.26, (C-11), 138.26 (C-13), 135.16 (C-12), 119.25 (C-10), 103.33 (C-1’), 101.13 (C-1’’’), 96.29 (C-1’’) 13C NMR (CDCl3) δ ppm 203.39 (C-20), 173.43 (C-1), 1.66.60 (C-9), amide C=O), 145.26, (C-11), 138.26 (C-13) , 135.16 (C-12), 119.25 (C-10), 103.33 (C-1'), 101.13 (C-1'''), 96.29 (C-1'')
Metoda B Method B
8a-aza-8a-homotilozin dimetilacetal, Ia, (0.60 g, 0.61 mmol) otopi se u 20 ml acetonitrila, doda se 20 ml vode i 0.11 ml trifluorooctene kiseline. Nakon 4 sata miješanja na sobnoj temperaturi, otopina se zaluži do pH 8-8.5 dodatkom zasićene otopine natrijevog hidrogenkarbonata i ekstrahira kloroformom. Sjedinjeni ekstrakti peru se vodom i suše nad K2CO3 te upare do suha. 0.45 g sirovog produkta čišćeno je na koloni silikagela (CH2Cl2:CH3OH:konc.NH4OH (90:9:1.5), te je dobiveno 0.32 g (56.4 %) naslovnog produkta. 8a-aza-8a-homotylosin dimethyl acetal, Ia, (0.60 g, 0.61 mmol) was dissolved in 20 ml of acetonitrile, 20 ml of water and 0.11 ml of trifluoroacetic acid were added. After stirring for 4 hours at room temperature, the solution is made alkaline to pH 8-8.5 by the addition of saturated sodium hydrogencarbonate solution and extracted with chloroform. The combined extracts are washed with water and dried over K2CO3 and evaporated to dryness. 0.45 g of the crude product was purified on a silica gel column (CH2Cl2:CH3OH:conc.NH4OH (90:9:1.5), and 0.32 g (56.4%) of the title product was obtained.
Primjer 3. Example 3.
4’-demikarozil-8a-aza-8a-homotilozin dimetilacetal (Ic) 4'-demicarosyl-8a-aza-8a-homotylosin dimethyl acetal (Ic)
Iz 1.0 g (1.2 mmol) 4’-demikaroziltilozin oksim dimetilacetala, IIc, otopljena u 15 ml acetona, 0.473 g (2.48 mmol) p-toluensulfoklorida otopljena u 10 ml acetona i 0.350 g (4.16 mmol) NaHCO3 otopljenog u 37 ml vode izolirano je prema postupku opisanom u primjeru 1., 0.70 g (70.1 %) naslovnog produkta slijedećih fizikalno-kemijskih karakteristika: From 1.0 g (1.2 mmol) of 4'-demicarosyltylosin oxime dimethylacetal, IIc, dissolved in 15 ml of acetone, 0.473 g (2.48 mmol) of p-toluenesulfochloride dissolved in 10 ml of acetone and 0.350 g (4.16 mmol) of NaHCO3 dissolved in 37 ml of water was isolated according to the procedure described in example 1, 0.70 g (70.1 %) of the title product with the following physico-chemical characteristics:
IR (CHCl3) 3400, 1700, 1690, 1645, 1500 cm-1 IR (CHCl3) 3400, 1700, 1690, 1645, 1500 cm-1
1H NMR (CDCl3) δ ppm 7.14 (H, d, H-11), 5.85 (H, d, H-10), 5.64 (H, d, H-13), 5.28 (H, d, NH) nestaje nakon izmučkavanja s D2O, 3.61 (3H, s, 3’’’ OCH3), 3.47 (3H, s, 2’’’ OCH3), 3.35 ((6H, s, 2x20-(OCH3), 2.49 (6H, s, N(CH3)2), 1.75 (3H, s, H-22) 1H NMR (CDCl3) δ ppm 7.14 (H, d, H-11), 5.85 (H, d, H-10), 5.64 (H, d, H-13), 5.28 (H, d, NH) disappears after trituration with D2O, 3.61 (3H, s, 3''' OCH3), 3.47 (3H, s, 2''' OCH3), 3.35 ((6H, s, 2x20-(OCH3), 2.49 (6H, s, N (CH3)2), 1.75 (3H, s, H-22)
13C NMR (CDCl3) δ ppm 173.08 (C-1), 166.42 (C-9, amidni C=O), 144.81, (C-11), 138.27 (C-13), 134.94 (C-12), 119.47 (C-10), 104.01 (C-20), 103.50 (C-1’), 101.02 (C-1’’’), 61.63 (C-3’’’ OCH3), 59.54 (C-2’’’ OCH3), 53.73 (C-20 OCH3), 50.92 (C-20 OCH3) 13C NMR (CDCl3) δ ppm 173.08 (C-1), 166.42 (C-9, amide C=O), 144.81, (C-11), 138.27 (C-13), 134.94 (C-12), 119.47 ( C-10), 104.01 (C-20), 103.50 (C-1'), 101.02 (C-1'''), 61.63 (C-3''' OCH3), 59.54 (C-2''' OCH3 ), 53.73 (C-20 OCH3), 50.92 (C-20 OCH3)
Primjer 4. Example 4.
4’-demikarozil-8a-aza-8a-homotilozin (Id) 4'-demicarosyl-8a-aza-8a-homotylosin (Id)
Metoda A Method A
Iz 0.50 g (0.64 mmol) 4’-demikaroziltilozin oksima, IId, otopljena u 8 ml acetona, 0.236 g (1.24 mmol) p-toluensulfoklorida otopljena u 5 ml acetona i 0.175 g (2.08 mmol) NaHCO3 otopljenog u 22 ml vode izolirano je prema postupku opisanom u primjeru 1., 0.38 g (76.0 %) produkta sa slijedećim karakteristikama: From 0.50 g (0.64 mmol) of 4'-demicarosyltylosine oxime, IId, dissolved in 8 ml of acetone, 0.236 g (1.24 mmol) of p-toluenesulfochloride dissolved in 5 ml of acetone and 0.175 g (2.08 mmol) of NaHCO3 dissolved in 22 ml of water was isolated according to the procedure described in example 1, 0.38 g (76.0%) of the product with the following characteristics:
IR (CHCl3) 3400, 1705, 1690, 1640, 1595 cm-1 IR (CHCl3) 3400, 1705, 1690, 1640, 1595 cm-1
1H NMR (CDCl3) δ ppm 9.76 (H, s, H-20), 7.19 (H, d, H-11), 5.91 (H, d, H-10), 5.75 (H, d, H-13), 5.47 (H, d, NH), nestaje nakon izmučkavanja s D2O, 3.61 (3H, s, 3’’’ OCH3), 3.49 (3H, s, 2’’’ OCH3), 2.50 (6H, s, N(CH3)2), 1.75 (3H, s, H-22) 1H NMR (CDCl3) δ ppm 9.76 (H, s, H-20), 7.19 (H, d, H-11), 5.91 (H, d, H-10), 5.75 (H, d, H-13) , 5.47 (H, d, NH), disappears after stirring with D2O, 3.61 (3H, s, 3''' OCH3), 3.49 (3H, s, 2''' OCH3), 2.50 (6H, s, N( CH3)2), 1.75 (3H, s, H-22)
13C NMR (CDCl3) δ ppm 173.12 (C-20), 173.48 (C-1), 166.93 (C-9), amidni C=O), 145.09, (C-11), 138.32 (C-13), 135.11 (C-12), 119.53 (C-10), 103.73 (C-1’), 101.07 (C-1’’’) 13C NMR (CDCl3) δ ppm 173.12 (C-20), 173.48 (C-1), 166.93 (C-9), amide C=O), 145.09, (C-11), 138.32 (C-13), 135.11 (C-12), 119.53 (C-10), 103.73 (C-1'), 101.07 (C-1''')
Metoda B Method B
4’-demikarozil-8a-aza-8a-homotilozin dimetilacetal, Ic, (0.40 g, 0.48 mmol) otopi se u 15 ml acetonitrila, doda se 15 ml vode i 0.075 ml trifluoroctene kiseline te prema postupku opisanom u primjeru 2., metoda B, izolira se 0.35 g (92.6 %) naslovnog produkta. 4'-demicarosyl-8a-aza-8a-homotylosin dimethyl acetal, Ic, (0.40 g, 0.48 mmol) is dissolved in 15 ml of acetonitrile, 15 ml of water and 0.075 ml of trifluoroacetic acid are added, and according to the procedure described in example 2, method B, 0.35 g (92.6 %) of the title product is isolated.
Primjer 5. Example 5.
8a-aza-9a-homorelomicin(Ie) i 9a-aza-9a-homorelomicin (Ie’) 8a-aza-9a-homorelomycin (Ie) and 9a-aza-9a-homorelomycin (Ie')
Iz 3.73 g (4.0 mmol) relomicin oksima, IIe, otopljenog u 30 ml acetona, 1.525 g (8.0 mmol) p-toluensulfoklorida otopljenog u 30 ml acetona i 1.14 g (13.57 mmol) NaHCO3 otopljenog u 90 ml vode dobiveno je kod pH 5.5 prema postupku opisanom u primjeru 1., 2.6 g sirovog produkta (Ie’), koji nakon čišćenja na koloni silikagela /CH2Cl2:CH3OH:konc.NH4OH (90:9:1.5)/ pokazuje slijedeće fizikalnokemijske karakteristike: From 3.73 g (4.0 mmol) of relomycin oxime, IIe, dissolved in 30 ml of acetone, 1.525 g (8.0 mmol) of p-toluenesulfochloride dissolved in 30 ml of acetone and 1.14 g (13.57 mmol) of NaHCO3 dissolved in 90 ml of water was obtained at pH 5.5 according to the procedure described in example 1, 2.6 g of crude product (Ie'), which after purification on a silica gel column /CH2Cl2:CH3OH:conc.NH4OH (90:9:1.5)/ shows the following physicochemical characteristics:
IR (CHCl3) 3400, 1700, 1690, 1645, 1500 cm-1 IR (CHCl3) 3400, 1700, 1690, 1645, 1500 cm-1
UV (EtOH) λmax 270 nm log ε 4.4 UV (EtOH) λmax 270 nm log ε 4.4
1H NMR (CDCl3) δ ppm 8.55 (H, d, NH) nestaje nakon izmučkavanja s D2O, 1H NMR (CDCl3) δ ppm 8.55 (H, d, NH) disappears after quenching with D2O,
13C NMR (CDCl3) δ ppm 175.67 (C-1), 174.77 (C-9, amidni C=O), 135.16, (C-12), 127.99 (C-11), 122.18 (C-13), 117.55 (C-10), 104.01 (C-1’), 101.18 (C-1’’’), 96.45 (C-1’’), 60.84 (C-20) M+ 932 13C NMR (CDCl3) δ ppm 175.67 (C-1), 174.77 (C-9, amide C=O), 135.16, (C-12), 127.99 (C-11), 122.18 (C-13), 117.55 ( C-10), 104.01 (C-1'), 101.18 (C-1''), 96.45 (C-1''), 60.84 (C-20) M+ 932
Kod pH 7.5 izolirano je 0.9 g sirovog produkta (Ie), koji nakon čišćenja na koloni silikagela u navedenom sistemu pokazuje slijedeće fizikalno-kemijske karakteristike: At pH 7.5, 0.9 g of the crude product (Ie) was isolated, which after purification on a silica gel column in the mentioned system showed the following physico-chemical characteristics:
IR (CHCl3) 3400, 1700, 1640, 1600 cm-1 IR (CHCl3) 3400, 1700, 1640, 1600 cm-1
UV (EtOH) λmax 262 nm log ε 4.43 UV (EtOH) λmax 262 nm log ε 4.43
1H NMR (CDCl3) δ ppm 5.66 (H, b, NH) nestaje nakon izmučkavanja s D2O, 1H NMR (CDCl3) δ ppm 5.66 (H, b, NH) disappears after quenching with D2O,
13C NMR (CDCl3) δ ppm 173.71 (C-1), 167.50 (C-9, amidni C=O), 145.72, (C-11), 138.60 (C-13), 135.10 (C-12), 119.08 (C-10), 103.50 (C-1’), 101.03 (C-1’’’), 96.28 (C-1’’), 60.05 (C-20) 13C NMR (CDCl3) δ ppm 173.71 (C-1), 167.50 (C-9, amide C=O), 145.72, (C-11), 138.60 (C-13), 135.10 (C-12), 119.08 ( C-10), 103.50 (C-1'), 101.03 (C-1''), 96.28 (C-1''), 60.05 (C-20)
M+ 923 M+ 923
Primjer 6. Example 6.
8a-aza-8a-homo-10,11,12,13 tetrahidrorelomicin (If) 8a-aza-8a-homo-10,11,12,13 tetrahydrorelomycin (If)
Metoda C Method C
8a-aza-8a-homorelomicin, Ie, (0.70 g, 0.75 mmol) otopi se u 20 ml 96%-tnog etanola a zatim doda 0.05 g 10%-tne Pt/C i hidrogenira 2 sata na sobnoj temperturi kod pritiska vodika od 2.0 Mpa. Nakon filtracije kataliaztora i uparavanje filtrata do suhog ostatka, dobiveno je 0.65 g (92.6%) produkta, koji je nakon čišćenja na koloni silikagela identičan produktu dobivenom prema metodi A: 8a-aza-8a-homorelomycin, Ie, (0.70 g, 0.75 mmol) was dissolved in 20 ml of 96% ethanol and then 0.05 g of 10% Pt/C was added and hydrogenated for 2 hours at room temperature under a hydrogen pressure of 2.0 Mpa. After filtration of the catalyst and evaporation of the filtrate to a dry residue, 0.65 g (92.6%) of the product was obtained, which after purification on a silica gel column is identical to the product obtained according to method A:
9a-aza-9a-homorelomicin-10,11,12,13-tetrahidrorelomicin (If’) 9a-aza-9a-homorelomicin, Ie’, (0.25 g, 0.27 9a-aza-9a-homorelomycin-10,11,12,13-tetrahydrorelomycin (If') 9a-aza-9a-homorelomycin, Ie', (0.25 g, 0.27
mmol) otopi se u 15 ml metanola te uz dodatak 0.05 g 10%-tnog Pd/C hidrogenira 6 sati na sobnoj temperaturi kod pritiska vodika od 0.3 Mpa. 0.240 g (95,7%) sirovog produkta čišćeno je na koloni silikagela, te je dobiveno 0.18 g (75.0%) produkta sa slijedećim karakteristikama: mmol) is dissolved in 15 ml of methanol and, with the addition of 0.05 g of 10% Pd/C, hydrogenated for 6 hours at room temperature at a hydrogen pressure of 0.3 Mpa. 0.240 g (95.7%) of the crude product was purified on a silica gel column, and 0.18 g (75.0%) of the product with the following characteristics was obtained:
IR (CHCl3) 3405, 1705, 1690, 1655 cm-1 IR (CHCl3) 3405, 1705, 1690, 1655 cm-1
1H NMR (CDCl3) δ ppm 6.30 (H, b, NH) nestaje nakon izmučkavanja s D2O, 3.62 (3H, s 3’’’OCH3), 3.51 (3H, s, 2’’’OCH3), 2.50 (6H, s N(CH3)2) 1H NMR (CDCl3) δ ppm 6.30 (H, b, NH) disappears after quenching with D2O, 3.62 (3H, with 3'''OCH3), 3.51 (3H, s, 2'''OCH3), 2.50 (6H, with N(CH3)2)
13C NMR (CDCl3) δ ppm 177.15 (C-9), amidni C=O), 173.48, (C-1), 106.97 (C-1’), 101.19 (C-1’’’), 96.90 (C-1’’), 60.67 (C-20) 13C NMR (CDCl3) δ ppm 177.15 (C-9), amide C=O), 173.48, (C-1), 106.97 (C-1'), 101.19 (C-1'''), 96.90 (C- 1''), 60.67 (C-20)
Primjer 7. Example 7.
8a-aza-8a-homo-10,11,12,13-tetrahidrotilozin dimetilacetal (Ig) 8a-aza-8a-homo-10,11,12,13-tetrahydrotylosin dimethyl acetal (Ig)
Metoda A Method A
Prema postupku opisnaom u primjeru 1, iz 1.0 g (1.02 mmol) 10,11,12,13.tetrahidrotilozin oksim dimetilacetala, IIg, 0.40 g (2.10 mmol) p-toluensulfoklorida i 0.30 g (3.57 mmol) NaHCO3 izolirani je 0.70 g (70.0 %) naslovnog produkta slijedećih karakteristika: According to the procedure described in example 1, from 1.0 g (1.02 mmol) of 10,11,12,13.tetrahydrotylosine oxime dimethylacetal, IIg, 0.40 g (2.10 mmol) of p-toluenesulfochloride and 0.30 g (3.57 mmol) of NaHCO3, 0.70 g ( 70.0 %) of the title product with the following characteristics:
IR (CHCl3) 1700, 1650 cm-1 IR (CHCl3) 1700, 1650 cm-1
1H NMR (CDCl3) δ ppm 5.58 (H, NH) nestaje nakon izmučkavanja s D2O, 3.60 (3H, s 3’’’OCH3), 3.52 (3H, s, 2’’’OCH3), 3.28 (3H, s, 20-OCH3), 3.23 (3H, s, 20-OCH3) 2.50 (6H, s N(CH3)2) 1H NMR (CDCl3) δ ppm 5.58 (H, NH) disappears after quenching with D2O, 3.60 (3H, s 3'''OCH3), 3.52 (3H, s, 2'''OCH3), 3.28 (3H, s, 20-OCH3), 3.23 (3H, s, 20-OCH3) 2.50 (6H, s N(CH3)2)
13C NMR (CDCl3) δ ppm 173.95 (C-1), 171.95 (C-9, amidni C=O), 103.5, (C-1’), 102.18 (C-20), 100.89 (C-1’’’), 96.22 (C-1’’), 61.66 (C-3’’’OCH3), 59,61 (C-2’’’OCH3), 53.19 (C-20 OCH3), 49.75 (C-20 OCH3) 13C NMR (CDCl3) δ ppm 173.95 (C-1), 171.95 (C-9, amide C=O), 103.5, (C-1'), 102.18 (C-20), 100.89 (C-1''' ), 96.22 (C-1''), 61.66 (C-3'''OCH3), 59.61 (C-2'''OCH3), 53.19 (C-20 OCH3), 49.75 (C-20 OCH3)
Metoda C Method C
Prema postupku opisanom u primjeru 6., metoda C, iz 0.25 g (0.26 mmol) 8a-aza-8a-homotilozin dimetilacetala, Ia, hidrogeniranog s Pd/C dobiveno je 0.16 g (62.7 %) naslovnog produkta. According to the procedure described in example 6, method C, 0.16 g (62.7 %) of the title product was obtained from 0.25 g (0.26 mmol) of 8a-aza-8a-homotylosine dimethyl acetal, Ia, hydrogenated with Pd/C.
Primjer 8. Example 8.
8a-aza-8a-homo-10,11,12,13-tetrahidrotilozin (Ih) 8a-aza-8a-homo-10,11,12,13-tetrahydrotylosin (Ih)
Metoda A Method A
Prema postupku opisanom u primjeru 1. iz 1.0 g (1.07 mmol) 10,11,12,13-tetrahidrotilozin oksima, IIh, 0.40 g (2.10 mmol) p-toluensulfoklorida i 0.30 g (3.57 mmol) NaHCO3 dobiveno je 0.75 g (75.0 5) produkta sa slijedećim fizikalno-kemijskim konstantama: According to the procedure described in example 1, 0.75 g (75.0 5) products with the following physical and chemical constants:
1H NMR (CDCl3) δ ppm 9.69 (H, s, H-20) 5.52 (H, d, NH) nestaje nakon izmučkavanja s D2O, 3.61 (3H, s 3’’’OCH3), 3.50 (3H, s, 2’’’OCH3), 2.49 (6H, s N(CH3)2) 1H NMR (CDCl3) δ ppm 9.69 (H, s, H-20) 5.52 (H, d, NH) disappears after quenching with D2O, 3.61 (3H, s 3'''OCH3), 3.50 (3H, s, 2 '''OCH3), 2.49 (6H, with N(CH3)2)
13C NMR (CDCl3) δ ppm 203.40 (C-20), 173.30 (C-1), 171.50 (C-9, amidni C=O), 103.58 (C-1’), 100.89 (C-3’’’), 96.22 (C-1’’) 13C NMR (CDCl3) δ ppm 203.40 (C-20), 173.30 (C-1), 171.50 (C-9, amide C=O), 103.58 (C-1'), 100.89 (C-3''') , 96.22 (C-1'')
Metoda C Method C
8a-aza-8a-homotilozin, Ib, (0.25 g, 0.27 mmol) hidrogeniran je s Pd/C prema postupku opisanom u primjeru 6. Nakon pročišćavanja 0.22 g sirovog produkta na koloni silikagela, izolirano je 0.16 g (64.0 %) naslovnog produkta. 8a-aza-8a-homotylosin, Ib, (0.25 g, 0.27 mmol) was hydrogenated with Pd/C according to the procedure described in Example 6. After purification of 0.22 g of the crude product on a silica gel column, 0.16 g (64.0 %) of the title product was isolated .
Primjer 9. Example 9.
4’-demikarozil-8a-aza-8a-homo-10,11,12,13-tetrahidrotilozin (Ii) 4'-demicarosyl-8a-aza-8a-homo-10,11,12,13-tetrahydrotylosin (Ii)
Metoda C Method C
U 15 ml metanola otopljeno je 0.20 g (0.25 mmol) 4’-demikarozil-8a-aza-8a-homotilozina, Id, dodano je 0.075 g 10% -tnog Pd/C i hidrogenirano prema postupku opisanom u primjeru 6., metoda C. Dobiveno je 0.180 g produkta slijedećih karakteristika: 0.20 g (0.25 mmol) of 4'-demicarosyl-8a-aza-8a-homotylosin, Id, was dissolved in 15 ml of methanol, 0.075 g of 10% Pd/C was added and hydrogenated according to the procedure described in example 6, method C 0.180 g of product with the following characteristics was obtained:
IR (CHCl3) 1715, 1650 cm-1 IR (CHCl3) 1715, 1650 cm-1
1H NMR (CDCl3) δ ppm 9.72 (H, s, H-20), 5.66 (H, b, NH) nestaje nakon izmučkavanja s D2O, 3.61 (3H, s 3’’’OCH3), 3.50 (3H, s, 2’’’OCH3), 2.49 (6H, s N(CH3)2) 1H NMR (CDCl3) δ ppm 9.72 (H, s, H-20), 5.66 (H, b, NH) disappears after quenching with D2O, 3.61 (3H, s 3'''OCH3), 3.50 (3H, s, 2'''OCH3), 2.49 (6H, with N(CH3)2)
Primjer 10. Example 10.
4’-demikarozil-8a-aza-8a-homorelomicin (Ij) i 4’-demikarozil-9a-aza-9a-homorelomicin (Ij’) 4'-demicarosyl-8a-aza-8a-homorelomycin (Ij) and 4'-demicarosyl-9a-aza-9a-homorelomycin (Ij')
Metoda B Method B
8a-aza-8a-homorelomicin, Ie, (0.40 g, 0.43 mmol) otopi se u 10 ml smjese 0.1 N HCl i CH3CN (2.5:1) i ostavi da stoji na sobnoj temperautri 24 sata. Izolacija produkata izvedena je prema postupku opisanom u primjeru 2., metoda B. Sirovi produkt 0.23 g čisti se na koloni silikagela, te je dobiveno 0.18 g (53.1 %) produkta (Ij) sa slijedećim karakteristikama: 8a-aza-8a-homorelomycin, Ie, (0.40 g, 0.43 mmol) was dissolved in 10 ml of a mixture of 0.1 N HCl and CH3CN (2.5:1) and left to stand at room temperature for 24 hours. The isolation of the product was carried out according to the procedure described in example 2, method B. The crude product 0.23 g was purified on a silica gel column, and 0.18 g (53.1 %) of the product (Ij) with the following characteristics was obtained:
IR (CHCl3) 3400, 1700, 1640, 1600 cm-1 IR (CHCl3) 3400, 1700, 1640, 1600 cm-1
1H NMR (CDCl3) δ ppm 5.66 (H, b, NH) nestaje nakon izmučkavanja s D2O 1H NMR (CDCl3) δ ppm 5.66 (H, b, NH) disappears after quenching with D2O
13C NMR (CDCl3) δ ppm 173.71 (C-1), 167.50 (C-9, amidni C=O), 145.72, (C-11), 138.60 (C-13), 135.11 (C-12), 119,08 (C-10), 103.50 (C-1’), 101.02 (C-1’’’), 60.42 (C-20) 13C NMR (CDCl3) δ ppm 173.71 (C-1), 167.50 (C-9, amide C=O), 145.72, (C-11), 138.60 (C-13), 135.11 (C-12), 119, 08 (C-10), 103.50 (C-1'), 101.02 (C-1''), 60.42 (C-20)
Iz 0.40 g (0.43 mmol) 9a-aza-9a-homorelomicina, Ie’, prema istom postupku izolirano je 0.19 g (56.1 %) produkta (Ij’) sa slijedećim karakteristikama: From 0.40 g (0.43 mmol) of 9a-aza-9a-homorelomycin, Ie', according to the same procedure, 0.19 g (56.1%) of the product (Ij') with the following characteristics was isolated:
IR (CHCl3) 1690, 1660, 1625 cm-1 IR (CHCl3) 1690, 1660, 1625 cm-1
1H NMR (CDCl3) δ ppm 8.55 (H, d, NH) nestaje nakon izmučkavanja s D2O 1H NMR (CDCl3) δ ppm 8.55 (H, d, NH) disappears after quenching with D2O
13C NMR (CDCl3) δ ppm 175.79 (C-1), 174.66 (C-9, amidni C=O), 135.16, (C-12), 127.99 (C-11), 122.18 (C-13), 117.55 (C-10), 103.50 (C-1’), 101.02 (C-1’’’), 60.42 (C-20) 13C NMR (CDCl3) δ ppm 175.79 (C-1), 174.66 (C-9, amide C=O), 135.16, (C-12), 127.99 (C-11), 122.18 (C-13), 117.55 ( C-10), 103.50 (C-1'), 101.02 (C-1'''), 60.42 (C-20)
Primjer 11. Example 11.
4’-demikarozil-8a-aza-8a-homo-10,11.12.13-tetrahidrorelomicin (Ik) i 4’-demikarozil-9a-aza-9a-homo- 4'-demicarosyl-8a-aza-8a-homo-10,11.12.13-tetrahydrorelomycin (Ik) and 4'-demicarosyl-9a-aza-9a-homo-
10,11,12,13-tetrahidrorelomicin (Ik’) 10,11,12,13-tetrahydrorelomycin (Ik')
Metoda C Method C
Prema postupku opisanom u primjeru 6, metoda C, iz 0.10 g (0.127 mmol) 4’-demiakrozl-8a-aza-8a-homorelomicina, Ij, dobiveno je 0.061 g (62.0 %) produkta (Ik) sa slijedećim karakteristikama: According to the procedure described in example 6, method C, from 0.10 g (0.127 mmol) of 4'-demiacrozl-8a-aza-8a-homorelomycin, Ij, 0.061 g (62.0%) of product (Ik) with the following characteristics was obtained:
IR (CHCl3) 1700, 1640 cm-1 IR (CHCl3) 1700, 1640 cm-1
13C NMR (CDCl3) δ ppm 173.315 (C-1), 171.50 (C-9, amidni C=O), 104.40, (C-1’), 101.02 (C-1’’’), 60.42 (C-20) 13C NMR (CDCl3) δ ppm 173.315 (C-1), 171.50 (C-9, amide C=O), 104.40, (C-1'), 101.02 (C-1'''), 60.42 (C-20 )
Iz 0.10 g (0.127 mmol) 4’-demikarozil-9a-aza-9a-homorelomicina, Ij’, prema istom postupku, dobiveno je 0.63 g (63.0 %) produkta (Ik’) sa slijedećim karakteristikama: From 0.10 g (0.127 mmol) of 4'-demicarosyl-9a-aza-9a-homorelomycin, Ij', according to the same procedure, 0.63 g (63.0%) of the product (Ik') with the following characteristics was obtained:
IR (CHCl3) 3405, 1705, 1655 cm-1 IR (CHCl3) 3405, 1705, 1655 cm-1
13C NMR (CDCl3) δ ppm 177.15 (C-9, amidni C=O), 173.48, (C-1), 106.75 (C-‘), 101.19 (C-1’’’), 60.67 (C-20) 13C NMR (CDCl3) δ ppm 177.15 (C-9, amide C=O), 173.48, (C-1), 106.75 (C-'), 101.19 (C-1'''), 60.67 (C-20)
Claims (16)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HR940257A HRP940257B1 (en) | 1989-07-26 | 1994-04-18 | Preparation and properties of certain tylosin derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU01498/89A YU149889A (en) | 1989-07-26 | 1989-07-26 | Process for preparing biologically active derivatives of tylozine |
| HR940257A HRP940257B1 (en) | 1989-07-26 | 1994-04-18 | Preparation and properties of certain tylosin derivatives |
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| Publication Number | Publication Date |
|---|---|
| HRP940257A2 true HRP940257A2 (en) | 1997-06-30 |
| HRP940257B1 HRP940257B1 (en) | 2000-12-31 |
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| HR940257A HRP940257B1 (en) | 1989-07-26 | 1994-04-18 | Preparation and properties of certain tylosin derivatives |
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| HR (1) | HRP940257B1 (en) |
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| HRP940257B1 (en) | 2000-12-31 |
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